Compounds for targeted internalization of extracellular molecules

Abstract

The present invention relates to compounds acting as synthetic receptors. The compounds are able to bind to the cell surface, capturing and internalizing extracellular target molecules into the cells. In the present disclosure, compounds for internalization of extracellular molecules into cells, compositions, methods and uses thereof are provided.

Description

[0001] P7115PC00 1 Compounds for targeted internalization of extracellular molecules Technical field The present invention relates to compounds acting as synthetic receptors. The compounds are able to bind to the cell surface, capturing and internalizing extracellular target molecules into the cells. In the present disclosure, compounds for internalization of extracellular molecules into cells, compositions, methods and uses thereof are provided. Background Targeted delivery into cells of biologically relevant agents is challenging. The cell membrane constitutes a barrier that prevents, or severely hinders, unspecific crossing ofcertain molecules, e.g. peptides, proteins, nucleic acids, oligosaccharides, drugs etc.thereby hindering their applicability in the fields of biomedicine or biotechnology. Numerous valuable therapeutic agents like therapeutic proteins, nucleic acids, and diagnostic agents are inherently unable to cross the cell membrane unless a specific endogenous receptor for their internalization exists. Other interesting modalities, such as therapy with nucleic acids or targeted protein degradation also require crossing the cell membrane. Targeted protein degradation is usually facilitated by proteolysis targeting chimeras (PROTACs), which typically rely on proteasome function of E3 ubiquitin ligase and thus is only applicable to intracellular proteins (Sun et al.). Hence, numerous strategies for targeted delivery of compounds have evolved aiming at overcoming said barrier and allowing extracellular agents of interest into cells. Typically, these strategies rely on cell-specific targeting involving conjugation of the desired payload to be delivered with a moiety that targets specific endogenous receptors of the desired cells. For example, targeting of certain endogenous cell-surface receptors allows for receptor-mediated endocytosis (RME) in which ligand-receptor complexes are internalized via endosomes exploiting the cell’s natural machinery. However, said strategies are limited to specific cells which express the endogenous receptor. Therefore, they entail cumbersome optimization of each payload-target moiety complex for each desired group of target cells given the application at hand. In view of this, there remains a strong need for strategies that allow internalization of extracellular compounds into cells, in a simple modular way that is adaptable across a P7115PC00 2 diverse range of extracellular compounds and beyond the requirements of endogenous cell receptors. Summary The present invention solves the above mentioned problem by providing compounds that are able to bind to the cell surface, capturing and internalizing an extracellular target molecule into the cells. The inventors have discovered that bifunctional compounds having a cholesteryl carbamate moiety and an extracellular targeting moiety are able topromote internalization of extracellular target molecules into cells, acting as mimics ofcell surface receptors and produce receptor-mediated endocytosis (RME). Thus, in one main aspect, the present disclosure provides for a compound of formula (I): formula (I), or a pharmaceutically acceptable salt thereof, whereinX is a linker, andRTcomprises a moiety that binds an extracellular target molecule. The examples of the present application surprisingly demonstrate that the compounds of formula (I) of the invention comprising a cholesteryl carbamate moiety as described herein efficiently promote internalization of extracellular target molecules. It is shown that the compounds of the invention efficiently bind and locate to the cell surface while circulating into the intracellular compartments, as well as promote RME of extracellular target compounds, with subsequent proteolytic release of a therapeutic payload. The inventors have found that the target moiety can be adapted in a versatile manner to targetdifferent extracellular binding motifs, e.g. via affinity of antibodies to non-endogenousantigens or oligohistidine groups to metal chelates.In contrast with prior art teachings (Boonyarattanakalin et al., Peterson), the inventorshave found that an N-alkyl derivative of cholesteryl amine is not essential, or particularlypreferred for the compounds to be able to mimic RME of extracellular target molecules. P7115PC00 3 In addition, the inventors have shown that the selection of specific linkers bearingsecondary amines increases the efficiency of internalization of extracellular targetmolecules. Particularly, the examples demonstrate that said linkers having one or more secondary amines improve the efficiency of internalization compared to compoundsdescribed in the prior art (Boonyarattanakalin et al., Monge et al.).The compounds of formula (I) according to the present disclosure may find use in overcoming current drawbacks in therapy or diagnosis applications involving limited cellular internalization of extracellular molecules. The extracellular target molecule of interest may be chosen by selection of a specific extracellular targeting moiety (RTin formula (I)) adapted to bind the extracellular target molecule. As such, the compounds according to the present disclosure may find application in various fields of therapy or diagnosis. For example, in the specific delivery and uptake of therapeutic agents, by improving crossing of cell membranes and biological barriers, or in improving conditions characterized by limited protein transport or protein storage in cells. The compounds of formula (I) of the present disclosure may also be used in the removal of a disease- associated protein or a disease-associated peptide of interest. The removal of the disease-associated protein or peptide may involve degradation of the disease- associated protein or peptide in the lysosomal compartments. Accordingly, in one aspect the present disclosure provides for use of a compound of formula (I) as described herein in a method of internalization of an extracellular target molecule into a cell. In another aspect, the present disclosure provides a method of internalizing an extracellular target molecule into a cell, the method comprising: a) providing a compound of formula (I) as described herein;b) contacting the compound in step a) with a cell having a cell surface, therebyobtaining a cell comprising the compound bound to the cell surface; c) contacting the cell of step b) with an extracellular target molecule, wherein saidextracellular target molecule binds the compound of formula (I); thereby internalizing the extracellular target molecule into the cell. The compound according to the present disclosure can be adapted to be incorporatedinto cells both in vivo or ex vivo, and thus may in one embodiment be used or contactedwith isolated cells outside of the body. P7115PC00 4 In one aspect, the present disclosure provides for an isolated cell comprising the compound of formula (I) as described herein. In another aspect, the present disclosure provides a compound of formula (I), or a composition comprising the compound of formula (I) as described herein, for use as a medicament. In yet another aspect, the present disclosure provides for a compound or composition as described herein, for use in treatment of a disease, wherein said treatment comprises a step of internalizing an extracellular target molecule as described herein into a cell. In one aspect, the present disclosure provides a compound of formula (I) as described herein, or a composition as described herein, for use in diagnosis. Description of DrawingsFigure 1. A) Fluorescence Microscopy pictures (FITC channel) of the incorporation ofcompounds CR1-CR4 in MOLT-4 cells after the addition of 10 µM of CR1-CR4 for 2 h at37 ⁰C, 5% CO2 and treated with antiFITC antibody or control. B) Corresponding brightfield images of panels in A). C) Fluorescence microscopy pictures of the control cells without incorporation of compounds. Imaging setting for all images: Exposure FITCchannel = 200 ms, Gain FITC channel = 0 and scale bar = 20 µm. See Example 2 forfurther experimental details.Figure 2. Dose-response curve of toxicity upon treatment of cells with compoundsCR1-CR4 in combination with ADC, ADC alone, or MMAF alone. Error bars show mean± standard deviation. See Example 3 for further experimental details.Figure 3. Cell viability data of cells treated with ADC at two different concentrationsimmediately after incorporation of compounds CR1-CR4 (A), or 24 h after incorporationof compounds CR1-CR4 (B). Error bars show mean ± standard deviation. See Example3 for further experimental details. Figure 4. Experimental data illustrating the cell viability for cells receiving ADC at 10 or150 nM ADC immediately after incorporation of compounds R1, and CR1-CR4 (A); and24 h after incorporation of compounds R1, and CR1-CR4 (B). The presented results arebased on three independent experiments and shown as mean ± standard deviation.Statistical evaluation was performed via a one-way or two-way ANOVA,*** p < 0.001, ** P7115PC00 5p < 0.01, * p < 0.05, ns = non-significant is not shown. See example 3 for furtherexperimental details. The X axis of the figure indicates the concentration of ADC for eachset of samples indicated as bards (No receptor, R1, CR1-CR4).Figure 5. Quantitative sandwich ELISA representing the antiFITC antibody concentrationin the extracellular media at time 0 and 72 hours of incubation with HepG2 cells havingincorporated R1, and CR1-CR4. Statistical evaluation was performed via the two-wayANOVA; *** = p < 0.001,** = p < 0.01, * = p < 0.05, ns = non-significant. See example 4for further experimental details. Figure 6. A) Flow cytometry analysis of HepG2 cells with 10 µM R1, CR1-CR4administered with or without LDL, MFI = median fluorescence intensity; B) Qualitativeevaluation of the surface percentage of the 10 µM receptors administered with or withoutLDL; C) Protein depletion ELISA analysis in HepG2 cells with 10 µM CR2 or CR3administered with or without LDL after 24 h of incubation. Results are represented asmean ± standard deviation of three independent experiments; statistical evaluation wasperformed via two way-ANOVA; ,*** p < 0.001, ** p < 0.01, * p < 0.05 ns = non-significant.See example 5 for further experimental details. Figure 7. Quantitative sandwich ELISA results of HepG2 cells receiving 10 µM CR3 followed by 20 nM antiFITCantibody at 0h, media was exchanged after 24 h including 20nM new anti FITC antibody. See example 6 for further experimental details.Figure 8. Confocal laser scanning microscopy images of HepG2 cells modified with CR3 in the presence of anti-FITC antibody labelled with Cyanine-5, and lysosomal tracker blue DND-22 (Lysotracker). Scale bar = 20 µm. See example 7 for further experimental details. The arrows highlight different areas where there is overlap of the antiFITC antibody and lysotracker signals.Figure 9. Cell viability of HepG2 cells in the presence of NR2, NR3 or triNR3 with orwithout divalent ions. The data represents three independent replicates with technicaltriplicates and is represented as mean ± standard deviation. See example 8 for furtherexperimental detailsFigure 10. Flow cytometry analysis of HepG2 cells with 10 µM NR2, NR3 or triNR3 inthe presence or absence of oligohistidine tagged green fluorescent protein (GFP-His6)and divalent metal ions. The data corresponds to three independent replicates containing P7115PC00 6 at least 3x103cells / sample after complete gating. See example 9 for further experimental details.Figure 11. Flow cytometry analysis of HepG2 cells with 10 µM NR2, NR3 in the presenceor absence of oligohistidine tagged red fluorescent protein (RFP-His6) and divalent metalions. The data corresponds to three independent replicates containing at least 3x103cells / sample after complete gating. See example 9 for further experimental details.Figure 12. Flow cytometry analysis of HepG2 or HAP1 cells with 10 µM NR2 (HAP1 cells)or triNR3 (HepG2 cells) respectively receiving divalent ions and GFP-His6 in thepresence or absence of 400 µM nitrilotriacetic acid (NTA) to outcompete all surfaceaccessible GFP-His6. The data corresponds to two independent replicates containing atleast 3x103cells / sample after complete gating and is presented as the percentage change of mean fluorescence intensity (MFI) upon NTA washing. Figure 13. Confocal laser scanning microscopy images of HepG2 cells modified with NR2 (A) or triNR3 (B) in the presence of absence of divalent nickel ions and GFP-His6. Controls without receptor treated with divalent nickel ions and GFP-His6 also shown. Scale bar = 20 µm. See example 10 for further experimental details. Definitions Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in art to which the subject matterherein belongs. As used herein, the following definitions are supplied to facilitate theunderstanding of the present invention. The term “comprise” is generally used in the sense of include, that is to say permitting the presence of one or more features or components. In addition, as used herein, the language "comprising" can include analogous embodiments described in terms of “consisting of” and / or “consisting essentially of”. As used herein, the term "and / or" used in a phrase such as "A and / or B" herein is intended to include "A and B", "A or B", "A", and "B". As used herein, the singular forms "a", "an" and "the" include also the plural referencesunless the context clearly dictates otherwise. Similarly, terms such as “one or more” or“at least one” include both the singular and plural form of the respective feature. P7115PC00 7 The term “alkyl” as used herein refers to a linear or branched hydrocarbon moietywherein hydrogen atom has been removed. For example, a C1-C5 alkyl refers to a linearor branched hydrocarbon moiety having 1 to 5 carbons. Examples of alkyl groups are for example but not limited to methyl, ethyl, propyl, butyl, pentyl, propyl, isopropyl, tert-butyl, sec-butyl, etc.As used herein the term “cycloalkyl” or “carbocycle” refers to a monocyclic or polycyclicsystem. For example, a C3-C10 cycloalkyl or carbocycle, refers to a monocyclic orpolycyclic system having a total of 3 to 10 ring atoms. Examples of cycloalkyl orcarbocycles are for example but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc. The carbocycles or cycloalkyl groups used herein can optionally contain one or more unsaturations or substituents, for example but not limited to 1-cyclobutenyl, 1-cyclopentenyl, 1,3-cyclopentadienly, 1-methylbutyl, 1-methylpentyl, 1-isopropylcyclobutyl, etc. The term “heterocycle”, refers to a monocyclic or polycyclic system, as defined forcarbocycles, wherein at least one of the ring atoms are heteroatom(s). Heterocycles maybe characterized by the number of ring atoms. For example, a 4-20 membered heterocycle refers to a heterocycle with 4 to 20 ring atoms. As used herein "heteroatom", particularly as a ring heteroatom, refers to sulfur, oxygenand nitrogen.The terms "substituents" or "substituted" as used herein, alone or in combination, referto groups that may be used to replace hydrogen. The substituted molecule may itself befurther substituted in some embodiments of the invention. As referred herein a“substituent derived from” or “moiety derived from” refers to a group of atoms derivedfrom a specific molecule or formula at any position of said molecule or formula. In someembodiments, a substituent derived from a molecule is the corresponding molecule wherein a hydrogen atom has been removed. For example, a substituent derived from CH4 may be –CH3. The term "aromatic" or “aryl” refers to a cyclic or polycyclic moiety having a conjugated unsaturated (4n+2)π electron system (where n is a positive integer), sometimes referred to as a delocalized π electron system.The term "heteroaromatic" or “heteroaryl” as used herein, alone or in combination, refersto an aromatic ring or an aromatic polycyclic system where at least one of the ring atoms P7115PC00 8 are heteroatom(s). For example, heteroaryl or heteroaromatic refers to systemscontaining from 5 to 12 ring atoms an where one or more ring atoms are individually andindependently selected from N, S, or O. As used herein, “cholesteryl” is used to refer to: By extension, "cholesteryl amine derivatives”, as used herein refers to refers tocompounds comprising the following molecular structure: Exemplary, when an optionally substituted alkyl (e.g. -CH2-) group is attached at the Nposition, an N-alkyl derivative of cholesteryl amine is formed. When an acyl group is attached at the N position (e.g. –(C=O)-), an N-acyl derivative of cholesteryl amine. Bothof these exemplary compounds are examples of cholesteryl amine derivatives. P7115PC00 9 As used herein, the term “cholesteryl carbamate derivatives” refers to compounds comprising the following molecular structure: “Therapeutic agent” as used herein refers a biologically active compound capable of treating at least on disease state or condition. A therapeutic agent may be a small molecule, a peptide or a protein, and may also sometimes be referred to as therapeutic drugs or simply therapeutics. The term “in vivo” as used herein refers to inside the living body of an animal or plant. The term “ex vivo” as used herein refers to outside the living body of an animal or plant. These terms may be used to refer to a compound, cell, method, measurement or processhappening inside or outside of the living body of an animal or plant, respectively.Detailed description A compound In one main aspect, the present disclosure provides for a compound of formula (I): salt thereof, whereinX is a linker, andRTcomprises a moiety that binds an extracellular target molecule. P7115PC00 10 Thus, as described herein the compounds of formula (I) comprise a cholesteryl carbamate moiety which is able to bind to the cell surface and a moiety (RT) which is specifically adapted to bind an extracellular target moiety.As used herein, when referring to RT being specifically adapted to bind the extracellulartarget molecule, it is considered that RT binds the extracellular target molecule and / orthat the extracellular target molecule binds RT. In some embodiments, the binding of RTand the extracellular target molecule involves formation of a complex due to an attractiveinteraction or association. Examples of such interactions or associations include but arenot limited to the known formation of complexes mediated by intramolecular forces, suchas the interaction of ligands to specific binding sites of biomolecules. The strength of thecomplex formation can be characterized by the association, or dissociation constant orother methods known in the art. In one embodiment, the binding of the cholesteryl carbamate moiety of formula (I) and embodiments thereof involves hydrophobic interaction of the cholesteryl unit with the plasma membrane. Thus, in one embodiment the compound of formula (I) binds the plasma membrane. In one embodiment, the compound of formula (I) is according to formula (Ia) The following sections describe embodiments of formula (I) in greater detail. Thereby when referring to RTand X, it is immediately understood as referring to the moieties of formula (I). The linker covalently binds at one end of the linker to the cholesteryl carbamate moiety and at the opposite end of the linker, to the moiety targeting an extracellular target. In one embodiment, the linker X comprises or consists of a linear bivalent, saturated or unsaturated, C1-C200 hydrocarbon chain wherein one or more methylene groups are individually and optionally replaced by one or more of the groups selected from: -O- P7115PC00 11 , -N(H)-, -N(RL1)-, -C(=O)O-, -C(=O)-, -N(H)C(=O)-, -N(RL1)C(=O)-, -NHC(=O)NH- , -NHC(=S)NH- , -S-, -S(=O)-, -S(=O)2-, -N(RL1)S(=O)2-, -S(=O)2N(RL1)-; an optionally substituted aromatic group; an optionally substituted carbocycle; an optionally substituted heterocycle; an optionally substituted aromatic heterocycle; or a bond; wherein RL1is C1-5alkyl. In one embodiment, X comprises or consists of a linear bivalent, saturated or unsaturated, C1-C180hydrocarbon chain, such as a C1-C160, C1-C140, C1-C120, C1-C100, C1-C80, C1-C60, C1-C40, or C1-C20hydrocarbon chain, wherein one or more methylene groups are optionally replaced as described herein. In one embodiment, X comprises or consists of a linear bivalent, saturated or unsaturated, C1-C20 hydrocarbon chain. In one embodiment, X comprises or consists of a linear bivalent, saturated or unsaturated, C1-C15 hydrocarbon chain. In one embodiment, X comprises or consists of a linear bivalent, saturated or unsaturated,C1-C10 hydrocarbon chain. In one embodiment, X comprises or consists of a linearbivalent, saturated or unsaturated, C5-C20 hydrocarbon chain. In one embodiment, X comprises or consists of a linear bivalent, saturated or unsaturated, C5-C15 hydrocarbon chain. In one embodiment, X comprises or consists of a linear bivalent, saturated or unsaturated, C5-C10 hydrocarbon chain. In one embodiment, one or more methylene groups in X are optionally replaced by a group as described herein. In one embodiment, one or more methylene groups in X are individually and optionally replaced by one or more of the groups selected from: -O-, -N(H)-, -C(=O)-, -N(H)C(=O)-, -N(RL1)C(=O)-, -NHC(=O)NH-, -NHC(=S)NH- , -S-, -S(=O)-, -S(=O)2-, -N(RL1)S(=O)2-,-S(=O)2N(RL1)-, an optionally substituted carbocycle, an optionally substituted heterocycle, wherein RL1is C1-5 alkyl. In one embodiment, one or more methylene groups in X are individually and optionally replaced by one or more of the groups selected from: -O-, -N(H)-, -C(=O)-, -N(H)C(=O)-, -N(RL1)C(=O)-, -NHC(=O)NH-, -NHC(=S)NH-, wherein RL1 C1-5 alkyl.In contrast with prior art teachings (Boonyarattanakalin et al., Peterson), the inventorshave found that an N-alkyl derivative of cholesteryl amine is not essential or particularly preferred for the cholesteryl derivatives to be able to mimic RME of extracellular target molecules. This is surprising and unexpected, since it had previously been shown that an ionizable N-alkyl derivative at position 3 of the cholesteryl moiety was necessary to P7115PC00 12 achieve RME with sufficient efficiency, and that modification by an N-acyl derivative severely decreased the efficiency of RME. In addition, the inventors have shown that the selection of specific linkers bearingsecondary amines increases the efficiency of internalization of the extracellular targetmolecules, as shown in Example 3 and 9. These examples demonstrate compounds offormula (I) bearing secondary amines in the linker internalize the extracellular target molecule to a larger extend, and can be targeted for a longer period of time compared toprior art cholesteryl amine compounds. Without wishing to be bound by theory, thepresent inventors expect this effect may be attributed to these groups conferring the linker X certain positive charge under lysosomal or endosomal pH (pH 4.5 to 6.5).Thus, in one embodiment, X comprises one or more groups e.g. amino groups, that aresubstantially positively charged at pH from below 6.5.In some embodiments, X comprises at least one secondary amine group. In oneembodiment, X comprises at least two secondary amine groups. In one embodiment, Xcomprises at least three secondary amine groups. In one embodiment, X comprises 1 to5 secondary amine groups, such as 1, 2, 3, 4, or 5 secondary amine groups. In oneembodiment, X comprises 1 secondary amine groups. In one embodiment, X comprises 2 secondary amine groups. In one embodiment, X comprises 3 secondary amine groups. In one embodiment, X comprises 2 or 3 secondary amine groups. In one embodiment, X comprises 2 to 5, or 3 to 5, secondary amine groups. In one embodiment, X comprises at least one group . In one embodiment, X comprises at least two groups . In one embodiment, X comprises at least three groups . In one embodiment, X comprises 1 to 5 groups , Nsuch as 1, 2, 3, 4, or 5 groupsH. In one embodiment, X comprises one group .In one embodiment, X comprises two groups . In one embodiment, X comprises three groups . P7115PC00 13 In one embodiment, X comprises only one group . In one embodiment, X comprises only two groups . In one embodiment, X comprises only three groups .In one embodiment, X comprises , wherein n is an integer from 1 to 70. Inone embodiment, n is an integer from 1 to 60, 1 to 50, 1 to 40, 1 to 30, 1 to 20, 1 to 10, such as n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment, X comprises one or more groups .In one embodiment, X comprises , wherein m1 is an integer from 1 to 10,such as an integer from 1 to 5, such as 1, 2, 3, 4, or 5.In one embodiment, X comprises , wherein m2 is an integer from 1 to10, such as an integer from 1 to 5, such as 1, 2, 3, 4, or 5. In one embodiment, Xcomprises wherein m3 is 1 to 10. In one embodiment,X comprises wherein m4 is 1 to 10, L1is -NH-, -C(=O)-, - C(=O)NH-, or -O-. P7115PC00 14 In one embodiment, X comprises a group formed by click-chemistry reaction between an alkyne group and an azide. In one embodiment, X comprises wherein A is a moiety comprising or consisting of any monocyclic orpolycyclic carbocycle or heterocycle. In one embodiment, X comprises , In one embodiment, X does not comprise a branch, such as a branched alkyl group. In one embodiment, X comprises one or more branches. In one embodiment, X comprises one or more branches, wherein each branch is optionally and individually a C1-C5alkyl, C1-C5alkoxy, or C3-C7cycloalkyl, each of which may optionally have one or more substituents. In one embodiment, X comprises one or more substituents selected from: -OH, - NH3, -C(=O)NH2, or an alkylamine.In one embodiment, X comprises or consists of any one selected from: ,and . P7115PC00 15In one embodiment, X comprises or consists of any one selected: , embodiment, X comprises or consists of . In one embodiment, X comprises or consists of . In one embodiment, X comprises or consists In one embodiment, X comprises or consists of a linear bivalent, saturated or unsaturated, C5-C20hydrocarbon chain, wherein one or more methylene groups in X are individually and optionally replaced by one ormore of the groups selected from: -O-, -N(H)-, -C(=O)-, -N(H)C(=O)-, -N(RL1)C(=O)-, -NHC(=O)NH-, -NHC(=S)NH-, wherein RL1is C1-5alkyl; and X comprises at least one group , such as 1, 2 or 3 groups , preferably 1 or 2 groups . In one embodiment, X comprises 1 or 2 groups of .In one embodiment, X comprises 2 or 3 groups of . In one embodiment, X comprises 2 or 3 groups of in direct connection with each other, such as successive moieties of the linker X. P7115PC00 16 Extracellular binding moiety As described herein the compounds of formula (I) comprise a cholesteryl carbamatemoiety which is able to bind to the cell surface, and a moiety (RT) which is specificallyadapted to bind an extracellular target molecule.The binding of RT to the extracellular target molecule is in one embodiment non-covalent.The selection of RTdepends on the target extracellular molecule of interest, which maybe e.g. a protein, a peptide, a nucleic acid, or a drug.In one embodiment, RTcomprises or consist of a moiety specifically adapted to be bound by an antibody or an antigen-binding fragment of an antibody. Examples of antibody-binding ligands are known to someone of skill in the art. In one embodiment, RTcomprises or consist of a moiety that binds to a disease proteinof interest, for example, RT comprises or consist of the structure of a known inhibitor ora ligand of a disease-associated protein of interest. Examples of said known inhibitorsor ligands are known to someone of skill in the art. In one embodiment, RTcomprises a group derived from fluorescein. In one embodiment, RTcomprises any one of formulas (F-I) or (F-II): acid-base form thereof. “Acid-base form” refers to any form that is obtained via acid-base equilibrium. In one embodiment, RTcomprises any one of formulas (F-Ia) or (F-IIa): wherein RFis absent or a C1-C5hydrocarbon chain, wherein one or more methylene groups is P7115PC00 17 optionally and individually replaced by -O-, -N(H)-, -C(=O)-, -N(H)C(=O)-, -N(RL1)C(=O)-, -NHC(=O)NH-, -NHC(=S)NH-; wherein RL1 is C1-5 alkyl.In one embodiment, RTis according to any one of formulas (F-Ib) or (F-IIb): In one embodiment, RFis a C1-C5hydrocarbon chain, wherein one or more methylene groups is optionally and individually replaced by -O-, -N(H)-, -C(=O)-, -N(H)C(=O)-, -N(RL1)C(=O)-, -NHC(=O)NH-, -NHC(=S)NH-, an optionally substituted carbocycle, anoptionally substituted heterocycle; wherein RL1is C1-5alkyl.In one embodiment, RF is -NHC(=S)NH-. In one embodiment, RF is absent.The extracellular target molecule may bind RTthrough any interaction, for example by affinity to metal complexes. Thus, in one embodiment RTcomprises or consists of a metal chelating moiety. In one embodiment, RTcomprises or consist of a metal complex.For example, oligohistidine groups, ubiquitously used in biotechnology for productionand purification of tagged proteins, bind with high affinity certain metal ions. In oneembodiment, RTcomprises a moiety specifically adapted to bind an oligohistidine group. It is known that oligohistidine groups bind to metal complexes of nitrilotriacetic acid (NTA, formula N-I). The examples presented herein demonstrate that compounds of the present disclosure bearing NTA moieties are able to efficiently mediate internalization of extracellular target proteins comprising oligohistidine groups in the presence of divalent metal ions. It isdemonstrated that the compounds of formula (I) mediate internalization at relevantconcentrations for application in biological and medicinal settings, without producing visible sign of toxicity.Thus, in one embodiment, RT comprises one or more moieties derived from nitrilotriaceticacid (NTA), or a derivative thereof. P7115PC00 18In one embodiment, RT comprises or consists of 1 to 3 moieties derived fromnitrilotriacetic acid (NTA) , or a derivative thereof, such as 1, 2, or 3 moieties derived from nitrilotriacetic acid (NTA).In one embodiment, RT comprises 1 moiety derived from NTA. In one embodiment, RTcomprises 2 moieties derived from NTA. In one embodiment, RT comprises 3 moietiesderived from NTA. It has been shown that groups having metal complexes with 3 NTA moieties have increased affinity to oligohistidine. As used herein, when referring to moieties derived from NTA it is considered anychemical derivative of NTA made by substitution at any position, provided that itscomplexation with metals with sufficient affinity is achieved and the binding tooligohistidine groups with enough affinity is not hindered. In one embodiment, RTcomprises 1 to 3 units of formula (N-I), such as 1, 2 or 3 units of formula (N-I): RT may comprise derivatives of formula (N-I), any derivative made by substitution at anyposition may be considered as long as complexation of metals with sufficient affinity isachieved and binding to oligohistidine groups with enough affinity is not hindered.In one embodiment, RTcomprises 1 to 3 units of formula (NI-a), such as 1, 2 or 3 units of formula (N-Ia): Ia),wherein RXis a C1-C20 hydrocarbon chain, wherein one or more methylene groups is optionally and individually replaced by -O-, -N(H)-, -C(=O)-, -N(H)C(=O)-, -N(RL1)C(=O)-, -NHC(=O)NH-, -NHC(=S)NH-, an optionally substitutedcarbocycle, or an optionally substituted heterocycle; and formula (N-Ia) is attached to Xof formula (I) via RX. P7115PC00 19 In one embodiment, wherein RXcomprises or consist of , wherein k is aninteger from 1 to 5, RN denotes attachment to formula (N-Ia), and RX denotesattachment to X. In one embodiment, RX comprises or consist of , wherein k isan integer from 1 to 5. In one embodiment, k is 1, 2, 3, 4, or 5. In one embodiment, k is 2. In one embodiment, the compound of formula (I) is according to formula (N-IIa): IIa), wherein X is as described herein,RX is selected from a C1-C20 hydrocarbon chain, wherein one or more methylenegroups is optionally and individually replaced by -O-, -N(H)-, -C(=O)-, -N(H)C(=O)-, -N(RL1)C(=O)-, -NHC(=O)NH-, -NHC(=S)NH-, an optionally substituted carbocycle, oran optionally substituted heterocycle; wherein RL1 is C1-5 alkyl.In some embodiments, RXmay be a bond.

[0002] P7115PC00 20In one embodiment, the compound of formula (I) is according to formula (N-IIb): wherein X is as described herein,each instance of RX1, RX2 and RX3 is individually and independently selected from a C1-C20hydrocarbon chain, wherein one or more methylene groups is optionally andindividually replaced by -O-, -N(H)-, -C(=O)-, -N(H)C(=O)-, -N(RL1)C(=O)-, -NHC(=O)NH-, -NHC(=S)NH-, an optionally substituted carbocycle, or an optionally substituted heterocycle.In one embodiment, each instance of RX1, RX2, and RX3 are individually andindependently selected form a C1-C5 linear hydrocarbon chain, wherein one or more methylene groups is optionally and individually replaced by -O-, -N(H)-, -C(=O)-, -N(H)C(=O)-, -N(RL1)C(=O)-, -NHC(=O)NH-, -NHC(=S)NH-, an optionally substitutedcarbocycle, or an optionally substituted heterocycle; wherein RL1is C1-5 alkyl. In one embodiment, RX1, RX2, and RX3comprise or consist of , wherein k is an integer from 1 to 5, RNdenotes attachment to formula (N-Ia), and RXdenotes P7115PC00 21attachment to X. In one embodiment, RX1, RX2, and RX3 comprise or consist of , wherein k is an integer from 1 to 5. In one embodiment, RX1, RX2, and RX3may individually and independently be a bond. whereinY is a heterocycle such as a 4-20 membered heterocycle, more preferably a 4-16membered heterocycle, such as a 4-18, or 11 to 16 membered heterocycle, andRY1, RY2, and RY3 is individually and independently selected form a C1-C5 linearhydrocarbon chain, wherein one or more methylene groups is optionally and individuallyreplaced by -O-, -N(H)-, -C(=O)-, -N(H)C(=O)-, -N(RL1)C(=O)-, -NHC(=O)NH-,or -NHC(=S)NH-; wherein RL1is C1-5 alkyl. P7115PC00 22In one embodiment, the compound of formula (I) is according to formula (N-IId): each instance of RY1, RY2, and RY3 is individually and independently selected form a C1-C5linear hydrocarbon chain, wherein one or more methylene groups is optionally andindividually replaced by -O-, -N(H)-, -C(=O)-, -N(H)C(=O)-, -N(RL1)C(=O)-, -NHC(=O)NH-, or -NHC(=S)NH-; wherein RL1is C1-5 alkyl. In one embodiment, RY1, RY2, and RY3comprise or consist of , wherein k is an integer from 1 to 5, RNdenotes attachment to formula (N-Ia), and RXdenotesattachment to X. In one embodiment, RY1, RY2, and RY3 comprise or consist of , wherein k is an integer from 1 to 5. In one embodiment, k is 1, 2, 3, 4, or 5. In one embodiment, k is 2. In some embodiments, RY1, RY2, and RY3may individually and independently be a bond.In one embodiment, RT comprises a complex with a metal formed via an NTA moietyas described herein. In one embodiment, RTcomprises 1, 2 or 3 complexes of nitrilotriacetic acid, or aderivative as described herein, with Co3+, Co2+, Ni2+, or Zn2+. P7115PC00 23In one embodiment, RT comprises a complex of Co2+. In one embodiment, RTcomprises a complex of NTA, or a derivative thereof as described herein, with Co2+. In one embodiment, RTcomprises a complex of Ni2+. In one embodiment, RTcomprises a complex of NTA, or a derivative thereof as described herein, with Ni2+. In one embodiment, RTcomprises a complex of Ni2+. In one embodiment, RTcomprises a complex of NTA, or a derivative thereof as described herein, with Zn2+.In one embodiment, each unit of formula (N-I) or (N-Ia) is forming a metal complex withone selected from: Co2+, Ni2+, and Zn2+. In one embodiment, each unit of formula (N-I) or (N-Ia) is forming a metal complex with Co2+.In one embodiment, each unit of formula (N-I) or (N-Ia) is forming a metal complexwith Ni2+. In one embodiment, each unit of formula (N-I) or (N-Ia) is forming a metalcomplex with Zn2+.In one embodiment, the compound of formula (I) is any one selected from the groupsshown in Table A, or a pharmaceutically acceptable salt thereof. Table A. CR1

[0003] P7115PC00 24 P7115PC00 25 NR3 triNR3In one embodiment, the compound of formula (I) is CR2, CR3 or CR4, or apharmaceutically acceptable salt thereof. In one embodiment, the compound of formula(I) is CR2 or CR3 or a pharmaceutically acceptable salt thereof.In one embodiment, the complex is NR2, NR3, or triNR3, or a pharmaceuticallyacceptable salt thereof, or a complex thereof with one or more of Co2+, Ni2+, or Zn2+,preferably with Ni2+.In one embodiment, the compound of formula (I) is P7115PC00 26In one embodiment, the compound of formula (I) is In one embodiment, the compound of formula (I) is In one embodiment, the compound of formula (I) is complex thereof with one or more of Co2+, Ni2+, or Zn2+, preferably with Ni2+.In one embodiment, the compound of formula (I) is complex thereof with one or more of Co2+, Ni2+, or Zn2+, preferably with Ni2+. P7115PC00 27In one embodiment, the compound of formula (I) is (triNR3), or a complex thereof with one or more of Co2+, Ni2+, or Zn2+, preferably with Ni2+.In one embodiment, the compound of formula (I) is In one embodiment, the compound of formula (I) is selected from CR2, CR3, and CR4,or a pharmaceutically acceptable salt thereof. In one embodiment, the compound offormula (I) is selected from CR2 or CR3, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound of formula (I) is NR2, NR3, or triNR3, or apharmaceutically acceptable salt thereof, or a complex with a divalent metal ion thereof, such as a complex with Ni2+.In one embodiment, RT does not comprise or consist of a lipid moiety. P7115PC00 28 In one embodiment, X does not comprise phosphorous atoms (P). In one embodiment, X does not comprise wherein RPis H or a substituent.In one embodiment, X of the compound of formula (I) does not comprise -B(OH)2.In one embodiment, the compound of formula (I) comprises only one group derivedfrom .In one embodiment, the compound of formula (I) comprises only one .In one embodiment, RT does not comprise or consist of a lipid moiety.In one embodiment, the compound of formula (I) is not one of selected from : P7115PC00 29 (CAS 635305-93-0);

[0004] P7115PC00 30 (CAS 2408741-47-7, n2 average molecular weight of ethylene glycol 5000g / mol). P7115PC00 31 In one embodiment, the compound according to the present disclosure is according to formula (I), salt thereof, wherein N X is a linker as described herein comprising at least one group H , such as 1, 2 or 3 groups , preferably 2 or 3 groups ; andRTis according to formula (F-Ib), (F-IIb), or (N-Ia): (N-Ia). Extracellular target molecule As shown in the Examples, the compounds of the present disclosure are able to bind tothe cell surface and promote internalization of an extracellular target molecule whichspecifically binds to RTin formula (I) as described herein. Thus, the present compounds of formula (I) as described herein are useful in many applications where crossing of the cell membrane of target molecules is necessary. P7115PC00 32 The examples disclosed herein make plausible that a diverse range of extracellular target molecules may be internalized using the compounds of formula (I) described herein. Forexample, the extracellular target molecule may be, without limitation, a peptide, a protein,a carbohydrate, a small molecule, or a nucleic acid. The extracellular target molecule isin one embodiment a protein or peptide.In one embodiment, the extracellular target molecule is a protein. In one embodiment,the extracellular target molecule is a therapeutic protein or a therapeutic peptide, e.g. aprotein or peptide that is capable of treating at least one disease or condition. In oneembodiment, the extracellular target molecule is an antibody, or an antigen-binding fragment thereof, a cytokine, an enzyme or a therapeutic peptide.In one embodiment, the extracellular target molecule is a therapeutic agent , e.g. asmall-molecule drug. In one embodiment, the extracellular target molecule is cytokine. Antibodies By the examples disclosed herein it is shown that compounds of formula (I) of the present disclosure wherein RTis specifically adapted to be bound by an antibody efficiently mediate internalization of said antibody. The examples demonstrate that compounds of formula (I) wherein the linker comprises secondary amine groups mediate internalization of antibodies for extended periods of time and to a larger extent that N-alkyl cholesterylamine compounds of the prior art. Thus, it is made plausible that a broad range of antibodies, fragments thereof, or drug conjugates thereof can be internalized into cells by selecting an antibody, fragment thereof, or drug conjugate thereof with affinity for the RTmoiety in formula (I). In one embodiment, the extracellular target protein is an antibody, or an antigen-binding fragment of an antibody. In one embodiment, the extracellular target protein is an antibody, or antigen-binding fragment thereof specifically adapted to bind RTof formula (I). Antigen-binding fragments of antibodies may be a single-domain antibody fragment able to bind its target with high affinity. In one embodiment, the antibody may be binding with high affinity to a non-endogenousmoiety, like fluorescein (FITC) or dinitrophenol.In one embodiment, the antibody is conjugated with a therapeutic agent, e.g. asmall-molecule drug exhibiting a therapeutic effect. As used herein covalent conjugates P7115PC00 33 of antibodies with therapeutic agents are referred to as antibody-drug conjugates (ADCs). As known in the art, the antibody may be conjugated to the therapeutic agent via a linker. The linker may be cleavable or non-cleavable. As known in the art, cleavable linkers for ADCs may be obtained by introducing sensitive moieties in the linker. In one embodiment, the linker of the ADC is a protease sensitive linker comprising aprotease-sensitive moiety as known in the art, for example a valine-citrulline dipeptide.In one embodiment, the extracellular target molecule is an antibody-drug conjugate, wherein the antibody is conjugated to a therapeutic agent. In one embodiment, the extracellular target molecule is an antibody-drug conjugate comprising a protease-cleavable linker, and an antimitotic therapeutic agent. In one embodiment, extracellular target molecule is according to formula (II): Ab-LX-RP(II), wherein Ab is an antibody, or an antigen-binding antibody fragment, LXis a linker, and RPis a therapeutic agent.In one embodiment, LX is a non-cleavable linker. In one embodiment, LX is a cleavablelinker. In one embodiment, LX is a protease-cleavable linker, such as a cathepsincleavable linker.In one embodiment, LX P7115PC00 34In one embodiment, LX In one embodiment, LX .In one embodiment, the antibody is an anti-fluorescein antibody (antiFITC).In one embodiment, RP is an anticancer agent. In one embodiment, RP is an antimitoticagent, such as a tubulin inhibitor. In one embodiment, RPis monomethyl auristatin E or monomethyl auristatin F. In one embodiment, the antibody in formula (II) is specifically adapted to bind to RTof formula (I) as described herein, such as the antibody in formula (II) is specifically adapted to bind RTderived from fluorescein as described herein above, e.g. the antibody in formula (II) is an anti-FITC antibody. P7115PC00 35 The antibody in formula (II) may be linked via to the linker via known chemistries in the field of antibody-drug conjugates known to the skilled person. For example, Michael reactions e.g. using a maleimide group, may be employed to form covalent bonds with a reduced disulfide of the antibody as known in the art. In one embodiment, the extracellular target molecule is according to formula (IIa) formula (IIa), wherein Ab represents an antibody as described herein. In one embodiment, the antibody is an antifluorescein antibody (anti-FTIC). In one embodiment, the extracellular target molecule is an antibody-drug conjugatecomprising an anti-fluorescein antibody (anti-FITC), covalently linked via aprotease-sensitive linker to a therapeutic agent as described herein.OligohistidineOligohistidine groups are used ubiquitously in recombinant protein expression, alsoreferred to as His-Tags. By the examples disclosed herein it is shown that compounds of formula (I) of the present disclosure bearing NTA moieties are able to efficiently mediate internalization of extracellular target proteins comprising oligohistidine groups in the presence of divalent metal ions. Thus, it is made plausible that a broad range ofextracellular molecules comprising a oligohistidine group, such as any protein or peptidecomprising a oligohistidine group, can be internalized into cells by the compounds offormula (I) bearing NTA moieties as described herein, because the interaction between NTA metal complexes and oligohistidine is well-established in the field. P7115PC00 36 Thus in one embodiment, the extracellular target molecule is a protein or a peptide comprising a oligohistidine group and RTis a moiety derived from nitrilotriacetic acid (NTA).In some embodiments, the extracellular target molecule is a protein or a peptidecomprising an oligohistidine group. In one particular embodiment, the extracellular targetmolecule is a therapeutic protein or peptide comprising a oligohistidine group.The oligohistidine labelled protein may in one embodiment be a oligohistidine labelled fluorescent protein, such as green fluorescent protein (GFP) or red fluorescent protein (RFP), or any other protein of the family of fluorescent proteins. In one embodiment, the oligohistidine labelled protein is labelled with a fluorescent moiety.In one embodiment, the extracellular target molecule is a protein or peptide comprisingan oligohistidine group at the N- or C- terminus.In one embodiment, the oligohistidine group comprises at least 6 sequential histidinegroups, such as 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 sequential histidine groups.In one embodiment, the oligohistidine group comprises 6 to 15 sequential histidinegroups. In one embodiment, the oligohistidine group comprises 6 to 12 sequentialhistidine groups. In one embodiment, the oligohistidine group comprises 6 sequentialhistidine groups.In one embodiment, the oligohistidine group is according to formula (H-I): wherein formula (H-I) is attached to the N-, or C- terminus of the extracellular target protein,wherein p is an integer from 6 to 15. In one embodiment, p is an integer from 6 to 12.In one embodiment, p is 6. A composition In one aspect, the present disclosure provides for a composition comprising the compound according to any one of the preceding items. P7115PC00 37 In one embodiment, the composition comprises a pharmaceutically acceptable excipient or carrier, such as in pharmaceutical compositions. A method of internalizing a compound As shown in the Examples, the compounds of the present disclosure are able to bind tothe cell surface and promote internalization of an extracellular molecule whichspecifically binds to RTin formula (I) as described herein.Without wishing to be bound by theory, it is thought that this process is mediated by theanchoring of the compounds of formula (I) described herein to the cell surface and simultaneously also to the extracellular target moiety and exploiting the natural cell machinery to internalize the extracellular target, in a process that mimics receptor-mediated endocytosis (RME).Thus, in one embodiment, the compound of formula (I) as described herein is able tobind the extracellular surface of a cell. In one embodiment, the compound of formula (I)is able to bind the cell membrane.In one embodiment, the compound of formula (I) is able to bind to the extracellularsurface of a cell and to the target molecule at the same time.In one embodiment, upon binding of the compound of formula (I) to a cell membrane andbinding of RTto the extracellular target molecule, the target molecule is internalized intothe cell. Thus, upon binding of the compound of formula (I) to a cell membrane and theformation of a complex between RTof formula (I) and the extracellular target molecule, the target molecule is internalized into the cell. Hence, in one aspect, the present disclosure provides for a method of internalizing an extracellular target molecule into a cell, the method comprising: a) providing a compound of formula (I) as described herein;b) contacting the compound in step a) with a cell having a cell surface, therebyobtaining a cell comprising the compound of formula (I) bound to the cell surface;c) contacting the cell of step b) with an extracellular target molecule, wherein saidextracellular target molecule binds the compound of formula (I), optionally wherein said extracellular target molecule binds the compound of formula (I) simultaneously or sequentially to the compound of formula (I) binding the cellsurface; thereby internalizing the extracellular target molecule into the cell. P7115PC00 38 The Examples demonstrate that the compounds of the present disclosure are able topromote RME of target molecules in cell lines derived from white blood cells and hepaticcells. Thus, in one embodiment the cell is a white blood cell or a hepatic cell. In oneembodiment, the cell is a lymphocyte, such as a T cell. In one embodiment, the cell is a hepatocyte. The examples disclosed herein demonstrate that the compounds of formula (I) described herein can be incorporated into cells and used for internalization of extracellular target molecules as defined herein in the presence of low density lipoprotein (LDL). This is important for the prospect of in vivo use of these compounds and for the delivery of extracellular molecules to the liver.In one embodiment, the method is performed on an isolated cell (ex-vivo), outside of thebody. Thus, in one aspect the present disclosure provides for a method of internalizing an extracellular target molecule into an isolated cell, the method comprising: a) providing an isolated cell having a cell surface;b) providing a compound of formula (I) as described herein,c) contacting the cell surface of said isolated cell of step a) with the compoundof step b), thereby obtaining a cell comprising the compound of formula (I) bound to the cell surface; and d) contacting the isolated cell of step c) with an extracellular target molecule,wherein said extracellular target molecule binds the compound of formula (I), optionally wherein said extracellular target molecule binds the compound of formula (I) simultaneously or sequentially to the compound of formula (I)binding the cell surface; thereby internalizing the extracellular target molecule into the cell. In one embodiment, the cell is preferably an eukaryotic cell. In one embodiment, the extracellular target molecule is as described elsewhere herein. In one embodiment, the extracellular target molecule is degraded upon internalization. The Examples demonstrate that the compounds of formula (I) described herein can target extracellular target proteins into the lysosomes. Lysosomes are cell organelles P7115PC00 39 that, among other functions, are involved in the degradation of biomolecules because they contain hydrolytic enzymes and acidic conditions that favour degradation.In one embodiment, the extracellular target molecule is degraded in a lysosome.In one embodiment, the extracellular target molecule is stored in the intracellularcompartments, e.g. endosomes or lysosomes.In one embodiment, the cell surface referred herein is the cell membrane, also referred to as plasma membrane. In one aspect the present disclosure relates to use of a compound according to formula (I) as described herein for internalization of an extracellular target molecule into a cell as described herein. In one embodiment, the method of internalizing an extracellular target molecule described herein comprises contacting a cell with a compound of formula (I); formula (I), or a pharmaceutically acceptable salt thereof, wherein X is a linker as described herein comprising at least one group , such as 1, 2 or 3 groups , preferably 1 or 2 groups ; andRTis a moiety binding the extracellular target moiety. Any of the embodiments described herein of a compound of formula (I) or of an extracellular target molecule may be combined with the methods and uses forinternalization of an extracellular target molecule described herein. P7115PC00 40 A cell In one aspect, the present disclosure provides for an isolated cell comprising thecompound of formula (I) as described herein.In one embodiment, the compound of formula (I) is located at the cell surface. In oneaspect, the cell is an eukaryotic cell. Thus, in one embodiment the cell is a white bloodcell or a hepatic cell. In one embodiment, the cell is a lymphocyte, such as a T cell. In one embodiment, the cell is a hepatocyte. Medical and diagnostic use The compounds of formula (I) according to the present disclosure may find use in overcoming current drawbacks in therapy or diagnosis applications involving limited cellular internalization of an extracellular molecule. The extracellular target molecule of interest may be chosen by selection of a specific extracellular targeting moiety (RTinformula (I) or embodiments thereof) adapted to bind the extracellular target molecule. Assuch, the compounds according to the present disclosure may find application in various fields of therapy or diagnosis. For example, in the specific delivery and uptake of therapeutic agents by improving crossing of cell membranes and biological barriers, or in improving conditions characterized by limited protein transport or protein storage in cells. The compounds of formula (I) of the present disclosure may also be used in theremoval of a disease-associated protein or a disease-associated peptide of interest. Theremoval of the disease-associated protein or peptide may involve degradation of the disease-associated protein or peptide. The Examples demonstrate that the compounds of the present disclosure promoteinternalization of target molecules even when administered after absorption on, orassociation with, low density lipoprotein (LDL) particles. LDL particles are present inabundance in the blood and participate in the transport of cholesterol molecules throughthe body. This highlights that the presence of LDL does not impede the installation of thecompounds and their ability to mediate RME.These results demonstrate the possibility of in vivo use of the compounds of the presentdisclosure to remove extracellular targets of interest. Without wishing to be bound by theory, based the presented results the inventors expect that, upon administration, thecompounds of formula (I) and embodiments thereof described herein associate withdifferent cells in the body and capture the extracellular target molecules. P7115PC00 41 Extracellular target internalization is demonstrated herein with cell lines derived from white blood cells and hepatic cells. Thus, the cells mediating protein capture in the body upon administration could include, but not be limited to, hepatic and / or white blood cells. For example, by association of the compounds to hepatic cells directly (or upon the prior association to LDL particles and posterior trafficking to the liver); or by association of the compounds with white blood cells.Thus, in one aspect, the present disclosure provides a compound of formula (I) asdescribed herein, or a composition as described herein, for use as a medicament. In one aspect, the present disclosure provides use of a compound of formula (I) as described herein for the manufacture of a medicament.In one aspect, the present disclosure provides a compound of formula (I) as describedherein, or a composition as described herein, for use in internalization of an extracellulartarget molecule. In one embodiment, the extracellular target molecule is a therapeuticprotein. In one embodiment, the therapeutic protein conjugated to an oligohistidinegroup. In one embodiment, the extracellular target molecule is a protein or peptideassociated with a disease. In one embodiment, the extracellular target molecule is acytokine. In one embodiment, the extracellular target molecule is an enzyme. In oneembodiment, the extracellular target molecule is degraded upon internalization into the cell.In another aspect, the present disclosure provides a compound of formula (I) asdescribed herein, or a composition as described herein for use in treatment of a diseaseor disorder, wherein said treatment comprises a step of internalizing an extracellular target molecule into a cell. In one embodiment, said disease is cancer. In one embodiment, the extracellular target molecule is an antibody-drug conjugate asdescribed herein. In one embodiment, the extracellular target molecule is an antibody-drug conjugate specifically adapted to bind RTof formula (I). In one embodiment, the extracellular target molecule is according to formula (II), as described herein, or any embodiments thereof. In one aspect, the present disclosure provides use of a compound of formula (I) as described herein for the manufacture of a medicament for the treatment of cancer. P7115PC00 42In one embodiment, the extracellular target molecule is as described herein. In oneembodiment, the extracellular target molecule is a therapeutic protein or peptidecomprising an oligohistidine group.In one embodiment, the extracellular target molecule is a disease-associated protein ora disease-associated peptide. In one embodiment, the extracellular target molecule is degraded upon internalization into the cell.In one aspect, the present disclosure provides a compound of formula (I) as describedherein, or a composition as described herein, for use in diagnosis.In one embodiment, the diagnosis is in vivo diagnosis. In one embodiment, the diagnosisis ex-vivo diagnosis. In one embodiment, said diagnosis comprises a step of internalizingan extracellular target molecule into a cell. In one embodiment, the cell is an isolated cell. In one embodiment, the cell is an eukaryotic cell. Any of the embodiments described herein of a compound of formula (I) or of an extracellular target molecule may be combined with the methods of treatment or diagnosis described herein. Items1. A compound according to formula (I): formula (I), or a pharmaceutically acceptable salt thereof, wherein Xis a linker, andRTcomprises a moiety that binds an extracellular target molecule. P7115PC00 432. The compound according to item, 1 wherein the compound of formula (I) isaccording to formula (Ia) 3. The compound according to any one of items 1 to 2, wherein X comprises orconsists of a linear bivalent, saturated or unsaturated, C1-C200hydrocarbon chain wherein one or more methylene groups are individually and optionally replaced by one or more of the groups selected from: -O-, -N(H)-, -N(RL1)-, -C(=O)O-, -C(=O)-, -N(H)C(=O)-, -N(RL1)C(=O)-, -NHC(=O)NH-, -NHC(=S)NH- , -S-, -S(=O)- , -S(=O)2-, -N(RL1)S(=O)2-, -S(=O)2N(RL1)-; an optionally substituted aromatic group; an optionally substituted carbocycle; an optionally substituted heterocycle; an optionally substituted aromatic heterocycle, wherein RL1is C1-5alkyl.4. The compound according to any one of the preceding items, wherein X comprisesor consists of a linear bivalent, saturated or unsaturated, C1-C180hydrocarbon chain, such as a C1-C160, C1-C140, C1-C120, C1-C100, C1-C80, C1-C60, C1-C40, or C1-C20hydrocarbon chain.5. The compound according to any one of the preceding items, wherein X comprisesor consists of a linear bivalent, saturated or unsaturated, C5-C20hydrocarbon chain, such as a C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C13, C14, C15, C16, C17, C18, C19, or C20hydrocarbon chain.6. The compound according to any one of the preceding items, wherein one or moremethylene groups in X are individually and optionally replaced by one or more of the groups selected from: -O-, -N(H)-, -C(=O)-, -N(H)C(=O)-, -N(RL1)C(=O)-, -NHC(=O)NH-, -NHC(=S)NH- , -S-, -S(=O)-, -S(=O)2-, -N(RL1)S(=O)2-, - S(=O)2N(RL1)-, an optionally substituted carbocycle, an optionally substituted heterocycle, wherein RL1is C1-5 alkyl.7. The compound according to any one of the preceding items, wherein one or moremethylene groups in X are individually and optionally replaced by one or more of the P7115PC00 44 groups selected from: -O-, -N(H)-, -C(=O)-, -N(H)C(=O)-, -N(RL1)C(=O)-, -NHC(=O)NH-, -NHC(=S)NH-, wherein RL1C1-5alkyl.8. The compound according to any one of the preceding items, wherein X comprisesat least one secondary amine group.9. The compound according to any one of the preceding items, wherein X comprisesat least two secondary amine group.10. The compound according to any one of items 1 to 8, wherein X comprises 1 to 5secondary amine groups, such as 1, 2, 3, 4, or 5 secondary amine groups.11. The compound according to any one of items 1 to 8 and 10, wherein X comprises atN least one group H .12. The compound according to any one of items 1 to 8, 10-11, wherein X comprises 1to 5 groups , such as 1, 2, 3, 4, or 5 groups .13. The compound according to any one of items 1 to 11, wherein X comprises at leasttwo groups .14. The compound according to any one of items 1 to 11, wherein X comprises at leastthree groups .15. The compound according to any one of items 1 to 12, wherein X comprises onegroup .16. The compound according to any one of items 1 to 13, wherein X comprises twogroups .17. The compound according to any one of items 1 to 15, wherein X comprises threeN groups H . P7115PC00 4518. The compound according to any one of the preceding items, wherein X comprisesor consists of a linear bivalent, saturated or unsaturated, C5-C20hydrocarbon chain, wherein one or more methylene groups in X are individually and optionally replaced by one or more of the groups selected from: -O-, -N(H)-, -C(=O)-, -N(H)C(=O)- , -N(RL1)C(=O)-, -NHC(=O)NH-, -NHC(=S)NH-, wherein RL1is C1-5alkyl; and X comprises at least one group , such as 1, 2 or 3 groups .19. The compound according to any one of the preceding items, wherein X comprises , wherein n is an integer from 1 to 7020. The compound according to any one of the preceding items, wherein n is an integerfrom 1 to 60, 1 to 50, 1 to 40, 1 to 30, 1 to 20, 1 to 10, such as n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.21. The compound according to any one of the preceding items, wherein X comprisesO N one or more groupsH.22. The compound according to any one of the preceding items, wherein X comprises , wherein m1 is an integer from 1 to 10, such as an integer from 1 to 5, such as 1, 2, 3, 4, or 5.23. The compound according to any one of the preceding items, wherein X comprises , wherein m2 is an integer from 1 to 10, such as an integer from 1 to 5, such as 1, 2, 3, 4, or 5.24. The compound according to any one of the preceding items, wherein X comprises ; wherein m3 is 1 to 10. P7115PC00 4625. The compound according to any one of the preceding items, wherein X comprises wherein m4 is 1 to 10, L1is -NH-, -C(=O)-, -C(=O)NH-, or -O-.26. The compound according to any one of the preceding items, wherein X comprises any monocyclic or polycyclic carbocycle or heterocycle.27. The compound according to any one of the preceding items, wherein X comprises , wherein Ax is either -CH- orN.28. The compound according to any one of the preceding items, wherein X comprisesone or more branches, wherein each branch is optionally and individually a C1-C5alkyl, C1-C5 alkoxy, or C3-C7 cycloalkyl, each of which may optionally have one or more substituents.29. The compound according to any one of items 1 to 27 wherein X does not comprisea branch.30. The compound according to any one of the preceding items, wherein X comprisesone or more substituents selected from: -OH, -NH3, -C(=O)NH2, or an alkylamine.31. The compound according to any one of items 1 to 7, wherein X comprises orconsists of any one selected from: P7115PC00 47 32. The compound according to any one of items 1 to 8, 10-12, and 15 , wherein Xcomprises or consists of any one selected from: .33. The compound according to any one of items 1 to 9, 10-13, and 15-16, wherein Xcomprises or consists of any one selected from: .34. The compound according to any one of the preceding items, wherein RT isspecifically adapted to bind the extracellular target molecule.35. The compound according to any one of the preceding items, wherein RT comprisesa moiety able to bind an antibody, or an antigen-binding antibody fragment. P7115PC00 4836. The compound according to any one of the preceding items, wherein RT isaccording to any one of formulas (F-I) or (F-II): 37. The compound according to any one of the preceding items, wherein RT comprisesany one of formulas (F-Ia) or (F-IIa): or acid-base form thereof, wherein RFis absent or a C1-C5hydrocarbon chain, wherein one or more methylene groups is optionally and individually replaced by -O-, -N(H)-, -C(=O)-, -N(H)C(=O)- ,-N(RL1)C(=O)-, -NHC(=O)NH-, -NHC(=S)NH- an optionally substitutedcarbocycle, an optionally substituted heterocycle; wherein RL1 is C1-5 alkyl.38. The compound according to any one of the preceding items, wherein RT isaccording to any one of formulas (F-Ib) or (F-IIb): IIb), or any tautomer, or or a chain, wherein one ormore methylene groups is optionally and individually replaced by -O-, -N(H)-, - C(=O)-, -N(H)C(=O)-, -N(RL1)C(=O)-, -NHC(=O)NH-, -NHC(=S)NH-, an optionallysubstituted carbocycle, an optionally substituted heterocycle; wherein RL1 is C1-5 P7115PC00 4939. The compound according to any one of items 37 to 38, whereinRFis a C1-C5hydrocarbon chain, wherein one or more methylene groups is optionally and individually replaced by -O-, -N(H)-, -C(=O)-, -N(H)C(=O)- ,-N(RL1)C(=O)-, -NHC(=O)NH-, -NHC(=S)NH-; wherein RL1 is C1-5 alkyl..40. The compound according to any one of items 37 to 38, wherein RF is-NHC(=S)NH-.41. The compound according to any one of items 37 to 38, wherein RF is absent.42. The compound according to any one of items 1 to 40, and 36 to 40, wherein thecompound is CR1, CR2, CR3 or CR4 as shown in Table A, or a pharmaceuticallyacceptable salt thereof.43. The compound according to any one of items 1 to 1 to 8, 10-12, 15, and 36 to 40 ,wherein the compound is CR2, CR3 or CR4 as shown in Table A, or apharmaceutically acceptable salt thereof.44. The compound according to any one of items 42 to 43, wherein the compound is 45. The compound according to any one of items 42 to 43, wherein the compound is (CR3). P7115PC00 5046. The compound according to any one of items 42 to 43, wherein the compound is 47. The compound according to any one of items 42 to 43, wherein the compound is 48. The compound according to any one of items 1 to 34, wherein RT comprises amoiety able specifically adapted to bind an oligohistidine group.49. The compound according to any one of items 1 to 34 and 48, wherein RT comprisesone or more moieties derived from nitrilotriacetic acid (NTA) , or a derivative thereof.50. The compound according to any one of items 1 to 34 and 48 to 49, wherein RTcomprises or consists of 1 to 3 moieties derived from nitrilotriacetic acid (NTA) , or a derivative thereof, such as 1, 2, or 3 moieties derived from nitrilotriacetic acid (NTA). P7115PC00 5151. The compound according to any one of items 1 to 34 or 48 to 50, wherein RTcomprises 1 to 3 units of formula (N-I), such as 1, 2 or 3 units of formula (N-I): 52. The compound according to any one of items 1 to 34 or 48 to 51, wherein RTcomprises 1 to 3 units of formula (NI-a), such as 1, 2 or 3 units of formula (N-Ia) Ia) wherein RX is a C1-C20 hydrocarbon chain, wherein one or more methylene groupsis optionally and individually replaced by -O-, -N(H)-, -C(=O)-, -N(H)C(=O)- ,-N(RL1)C(=O)-, -NHC(=O)NH-, -NHC(=S)NH-, an optionally substitutedcarbocycle, or an optionally substituted heterocycle; and formula (N-Ia) is attached to X via RX.53. The compound according to item 52, wherein RX comprises or consist of wherein k is an integer form 1 to 5, RNdenotes attachment to formula (N-Ia), and RXdenotes attachment to X.54. The compound according to any one of items 52 to 53, wherein k is 1, 2, 3, 4, or 5.55. The compound according to any one of items 52 to 54, wherein k is 2. P7115PC00 5256. The compound according to any one of items 1 to 34 or 48 to 55, wherein thecompound is according to formula (N-IIa) or (N-IIb): wherein Xis as described in any one of items 3 to 32,each instance of RX, RX1, RX2and RX3is individually and independently selected from a C1-C20 hydrocarbon chain, wherein one or more methylene groups isoptionally and individually replaced by -O-, -N(H)-, -C(=O)-, -N(H)C(=O)- ,-N(RL1)C(=O)-, -NHC(=O)NH-, -NHC(=S)NH-, an optionally substitutedcarbocycle, or an optionally substituted heterocycle. P7115PC00 5357. The compound according to item 56, wherein the compound is according toformula (N-IIc): wherein Yis a 4-20 membered heterocycle, such as a 4-16 membered heterocycle, suchas a 4-18, or 11 to 16 membered heterocycle, andRY1, RY2, and RY3are individually and independently selected form a C1-C5 linear hydrocarbon chain, wherein one or more methylene groups is optionally and individually replaced by -O-, -N(H)-, -C(=O)-, -N(H)C(=O)-, -N(RL1)C(=O)-, - NHC(=O)NH-, or -NHC(=S)NH-; wherein RL1is C1-5 alkyl.

[0005] P7115PC00 5458. The compound according to item 57, wherein the compound is according toformula (N-IId): wherein each instance of RY1, RY2, and RY3 are individually and independently selectedform a C1-C5 linear hydrocarbon chain, wherein one or more methylene groups is optionally and individually replaced by -O-, -N(H)-, -C(=O)-, -N(H)C(=O)- ,-N(RL1)C(=O)-, -NHC(=O)NH-, or -NHC(=S)NH-; wherein RL1 is C1-5 alkyl.59. The compound according to any one of items 1 to 9, 10-13, 15-16 and 48 to 5655, pharmaceutically acceptable salt thereof. P7115PC00 5560. The compound according to any one of items 1 to 9, 10-13, 15-16 and 48 to 55,wherein the compound is or a pharmaceutically acceptable salt thereof.61. The compound according to any one of items 1 to 9, 10-13, 15-16 and 48to 55, wherein the compound is , (triNR3), or a pharmaceutically acceptable salt thereof.62. The compound according to any one of items 1 to 34 and48 to61, wherein RTcomprises a complex with a metal.63. The compound according to any one of items 1 to 34 and 48 to 62, wherein RTcomprises a 1, 2 or 3 metal complexes of nitrilotriacetic acid with Co2+, Ni2+, orZn2+.64. The compound according to any one of items 1 to 34 or 48 to 63, wherein RTcomprises a metal complex of Co2+. P7115PC00 5665. The compound according to any one of items 1 to 34 or 48 to 63, wherein RTcomprises a metal complex of Ni2+.66. The compound according to any one of items 49 to 62, wherein each unit offormula (N-I) or (N-Ia) is forming a metal complex with one selected from: Co2+, Ni2+, and Zn2+.67. The compound according to item 66, wherein each unit of formula (N-I) or (N-Ia) isforming a metal complex with Co2+.68. The compound according toitem 66, wherein each unit of formula (N-I) or (N-Ia) isforming a metal complex with Ni2+.69. The compound according to any one of the preceding items, wherein X does notcomprise one or more phosphorous atoms (P).70. The compound according to any one of the preceding items, wherein X does notO O P P OH O comprise O , or RP, wherein RPis H or a substituent.71. The compound according to any one of the preceding items, wherein thecompound does not comprise -B(OH)2.72. The compound according to any one of items 1 to 47, wherein the compoundcomprises only one group derived from .73. The compound according to any one of the preceding items, wherein thecompound comprises only one cholesteryl unit.74. The compound according to any one of the preceding items, wherein thecompound is not one of selected from the group consisting of: P7115PC00 57 5

[0006] P7115PC00 58 2138461-86-4); and P7115PC00 59 (CAS 2408741-47-7, n2 average molecular weight of PEG 5000 g / mol);75. A composition comprising the compound according to any one of the precedingitems.76. The composition according to item 75, wherein said composition comprises apharmaceutically acceptable excipient or carrier.77. A method of internalizing an extracellular target molecule into a cell, the methodcomprising: a) providing a compound according to any one of items 1 to 74;b) contacting a cell with the compound in step a), with a cell having a cellsurface, thereby obtaining a cell comprising the compound bound to the cell surface; c) contacting the cell of step b) with an extracellular target molecule, whereinsaid extracellular target molecule binds the compound of step a) as describedherein; thereby internalizing the extracellular target molecule into the cell.78. A method of internalizing an extracellular target molecule into an isolated cell, themethod comprising: a) providing an isolated cell having a cell surface;b) providing a compound according to any one of items 1 to 74;c) contacting a cell surface of said isolated cell of step a) with the compound ofstep b), thereby obtaining a cell comprising the compound bound to the cell surface; andd) contacting the isolated cell of step c) with an extracellular target molecule,wherein said extracellular target molecule binds the compound of step b); thereby internalizing the extracellular target molecule into the cell. P7115PC00 6079. Use of a compound according to any one of items 1 to 74 for internalization of anextracellular target molecule into a cell.80. The method according to item 77, or use according to item 79, wherein the cell isan isolated cell.81. The method according to any one of items 77 to 78, or the use according to item79, wherein the compound is according to formula (I): formula (I), or a pharmaceutically acceptable salt thereof, wherein X is a linker comprising at least one group , such as 1, 2 or 3 groups RTis a moiety binding the extracellular target moiety.82. The method according to any one of items 77 to 78 and 81, or the use accordingto any one of items 79 to 80, wherein target molecule is degraded uponinternalization.83. The method according to any one of items 77 to 78, or the use according to anyone of items 79 to 81, wherein the target molecule is stored in the intracellularcompartments.84. The method according to any one of items 77 to 78 and 81-83 , or the use accordingto any one of items 79 to 82, wherein the cell is an eukaryotic cell.85. The compound according to any one of items 1 to 74, or the method according toany one of items 77, 78, and 80 to 84, or the use according to any one of items79 to 84, wherein the compound binds the extracellular surface of a cell.86. The compound, the method, or the use according to item 85, wherein thecompound binds the cell membrane. P7115PC00 6187. The compound, the method, or the use according to any one of items 85 to 86,wherein the compound binds to the extracellular surface of a cell and to theextracellular target molecule at the same time.88. The compound, the method, or the use according to any one of items 85 to 87,wherein upon binding of the compound to a cell membrane and binding of RTto the extracellular target molecule, the extracellular target molecule is internalizedinto the cell.89. The compound, the method, or the use according to any one of items 85 to 88,wherein the target molecule is degraded upon internalization into the cell.90. The compound, the method, or the use according to any one of items 85 to 88,wherein the extracellular target molecule is stored in the intracellular compartments.91. The compound according to any one of items 1 to 74 and 85 to 90, or the methodaccording to any one of items 77, 78, 80 to 90, or the use according to any one ofitems 79 to 90, wherein the extracellular target molecule is a peptide, a protein, acarbohydrate, a small molecule, or a nucleic acid.92. The compound, the method, or the use according to item 91, wherein theextracellular target molecule is a protein.93. The compound, the method, or the use according to any one of items 91 to 92,wherein the extracellular target molecule is a therapeutic protein.94. The compound, the method, or the use according to any one of items 91 to 92,wherein the extracellular target molecule is a cytokine.95. The compound, the method, or the use according to any one of items 91 to 94,wherein the extracellular target molecule comprises an oligohistidine group.96. The compound, the method, or the use according to any one of items 91 to 95,wherein the extracellular target molecule is a protein or peptide comprising a oligohistidine group at the N- or C- terminus.97. The compound, the method, or the use according to any one of items 95 to 96,wherein the oligohistidine group comprises at least 6 sequential histidine groups, such as 7, 8, 9, 10, 11, 12, 13, 14 or 15 sequential histidine groups. P7115PC00 6298. The compound, the method, or the use according to any one of items 95 to 97,wherein the oligohistidine group comprises 6 to 12 sequential histidine groups.99. The compound, the method, or the use according to any one of items 95 to 98,wherein the oligohistidine group is according to formula (H-I): wherein formula (H-I) is attached to the N-, or C- terminus of the extracellular target protein,wherein p is an integer from 6 to 15.100. The compound, the method, or the use according to any one of items 91 to 93,wherein the extracellular target molecule is an antibody, or an antigen-binding antibody fragment.101. The compound, the method, or the use according to item 100, wherein theextracellular target molecule is according to formula (II): Ab-LX-RP(II), wherein Ab is an antibody, or an antigen-binding antibody fragment,LXis a linker, and RPis a therapeutic agent.102. The compound, the method, or the use according to any one of items 100 to 101,wherein LXis a non-cleavable linker.103. The compound, the method, or the use according to any one of items 100 to 101,wherein LXis a cleavable linker.04. The compound, the method, or the use according to any one of items 100 to 101,wherein LXis a protease-cleavable linker, such as a cathepsin cleavable linker. P7115PC00 63105. The compound, the method, or the use according to any one of items 103 to 104,wherein LXcomprises 106. The compound, the method, or the use according to any one of items 103 to 105,wherein LXcomprises 107. The compound, the method, or the use according to any one of items 103 to 106,wherein LXcomprises .108. The compound, the method, or the use according to any one of items 100 to 107,wherein RPis an anticancer agent.109. The compound, the method, or the use according to any one of items 100 to 108,wherein RPis an antimitotic agent, such as a tubulin inhibitor.110. The compound, the method, or the use according to any one of items 100 to 109,wherein RP is monomethyl auristatin E (MMAE) or monomethyl auristatin F(MMAF). P7115PC00 64111. The compound, the method, or the use according to any one of items 100 to 110,wherein RPis .112. The compound, the method, or the use according to any one of items 100 to 110,wherein RPis .113. The compound, the method, or the use according to any one of items 91 to 92, and100 to 112, wherein the antibody or antibody fragment binds a non-endogenousmoiety.114. The compound, the method, or the use according to any one of items 91 to 92,and 100 to 113, wherein the antibody is an anti-fluorescein antibody (antiFITC).15. An isolated cell comprising the compound according to any one of items 1 to 74.16. The isolated cell according to item 115, wherein the compound is located at thecell surface.17. The isolated cell according to cell according to any one of items 115 or 116,wherein the cell is an eukaryotic cell.118. A compound according to any one of items 1 to 74, or a composition according toany one of items 75 to 76, for use as a medicament.119. A compound according to any one of items 1 to 74, or a composition according toany one of items 75 to 76, for use in internalization of an extracellular targetmolecule P7115PC00 65120. A compound according to any one of items 1 to 74, or a composition according toany one of items 75 to 76 for use in treatment of a disease or disorder, wherein saidtreatment comprises a step of internalizing an extracellular target molecule into a cell.121. The compound for use according to item 120, wherein said disease is cancer.122. The compound for use according to any one of items 118 to 121, wherein theextracellular target molecule is according to any one of items 91 to 114.123. A compound according to any one of items 1 to 74, or a composition according toany one of items 75 to 76, for use in diagnosis.124. The compound or the composition for use according to item 123, wherein thecompound is for use in in vivo diagnosis of diseases.125. The compound or the composition for use according to item 123, wherein thecompound is for use in ex vivo diagnosis.126. The compound or the composition for use according to any one of items 123 to 125,wherein said use comprises a step internalizing an extracellular target molecule into a cell.127. The compound or the composition for use according to any one of items 123 to 126,wherein the extracellular molecule is according to any one of items 91 to 114.Items AA1. A compound according to formula (I): formula (I), or a pharmaceutically acceptable salt thereof, wherein X is a linker, and P7115PC00 66 RTcomprises a moiety that binds an extracellular target molecule. A2. The compound according to item A1, wherein X consists of a linear bivalent,saturated or unsaturated, C1-C200hydrocarbon chain wherein one or more methylene groups are individually and optionally replaced by one or more of the groups selected from: -O-, -N(H)-, -N(RL1)-, -C(=O)O-, -C(=O)-, -N(H)C(=O)-, - N(RL1)C(=O)-, -NHC(=O)NH-, -NHC(=S)NH- , -S-, -S(=O)-, -S(=O)2-, - N(RL1)S(=O)2-, -S(=O)2N(RL1)-; an optionally substituted aromatic group; an optionally substituted carbocycle; an optionally substituted heterocycle; an optionally substituted aromatic heterocycle; or a bond; wherein RL1is selected from the group consisting of C1-5alkyl. A3.The compound according to item A1, wherein X comprises at least one group . A4.The compound according to item A1, wherein X comprises at least two groups . A5.The compound according to any one of items A3 to A4, wherein RTcomprises 1 to 3 units of formula (N-Ia), such as 1, 2 or 3 units of formula (N-Ia): Ia) wherein RX is a C1-C20 hydrocarbon chain, wherein one or more methylene groups isoptionally and individually replaced by -O-, -N(H)-, -C(=O)-, -N(H)C(=O)- ,-N(RL1)C(=O)-, -NHC(=O)NH-, -NHC(=S)NH-, an optionally substituted carbocycle,or an optionally substituted heterocycle; and formula (N-Ia) is attached to X via RX. P7115PC00 67 A6.The compound according to item A5, wherein the compound is . A7.The compound according to any one of items A5 to A6, wherein each unit of formula (N-Ia) is forming a metal complex with one selected from the group consisting of:Co3+, Ni2+, and Zn2+. A8.The compound according to any one of items A1 to A4, wherein RTis according to wherein RFis absent or a C1-C5 hydrocarbon chain, wherein one or more methylene groups are optionally and individually replaced by -O-, -N(H)-, -C(=O)-, -N(H)C(=O)- ,-N(RL1)C(=O)-, -NHC(=O)NH-, -NHC(=S)NH-.A9.The compound according to item A8, wherein the compound is selected from the group consisting of: P7115PC00 68 A10. A method of internalizing an extracellular molecule into an isolated cell, themethod comprising: P7115PC00 69 a. providing an isolated cell;b. providing a compound according to any one of items A1 to A9,c. contacting a cell surface of said isolated cell of step a) with the compoundof step b), thereby obtaining a cell comprising the compound bound to the cell surface; and d. contacting the isolated cell of step c) with an extracellular target molecule,wherein said extracellular target molecule binds the compound of formula (I); thereby internalizing the extracellular target molecule into the cell.A11. An isolated cell comprising the compound according to any one of items A1 toA9.A12. A compound according to any one of items A1 to A9 for use in treatment of adisease or disorder, wherein said treatment comprises a step of internalizing anextracellular target molecule into a cell.A13. The method according to item A10, or the compound for use of item A12,wherein RTcomprises 1 to 3 units of formula (N-Ia), such as 1, 2 or 3 units of formula (N-Ia): wherein RX is a C1-C20 hydrocarbon chain, wherein one or more methylenegroups is optionally and individually replaced by -O-, -N(H)-, -C(=O)- ,-N(H)C(=O)-, -N(RL1)C(=O)-, -NHC(=O)NH-, -NHC(=S)NH-, an optionallysubstituted carbocycle, or an optionally substituted heterocycle; and formula (N-Ia) is attached to X via RX; wherein each unit of formula (N-Ia) is forming a metal complex with one selected from the group consisting of: Co3+, Ni2+, and Zn2+; and the extracellular target molecule is a protein or peptide comprising anoligohistidine group at the N- or C- terminus. A14. The method according to item A10, or the compound for use according to itemA12, wherein RTis according to any one of formulas (F-Ib) or (F-IIb): P7115PC00 70 IIb), or any isomer or tautomer thereof; wherein RFis a C1-C5hydrocarbon chain, wherein one or more methylene groups is optionally and individually replaced by -O-, -N(H)-, - C(=O)-, -N(H)C(=O)-, -N(RL1)C(=O)-, -NHC(=O)NH-, -NHC(=S)NH-, an optionally substituted carbocycle, an optionally substituted heterocycle, or RFis absent; and the extracellular target molecule is an anti-fluorescein antibody (antiFITC). A15. The method, or the compound for use according to item A14, wherein theextracellular target molecule is an anti-fluorescein antibody (antiFITC) covalently linked via a protease-sensitive linker to a therapeutic agent. ExamplesExample 1: Preparation of compoundsMaterials and MethodsAbbreviations. BOC as used herein refers to the tert-butyloxycarbonyl group (-(C=O)-O-(CH3)3). FITC refers to fluorescein isothiocyanate, the examples have used FITC isomer 5 (CAS: 3326-32-7), but similar bifunctional compounds could be prepared with FTIC isomer 6 or a mixture of said isomers. EtTFA refers to ethyl trifluoroacetate. TIPS refers to triisopropylsilane.Chemicals and general methods. All reactions containing air- and moisture-sensitivechemicals were conducted in flame-dried glassware and kept under an atmosphere of nitrogen or argon. MMAF was purchased from ApiChem Technology. All other chemicals were purchased from commercial vendors (Sigma-Aldrich, TCI, Iris Biotech) and used P7115PC00 71 without further purification. Deuterated solvents were supplied from Euroiso-Top. Dichloromethane (CH2Cl2) and acetonitrile (MeCN), were dried over aluminium oxide via a Mbraun SPS-800 solvent purification system and anhydrous N,N-dimethylformamide (DMF) and methanol (MeOH) were purchased from Sigma-Aldrich. Ultrapure water was dispensed from MiliQ Direct 8 (Milipore) [18.2 MΩ·cm]. Thin-layer chromatography (TLC) with silica gel on aluminium foil (Merck Kieselgel 60 Å F254) was used to monitor the reactions. TLC plates were visualised by UV-absorption (254 / 365 nm) and / or stained with KMnO4(0.8% KMnO4and 5% K2CO3in water with 0.8% 2M NaOH) or ninhydrin (1.5% ninhydrin in absolute ethanol with 3.0% acetic acid) and heating.Flash column chromatography was carried out manually with Merck silica gel 60 Å(230-400 mesh particle size) in the stated solvents.1H- and 13C nuclear magnetic resonance.(NMR) spectra were recorded on a VarianAS 400 MHz spectrometer (running 400 MHz and 100 MHz, respectively). The chemical shifts are given in ppm relative to the residual solvent peak (CDCl3, CD3OD, DMSO-d6). All spectra recorded in a mixture of solvents are relative to CD3OD.High-resolution mass spectra (HRMS) were recorded on a Bruker Micromass LC-TOFspectrometer with positive electrospray ionisation (ESI) and analyzed with Bruker Data Analysis.Preparative High-Performance Liquid Chromatography (prep. HPLC) was carriedout on an Agilent 1260 Infinity II system. The mobile phases were ultrapure water (MQ)and acetonitrile with 0.1% TFA (v / v) unless stated otherwise. The column was a ZORBAXEclipse XDB-C18 with particle size 5 µm, an inner diameter of 9.4 mm, and a length of 250 mm.Analytical High-Performance Liquid Chromatography (HPLC). was done on anAgilent 1260 Infinity II with a ZORBAX Eclipse XDB-C8 column with particle size 5 µm,inner diameter of 4.6 mm, and length of 150 mm from Agilent. The mobile phases wereultrapure water (MQ) and acetonitrilecontaining 0.1% TFA (v / v).50% MeCN to 70% from0 to 3 min, 70% MeCN to 100% from 3 to 20 min, 100% MeCN from 20 to 25 min, 100%MeCN to 50% from 25 to 27 min, and 50% MeCN from 27 to 32 min. The concentrationsof the NTA receptor samples were 1 mM in 1:1 DMSO / MeOH with detection at 210 nm. P7115PC00 72 General protocol for the synthesis of fluorescein cholesteryl carbamate receptors (CR1-CR4). Cholesteryl carbamate precursors were prepared according to Scheme 1 below. Step 1. The linker precursor (deprotonated cadaverine or compounds 1.2-1.4) was dissolved in anhydrous CH2Cl2(700 mM) and the solution was cooled to 0 °C before DIPEA (4 to 8 eq.) was added. In another flask, cholesteryl chloroformate was dissolved in anhydrous CH2Cl2(100 mg / mL) and added dropwise to the flask containing the linker precursor under stirring. The reaction mixture was stirred at room temperature for 2 to 4 hours before it was diluted with a mixture of H2O and CH2Cl2and the organic and aqueous phases were separated. For compound 2.1, the aqueous phase was extracted 1-3 times with CH2Cl2, and the organic phase was dried over Na2SO4, filtered, andconcentrated. For compounds 2.2-2.4, the organic phase was washed with H2O once,then washed with brine once, dried over Na2SO4, filtered, and concentrated. The crudecompound was purified by flash column chromatography (stationary phase silica gel,mobile phase 5-10% MeOH, 0-5% EtOH, 1-5% NH4OH in CH2Cl2) to yield the productas a solid upon solvent removal.Step 2. The product obtained in step 1 (Compounds 2.1-2.4) and TEA (1 to 2 eq.) wasdissolved in anhydrous MeOH or anhydrous mixture of MeOH / CH2Cl2 (130-220 mM) andcooled to 0 °C. In another flask, FITC was dissolved in a 2:1 anhydrous MeOH / DMF (130mM) solvent and added dropwise to the precursor (Compounds 2.1-2.4). The reaction mixture was stirred in the dark at room temperature for 24 h before it was concentrated in vacuo and redissolved in CH2Cl2. The organic phase was washed with H2O and brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by flash column chromatography (mobile phase of increasing gradients of up to 50% MeOH inCH2Cl2) resulting in the product as an orange powder upon solvent removal.For the BOC-protected compounds (compounds 3.2, 3.3, and 3.4), deprotection wasperformed by dissolving the compound in CH2Cl2 before trifluoroacetic acid (100 eq.) was added dropwise. The reaction mixture was stirred in the dark at room temperature for 2-3.5 h before it was concentrated in vacuo and lyophilized resulting in the productas a yellow solid in quantitative yield (Compounds CR2, CR3, CR4). P7115PC00 73 Scheme 1. Preparation of compounds CR1-CR4. General protocol for the protection of the linker precursors. Protected precursors(compounds 1.2-1.4) for the linkers were prepared according to Scheme 2.The amine precursors (1 eq.) were dissolved in anhydrous MeOH (50-60 mM) andcooled to between -46 ⁰C and -78 ⁰C before ethyl trifluoroacetate (EtTFA, 2.2 eq.) wasadded slowly over the course of 30 minutes (Step A). The reaction was stirred for an additional 30 min at 0⁰C, before BOC-anhydride (1.5-6.4 eq.) dissolved in MeOH (1.4-3M) was added dropwise. The reaction mixture was stirred overnight while left to reachroom temperature (Step B). Subsequently, 2M aq. NaOH was added until pH > 11, andthe mixture was stirred for an additional 4 h. MeOH was removed under reduced pressure and the resulting residue was dissolved in CH2Cl2 and water. The aqueous phase was extracted with CH2Cl2 (x5), and the combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo. The crude compound was purified by flash column chromatography (mobile phase of increasing gradients of up to 50% MeOH inCH2Cl2 having up to 5% NH4OH, see further information below for each compound) P7115PC00 74resulting in the product as a solid upon solvent removal (Step C). Scheme 2. Preparation of compounds 1.2-1.4.Deprotonation of cadaverine (Compound 1.1). For the reaction of cadaverine withcholesteryl chloroformate, cadaverine hydrochloride was treated to obtain the deprotonated compound. Briefly, pentane 1,5-diamine dihydrochloride (2004 mg, 11.42 mmol, 1 eq.) was dissolved in a solution of KOH (1684 mg, 30.02 mmol, 2.6 eq.) in MeOH (10 mL). The reaction mixture was stirred for 10 min at which the KCl salt precipitated out. The slurry was filtered and washed with CH2Cl2 before the solvent was removed in vacuo. The crude liquid was redissolved in CH2Cl2 and dried over MgSO4, filtered, andconcentrated in vacuo resulting in the product as a yellow liquid in quantitative yield.General protocol for the synthesis of nitrilotriacetic acid (NTA) cholesterylcarbamate receptors (monoNTA-CR2 (NR2), monoNTA-CR3 (NR3)).Nitrilotriacetic acid (NTA) cholesteryl carbamate precursors (were prepared according toScheme 3 below. The cholesteryl carbamate precursor molecule (2.2) was prepared according to Scheme 1 above. The NTA-precursor (d.2) was prepared according to Scheme 4 below. P7115PC00 75 Step 1. The cholesteryl carbamate precursor (Compound 2.2, 1 eq.) and NTA precursor (d.2, 1.2 eq.) were dissolved in a 1:1 mixture of anhydrous CH2Cl2and DMF (40 mM of compound 2.2). HATU (2.5 eq.) and DIPEA (3.3 eq.) were added to the reaction mixture before the reaction mixture was stirred at room temperature for 24 h, before it waspartially concentrated in vacuo. The crude mixture was diluted with CH2Cl2, washed withH2O (x3) and sat. aq. NaHCO3(x3), dried over Na2SO4, filtered and concentrated underreduced pressure. The crude product was purified by flash column chromatography(mobile phase of 45-50% EtOAc in pentane) resulting in the product as a colourless oilupon solvent removal.Step 2. For the BOC-protected compound (compound 4.2, 1 eq.), deprotection wasperformed by dissolving the compound in CH2Cl2 (20 mM) and TIPS (11 eq.) before trifluoroacetic acid (45 v / v%) was added dropwise. The reaction mixture was stirred atroom temperature for 6h before MeOH and H2O were added to the solution and thereaction mixture was concentrated in vacuo. The residue was triturated with ice-coldEt2O, and the precipitate was washed with ice-cold Et2O (x3), before it was dried under reduced pressure resulting in the product as a white solid. Scheme 3. Preparation of compound NR2. P7115PC00 76Compound NR3 was prepared following a similar procedure as described in Scheme 3.For step 1, d.2 (90 mg, 0.21 mmol, 1.0 equiv.) was dissolved in a 1:1 mixture of anhydr.DCM and DMF (2 mL). HATU (197 mg, 0.518 mmol, 2.5 equiv.) and DIPEA (0.14 mL,0.80 mmol, 3.9 equiv.) were added to the reaction flask at room temperature and wereleft stirring for 30 min under an argon atmosphere. Compound 2.3 (205 mg, 0.251 mmol,1.2 equiv.) was dissolved in a 1:1 mixture of anhydr. DCM and DMF (2 mL) and added to the reaction mixture dropwise, at which the solution turned orange and then dark brown. The reaction was stirred o / n at rt, and then partially concentrated under reduced pressure. The reaction residue was diluted with DCM, washed with water (x3) and a saturated aq. NaHCO3solution (x3), dried over Na2SO4, filtered, and concentrated under reduced pressure, yielding a dark brown crude product. The product was purified by flash column chromatography (40% EtOAc in pentane → 50% EtOAc in pentane), yieldingcompound 4.3 (100 mg, 0.0814 mmol, 39%) as a straw-colored sticky solid.For step 2, compound 4.3 (25 mg, 0.020 mmol, 1 equiv.) was dissolved in anhydr. DCM(1 mL) under an argon atmosphere. Triisopropylsilane (40 µL, 0.20 mmol, 10 equiv.) and TFA (0.8 mL, 10 mmol, 510 equiv.) were added to the flask under vigorous stirring. After 7 hours, MeOH (0.5 mL) and H2O (0.5 mL) were added to the reaction mixture, followed by concentration under reduced pressure. The resulting residue was triturated with ice- cold diethyl ether and washed extensively with cold diethyl ether. The precipitant was dried under reduced pressure, redissolved in 1:1 MeOH / DMSO (10 mg / mL) and purified by preparative HPLC (30% MeCN from 0 to 3 min, 30% MeCN → 52% MeCN from 3 min to 4 min, 52% MeCN → 62% MeCN from 4 min to 20 min, 62% MeCN → 100% MeCN from 20 min to 21 min, 100% MeCN from 21 min to 26 min, 100% MeCN → 30% MeCN from 26 min to 27 min and 30% MeCN from 27 min to 30 min) with a retention time of 13.4 min, yielding the CR3 mono-NTA receptor (NR3) (2.9 mg, 0.0027 mmol, 17%) as a white solid.General protocol for the synthesis of NTA precursor. NTA precursor d.2 wasprepared as shown in Scheme 4.Step A. d.0 (1.0 eq.) was dissolved in anhydrous DMF (150 mM). DIPEA (4.9 equiv.) andtert-butyl bromoacetate (3.9 equiv.) were added to the reaction mixture, before the reaction mixture was stirred overnight at 55°C. The reaction mixture was concentrated under reduced pressure after which the resulting brown slurry was resuspended in EtOAc. The suspension was filtrated, and the residue was washed extensively with P7115PC00 77 pentane / EtOAc (3:1). The filtrate was collected and concentrated under reduced pressure, resulting in a brown oil. The product was purified by flash column chromatography (5-7% EtOAc in pentane) yielding the product (d.1) as a straw-coloured oil. The product from step 1 (d.1, 1.0 equiv.) was dissolved in anhydr. MeOH (80mM) and the flask was purged with N2. To the flask, Pd / C 10% was added and H2was bubbled through the reaction mixture at rt. After 2 hours the reaction was quenched by bubbling N2through the solution. The reaction mixture was then filtered through a Celite® plug and concentrated under reduced pressure, yielding the product (d.2) as a slightly yellow sticky and viscous oil. Scheme 4. Preparation of NTA precursor d.2.Maleimide-vc-MMAF. Was prepared as shown in Scheme 5. MC-Val-C1t-PABC-PNP(e.1) (9.7 mg, 0.0131 mmol, 1 equiv.) was dissolved in dry DMF (0.25 mL) and a solutionof MMAF (20.4 mg, 0.0279 mmol, 2 equiv.), TEA (4.56 uL, 0.0328 mmol, 2.5 equiv.) and HOBt (4.1 mg, 0.0303 mmol, 2.3 equiv.) in dry DMF (0.25 mL) was added. The reaction mixture was left stirring under N2 atmosphere for 6 days followed by purification on preparative HPLC, method: 30% MeCN and 70% H2O to 100% MeCN over 20 min,isocratic until 22 min, 100% to 30% MeCN from 22 to 25 min. The mobile phasecontained 0.1% formic acid. Retention time = 8.9 min, yielding the product, Mal-vc- MMAF, as a white powder (4.8 mg, 0.004 mmol, 28 %). P7115PC00 78 Scheme 5. Preparation of Mal-vc-MMAFGeneral protocol for the synthesis of tris(nitrilotriacetic acid (NTA)) cholesterylcarbamate receptors The general synthesis is shown in Schemes 6.1 and 6.2.Synthesis of compound d.4 (triNTA-head precursor) (Scheme 6.1). d.2 (90 mg, 0.21mmol, 3.0 equiv.) was dissolved in DCM (4 mL) under an argon atmosphere. Cyclam (15 mg, 0.075 mmol, 1.0 equiv.), HATU (441 mg, 1.16 mmol, 4.0 equiv.) and DIPEA (0.27mL, 1.55 mmol, 5.4 equiv.) were added and the reaction was stirred overnight at roomtemperature. By the next day, the reaction mixture had turned red, and it was P7115PC00 79 concentrated under reduced pressure. The residue was resuspended in DCM and washed with water (x3), dried over Na2SO4and concentrated. The crude product was purified by flash column chromatography (EtOAc → 25% MeOH in EtOAc), yielding compound 7 (213 mg, 0.148 mmol, 51%) as a straw-colored oil. Scheme 6.1. Preparation of d.4

[0007] P7115PC00 80 Scheme 6.2 Synthesis of triNTA-CR3 (triNR3). P7115PC00 81 Synthesis of compound triNTA-CR3 (triNR3) (Scheme 6.2). Step 1. 4-Nitrophenyl chloroformate (90 mg, 0.45 mmol, 3.5 equiv.) was dissolved in anhydr. DCM (1 mL) under an Ar atmosphere and cooled to 0°C. DIPEA (0.05 mL, 0.3 mmol, 2 equiv.) was added to the reaction mixture. In another flask, compound 2.3 (105 mg, 0.13 mmol, 1.0 equiv.) was dissolved in anhydr. DCM (1 mL) and then added dropwise to the reaction mixture. The reaction mixture was allowed to reach roomtemperature and after 6 hours it was concentrated under reduced pressure. The crudeproduct was purified by AFCC (5% EtOAc in pentane for 3 CV (CV: column volumes),5% EtOAc → 50% EtOAc in pentane over 13 CV, 50% EtOAc in pentane for 3 CV, eluting at CV 16), yielding compound 5.3 (90 mg, 0.092 mmol, 71%) as a colorless oil.Step 2. Compound 5.3 (65 mg, 0.0066 mmol, 1.2 equiv.) was dissolved in anhydr. DCM(0.9 mL) and DIPEA (40 µL, 0.23 mmol, 4.2 equiv.) was added under an Ar atmospherewith stirring. In another flask, compound d.4 (80 mg, 0.056 mmol, 1.0 equiv.) wasdissolved in anhydr. DCM (0.8 mL) and added to the reaction mixture. HOBt (15 mg, 0.11 mmol, 2.0 equiv.) was subsequently added to the reaction. After stirring at rt for 23 hr, the reaction mixture was concentrated under reduced pressure. The crude product was purified by AFCC (80% EtOAc in pentane for 3 CV, 80% EtOAc in pentane → 100% EtOAc over 10 CV, EtOAc for 2 CV, EtOAc → 10% MeOH in EtOAc over 10 CV, elutingfrom CV 14 to CV 22), yielding compound 6.3 (46 mg, 0.055 mmol, 37%) as a colourlessoil.Step 3. Compound 6.3 (23 mg, 0.010 mmol, 1.0 equiv.) was dissolved in anhydr. DCM(1 mL) under an Ar atmosphere. Triisopropylsilane (0.11 mL, 0.54 mmol, 54 equiv.) and TFA (0.82 mL, 10.6 mmol, reaching a final v / v% concentration of 45%) was added to the solution under vigorous stirring at rt. After 8 hr, MeOH (0.2 mL) and H2O (0.1 mL) was added, and the reaction mixture was concentrated twice under reduced pressure with re-addition of DCM to remove residual TFA. The residue was triturated and washed (x3) with ice-cold Et2O. The white precipitate was dried under reduced pressure andlyophilized, yielding compound triNR3 in quantitative yields. P7115PC00 82 ResultsDeprotonated cadaverine (Compound 1.1) 1H NMR (400 MHz, CDCl3) δH(ppm) 2.69 (t, 4H, JCH2,CH26.9 Hz, CH2CH2NH2), 1.51-1.40 (m, 4H, CH2CH2NH2), 1.40-1.29 (m, 2H, CH2CH2CH2), 1.28-1.12 (bs, 4H, NH2).13C NMR (100 MHz, CDCl3) δC(ppm) 42.2 (2xCH2CH2NH2), 33.7 (2xCH2CH2NH2), 24.2 (CH2). HRMS (ESI) Calcd. for C5H14N2H+m / z 103.1230, found m / z 103.1233. Compound 1.2 Flash chromatography mobile phase: 20% MeOH, 2% NH4OH in CH2Cl2→30% MeOH, 5% NH4OH in CH2Cl2, 1 step Rf (30% MeOH+ 5% NH4OH in CH2Cl2) 0.45.1H NMR (400 MHz, MeOD) δH (ppm) 3.29 (t, 4H, JCH2,CH27.1 Hz, CH2x2), 2.76 (t, 4H, CH2x2), 1.47 (s, 9H, CH3x3).13C NMR (100 MHz, MeOD) δC (ppm) 156.3 (C=O), 79.9 (CCH3), 49.8 (CH2), 39.6 (CH2), 27.3 (CH3). HRMS (ESI) Calcd. for C9H21N3O2[Na+] m / z 226.1526, found m / z 226.1535. Flash chromatography mobile phase: 15% MeOH, 1% NH4OH in CH2Cl2→50% MeOH, 3% NH4OH in CH2Cl2, in 3 steps Rf (15% MeOH in CH2Cl2, 1% NH4OH) 0.17. P7115PC00 831H NMR (400 MHz, CDCl3) δH(ppm) 3.29-3.05 (m, 8H, 2xCH2NHCH2), 2.65 (t, 4H, JCH2,CH26.7 Hz, 2xNH2CH2), 1.71-1.54 (m, 8H, 2xNH2, 2xCH2CH2CH2), 1.45-1.41 (m, 22 H, 2xCH2CH2, 2xOC(CH3)3).13C NMR (101 MHz, CDCl3) δC(ppm) 155.7 (NCOO), 79.4 (OC(CH3)3), 46.8 (broad, CH2N), 44.5, 44.0 (CH2N), 39.5, 39.2 (CH2NH2), 32.6, 31.8 (CH2), 28.5 (CH3), 26.1, 25.6 (CH2). (Rotamers exist for this compound, therefore several peaks were observed for some carbons.) HRMS(ES) Calcd. for C20H42N4O4[H+] m / z 403.3279, found m / z 403.3286. Compound 1.4 Flash chromatography mobile phase: 10% MeOH in CH2Cl2→20% MeOH + 4% NH4OH in CH2Cl2, 3 steps Rf (10% MeOH + 2% NH4OH in CH2Cl2) 0.51.1H NMR (400 MHz, CDCl3) δH (ppm) 3.31-3.12 (m, 12H, NHCH2CH2NH+NH2CH2CH2), 2.76 (t, 4H, JCH2,CH26.2 Hz, NH2CH2), 1.65 (s, 4H, NH2), 1.40 (s, 27H, C(CH3)3).13C NMR (100 MHz, CDCl3) δC(ppm) 155.7 (C=Ox2), 155.3 (C=O), 79.9 (OC(CH3)3), 51.1 (CH2), 50.4 (CH2), 45.7 (CH2), 45.4 (CH2), 40.9 (CH2), 40.5 (CH2), 28.5 (C(CH3)3), 28.5 (C(CH3)3x2). HRMS (ESI) Calcd. for C28H47N5O6[H+] m / z 490.3600, found m / z 490.3623. Compound 2.1 Flash chromatography mobile phase: 5% MeOH, 5% NH4OH in CH2Cl2→5% MeOH, 5% NH4OH, 5% EtOH in CH2Cl2. P7115PC00 84 Rf(10% MeOH, 5% NH4OH in CH2Cl2) 0.31.1H NMR (400 MHz, CDCl3) δH(ppm) 5.35 (d, 1H, JCH,CHH4.2 Hz, C=CH), 4.69 (t, 1H, JNH,CH25.6 Hz, NHC=O), 4.53-4.04 (m, 1H, CHOCO), 3.15 (dd, 2H, Jgem13.7 Hz, CH2NH), 2.68 (t, 2H, JCH2,CH27.0 Hz, NH2CH2), 2.34 (dd, 1H, Jgem12.0 Hz, JCH2,CH3.7 Hz, CHH), 2.24 (dd, 1H, JCH2,CH2.8 Hz, CHH), 2.09-1.74 (m, 7H, Chol-H), 1.57-0.91 (m, 30H, Chol- H+NH2+(CH2)3), 0.89 (d, 3H, JCH3,CH6.4 Hz, CH3), 0.84 (d, 3H, JCH3,CH6.6 Hz, CH3), 0.84 (d, 3H, JCH3,CH6.6 Hz, CH3), 0.66 (s, 3H, CH3).13C NMR (100 MHz, CDCl3) δC(ppm) 156.3 (C=O), 139.9 (C=CH), 122.6 (C=CH), 74.2 (CHO), 56.8, 56.2, 50.1, 42.4, 42.1, 40.9, 39.8, 39.6, 38.7, 37.1, 36.3, 35.9, 33.4, 32.0, 32.0, 30.0, 28.3, 28.3, 28.1, 24.4, 24.1, 23.9, 22.9, 22.7, 21.1, 20.4, 19.4, 18.8, 12.0. HRMS (ESI) Calcd. for C33H58N2O2H+m / z 515.4572, found m / z 515.4590. Compound 2.2 Flash chromatography mobile phase: 5% MeOH, 2% NH4OH in CH2Cl2. Rf (10% MeOH+ 2% NH4OH in CH2Cl2) 0.47.1H NMR (400 MHz, CDCl3) δH (ppm) 5.77 (bs, 1H, NHH), 5.53 (bs, 1H, NHH), 5.34 (d, 1H, JCH,CHH = 1.8 Hz, CH=C), 4.56-4.39 (m, 1H, CH-O), 3.49-3.16 (m, 6H, CH2), 2.85 (bs, 2H, CH2), 2.39-2.17 (m, 2H), 2.05-1.74 (m, 6H), 1.69-0.91 (m, 32H, BOC+Chol), 0.89 (d,3H, JCH3,CH 6.5 Hz, CH3), 0.84 (m, 6H, CH3), 0.65 (s, 3H, CH3). (The integral shows ahigher number of protons present in the cholesterol-area, which originates from H2O.)13C NMR (100 MHz, MeOD) δC (ppm) 156.5 (C=Ox2), 139.9 (C=CH), 122.5 (C=CH), 80.0 (CHO), 79.8 (OC(CH3)3), 56.7, 56.2, 50.6 (CH2), 50.0, 47.7 (CH2), 42.3, 40.7 (CH2), 40.0, 39.8, 39.6, 38.6, 37.0, 36.6, 36.2, 35.8, 31.9, 31.9, 28.5 (C(CH3)3), 28.3, 28.2, 28.0, 24.3, 23.9, 22.9, 22.6, 21.1, 19.4, 18.8, 11.9. HRMS (ESI) Calcd. for C37H65N3O4[H+] m / z 616.5048, found m / z 616.5083. P7115PC00 85 Flash chromatography mobile phase: 5% MeOH, 1% NH4OH in CH2Cl2 Rf (5% MeOH in CH2Cl2, 1% NH4OH) 0.21.1H NMR (400 MHz, CDCl3) δH (ppm) 5.53 (bs, 1H, NHCOO), 5.35 (s, 1H, C=CH), 4.46 (s, 1H, CHO), 3.34-3.00 (m, 10H), 2.89-2.62 (m, 4H), 2.39-2.18 (m, 2H), 2.03-1.89 (dt, 2H), 1.89-0.76 (m, 62H, CholH, NCH2CH2CH2CH2N, 2xOC(CH3)3), 0.66 (s, 3H, CH3).13C NMR (101 MHz, CDCl3) δC (ppm) 156.2 (NCOO), 140.0 (CH=C), 122.4 (CH=C), 79.6 (OC(CH3)3), 74.1 (CHO), 70.6, 56.7, 56.1, 50.0, 46.8 (*), 46.4 (*), 43.6 (*), 42.3, 39.7, 39.5, 38.6, 37.5 (*), 37.0, 36.6, 36.2, 35.8, 31.9, 31.9 , 28.5 (OC(CH3)3), 28.2, 28.2, 28.0, 25.9 (*), 24.3, 23.8, 22.8, 22.6, 21.0, 19.3, 18.7, 11.9. (Rotamers exists for this compound, therefore several peaks were observed for some carbons.) HRMS(ES) Calcd. for C48H86N4O6[H+] m / z 815.6620, found m / z 815.6683. Peaks marked with * are broad peaks from the spermine linker caused by rotamers of the compound. Compound 2.4 Flash chromatography mobile phase: 5% MeOH, 2% NH4OH in CH2Cl2Rf (5% MeOH + 2% NH4OH in CH2Cl2) 0.32.1H NMR (400 MHz, CDCl3) δH (ppm) 5.34 (d, 1H, JCH,CHH 3.2 Hz, CH=C), 4.53-4.38 (m, 1H, CHO), 3.41-3.15 (m, 14H, CH2), 2.92-2.77 (m, 2H, CH2), 2.37-2.17 (m, 2H, CholH), P7115PC00 86 2.13-1.73 (m, 8H, CholH), 1.63-0.78 (m, 60, C(CH3)3, CholH, NH2, NH), 0.65 (s, 3H, CH3).13C NMR (100 MHz, CDCl3) δC(ppm) 155.6 (C=Ox2), 140.0 (C=CH), 122.5 (C=CH), 80.1 (CHO), 77.4 (OC(CH3)3), 74.3 (CH2), 56.8, 56.2, 50.1, 45.7 (CH2x2), 42.4, 40.7 (CH2x2), 40.1 (CH2), 39.8, 39.6, 38.7, 37.1, 36.7, 36.3, 35.9, 32.0, 32.0, 28.6 (2xC(CH3)3), 28.5 (C(CH3)3), 28.3, 28.3, 28.1, 24.4, 23.9, 22.9, 22.7, 21.1, 19.4, 18.8, 12.0. HRMS (ESI) Calcd. for C51H91N5O8[H+] m / z 902.6941, found m / z 902.6992. Compound 3.2 Flash chromatography mobile phase: 5% MeOH in CH2Cl2→20% MeOH in CH2Cl2, 4 steps Rf(7% MeOH in CH2Cl2) 0.37.1H NMR (400 MHz, MeOD + CDCl3) δH(ppm) 8.19 (d, 1H, Jortho7.8 Hz, Ar-H), 7.80 (d,1H, Jortho 7.8 Hz, Ar-H), 7.14 (d, 1H, Jortho 8.3 Hz, Ar-H), 6.73 (d, 2H, Jortho 8.8 Hz, Ar-H),6.68 (d, 2H, Jmeta2.3 Hz, Ar-H), 6.54 (dd, 2H, Jortho8.8 Hz, Jmeta2.3 Hz, Ar-H), 5.32 (d, 1H, JCH,CH23.4 Hz, C=CH), 4.45-4.33 (m, 1H, CHO), 3.79 (m, 2H, CH2), 3.54-3.46 (m, 2H, CH2), 3.38 (t, 2H, JCH2,CH25.8 Hz, CH2), 3.35 (s, 1H, NH), 3.26 (t, 2H, JCH2,CH25.8 Hz, CH2), 2.41-2.19 (m, 2H, Chol-H), 2.04-1.75 (m, 5H, Chol-H), 1.60-0.80 (m, 45H, BOC+Chol+NH+OH), 0.66 (s, 3H, CH3).13C NMR (100 MHz, MeOD + CDCl3)* δC (ppm) 170.3 (C=O), 156.6 (C=O), 153.7 (C=S),140.8 (ArC), 139.7 (C=CH), 129.5 (ArCHx3), 125.4 (ArC), 122.5 (C=CH), 119.9 (ArC), 113.9 (ArC), 111.0 (ArC), 102.7 (ArCHx6), 80.8 (CHO), 79.8 (OC(CH3)3), 77.4, 74.2, 56.6, 56.1, 50.0, 49.4, 42.2, 39.7, 39.4, 38.5, 36.9, 36.5, 36.1, 35.7, 31.8, 28.1 (C(CH3)3), 27.9, 24.2, 23.7, 22.5 , 22.3, 20.9 , 19.1, 18.5, 11.6. HRMS (ESI) Calcd. for C58H76N4O9S[H+] m / z 1005.5406, found m / z 1005.5443. * Not all aromatic C-atoms are present due to low concentration. P7115PC00 87 Compound 3.3 Flash chromatography mobile phase: 6% MeOH in CH2Cl2→50% MeOH in CH2Cl2, in 5 steps Rf(10% MeOH in CH2Cl2) 0.56.1H NMR (400 MHz, 1:1 CDCl3+ CD3OD) δH8.06 (s, 1H, ArH), 7.91-7.75 (m, 1H, ArH), 7.13 (d, 1H, Jortho8.2 Hz, ArH), 6.73 (d, 2H, Jortho8.6 Hz, ArH), 6.67 (d, 2H, Jmeta2.3 Hz, ArH), 6.52 (dd, 2H, Jortho8.8 Hz, Jmeta1.6 Hz, ArH), 5.35-5.30 (m, 1H, C=CH), 4.44-4.32 (m, 1H, CHO), 3.61 (t, 2H, JCH2,CH26.2 Hz, CH2NHCS), 3.34 (s, 1H, NH), 3.28-3.12 (m, 8H, COONCH2), 3.08 (t, 2H, JCH2,CH26.2 Hz, COONHCH2), 2.35-2.20 (m, 2H, C=CCH2CO), 2.03-0.77 (m, 66H, CholH, NCH2CH2CH2CH2N, O(CH3)3), 0.65 (s, 3H, CH3). HRMS(ES) Calcd. for C69H97N5O11S[H+] 1204.6978, found m / z 1204.7028. P7115PC00 88 Compound 3.4 Flash chromatography mobile phase: % MeOH in CH2Cl2→15% MeOH in CH2Cl2, 3 steps Rf (10% MeOH in CH2Cl2) 0.65.1H NMR (400 MHz, CDCl3 + MeOD) δH (ppm) 8.42 (m, 1H, ArH), 8.12-7.93 (m, 1H, ArH), 7.26 (d, 1H, Jortho 7.8 Hz, ArH), 7.02 (d, 2H, Jortho 8.3 Hz, ArH), 6.84 (s, 2H, ArH), 6.73 (d, 2H, Jortho 8.7 Hz, ArH), 5.49-5.41 (m, 1H, C=CH), 4.58-4.44 (m, 1H, CHO), 3.91 (s, 2H, CH2), 3.68-3.30 (m, 12H, 6xCH2), 2.49-2.30 (m, 2H, CholH), 2.17-1.85 (m, 6H, CholH+NH), 1.79-0.89 (m, 66H, C(CH3)3, CholH, NH), 0.78 (s, 3H, CH3). HRMS (ESI) Calcd. for C72H102N6O13S[H+] m / z 1291.7299, found m / z 1291.7353. Calcd. for C72H102N6O13S[H+Na+] m / z 657.3596, found m / z 657.3581. Calcd. for C72H102N6O13S[H+K+] m / z 665.3465, found m / z 665.3418. CR1. P7115PC00 89 Flash chromatography mobile phase: 2 sequential purificaitons.1st: 7% MeOH→12%MeOH + 1% NH4OH in CH2Cl2, 3 steps; 2nd: 10% MeOH→50% MeOH in CH2Cl2, 5steps Rf(10% MeOH in CH2Cl2) 0.49.1H NMR (400 MHz, 1:1 CD3OD / CDCl3) δH(ppm) 8.23 (s, 1H, ArH), 8.04 (d, 1H, ArH), 7.35 (d, 1H, ArH), 7.17 (d, 2H, ArH), 6.93-6.74 (m, 4H, ArH), 5.58-5.52 (m, 1H, C=CH), 4.69-4.54 (m, 1H, CHO), 3.88-3.77 (m, 1H, CH), 3.57 (s, 1H, CH), 3.33 (t, 2H, CH2), 2.58- 2.42 (m, 2H), 2.27-1.97 (m, 5H), 1.94-1.00 (m, 44H), 0.88 (s, 3H, CH3). HRMS (ESI) Calcd. for C54H69N3O7S[H+] m / z 904.4929, found m / z 904.4952. CR2. 1H NMR (400 MHz, CDCl3) δH (ppm) 8.19 (d, 1H, Jmeta 1.4 Hz, ArH), 7.90 (dd, 1H, Jortho 8.4 Hz, Jmeta 1.4 Hz, ArH), 7.22 (d, 1H, Jortho 8.4 Hz, ArH), 6.79-6.72 (m, 4H, ArH), 6.62 (m, 2H, ArH), 5.49 s, 1H, NH), 5.31 (d, 1H, JCH,CHH 4.3 Hz, CH=C), 4.43 (tt, 1H, Ja,e 4.6Hz, Ja,a = 11.3 Hz, CHO), 4.03 (t, 2H, JCH2,CH25.3 Hz, CH2), 3.44 (t, 2H, JCH2,CH25.2 Hz,CH2), 3.37 (t, 2H, JCH2,CH25.3 Hz, CH2), 3.35 (s, 1H, NH), 3.23 (t, 2H, JCH2,CH25.2 Hz, CH2), 2.41-2.23 (m, 2H, CholH), 2.04-1.74 (m, 5H, CholH), 1.63-0.77 (m, 37H, CholH), 0.68 (s, 3H, CH3). HRMS (ESI) Calcd. for C53H68N4O7S[H+] m / z 905.4882, found m / z 905.4904. P7115PC00 90 CR3. Rf (9:1 CH2Cl2 / MeOH) 0.24.1H NMR (400 MHz, MeOD) δH 8.19 (d, 1H, Jmeta 1.6 Hz, ArH), 7.71 (dd, 1H, J = 7.7 Hz,Jmeta 1.8 Hz, ArH), 7.17 (d, 1H, Jortho 8.3 Hz, ArH), 6.69 (d, 2H, Jmeta 2.3 Hz, ArH), 6.67 (d, 2H, Jortho 8.9 Hz, ArH), 6.54 (dd, 2H, Jmeta 2.3, Jortho 8.7 Hz, ArH), 5.35 (m, 1H, C=CH), 4.44-4.32 (m, 1H, CHO), 3.82 (t, 2H, JCH2,CH26.1 Hz, CH2NHCS), 3.34 (s, 4H, NH), 3.24- 2.97 (m, 10H, CH2), 2.31 (m, 2H, C=CCH2CO), 2.10-0.83 (m, 46H, CholH, CH2), 0.70 (s, 3H, CH3). HRMS(ES) Calcd. for C59H81N5O7S[2H+] m / z 502.8001, found m / z 502.7996. Calcd. for C59H81N5O7S[H+] m / z 1004.5930, found m / z 1004.4964. CR4 Rf(10% MeOH in CH2Cl2) 0.31.1H NMR (400 MHz, MeOD) δH(ppm) 8.36 (d, 1H, Jmeta1.8 Hz, ArH), 7.87 (dd, 1H, Jortho8.2 Hz, Jmeta1.8 Hz, ArH), 7.24 (d, 1H, Jortho8.2 Hz, ArH), 6.98-6.81 (m, 4H, ArH), 6.74 (dd, 2H, Jortho8.8 Hz, Jmeta2.2 Hz, ArH), 5.49 (s, 1H, NH), 5.36 (d, 1H, JCH,CH4.57 Hz, C=CH), 4.40 (tt, 1H, Ja,a10.7 Hz, Ja,e4.9 Hz, CHO), 4.08 (t, 2H, JCH2,CH25.8 Hz, CH2), 3.98 (s, 1H, NH), 3.55 (t, 2H, CH2), 3.51 (m, 11H, CH2+NH), 3.34 (s, 3H, NH), 3.23 (t, 2H, CH2), 2.38-2.22 (m, 2H, CholH), 2.06-1.79 (m, 6H, CholH), 1.66-0.91 (m, 34H, P7115PC00 91 CholH), 0.87 (d, 3H, JCH3,CH6.6 Hz, CH3), 0.87 (d, 3H, JCH3,CH6.6 Hz, CH3), 0.70 (s, 3H, CH3). HRMS (ESI) Calcd. for C57H78N6O7S[H+] m / z 991.5726, found m / z 991.5756. Calcd. for C57H78N6O7S[2H+] m / z 496.2899, found m / z 496.2900. R1. R1 was prepared as previously described in literature (Monge et al.2020). Compound d.1 Rf (5% EtOAc in pentane) 0.21.1H NMR (400 MHz, CDCl3) δH (ppm) 7.36-7.30 (m, 5H, Ar-H), 5.11 (s, 2H, PhCH2O-),3.44 (s, 4H, 2 x -NCH2COO-), 3.37 (dd, J = 10.0, 5.5 Hz, 1H, -CHCOO-), 2.74-2.55 (m, 2H, BnOOCCH2CH2-), 2.05-1.86 (m, 2H, BnOOCCH2CH2-), 1.45 (s, 9H, -OC(CH3)3), 1.43 (s, 18H, 2 x -OC(CH3)3).13C NMR (101 MHz, CDCl3) δC (ppm) 173.6 (BnOOC-), 171.9 (-NCHCOO-), 170.6 (2 x -NCH2COO-), 136.3, 128.6, 128.3, 128.2 (Ar C), 81.4, 80.8 (-OC(CH3)3), 66.2 (- P7115PC00 92 NCHCOO-), 64.4 (PhCH2O-), 53.9 (2 x -NCH2COO-), 30.7 (-CH2-), 28.3 (3 x -CH3), 28.2 (6 x -CH3), 25.5 (-CH2-). HRMS(ES): calcd. for C28H44NO8+: 522.3061; found: 522.3081. calcd. for C28H43NO8Na+: 544.2881; found: 544.2896. Compound d.2 Rf(50% EtOAc in pentane) 0.41.1H NMR (400 MHz, CDCl3) δH(ppm) 3.45 (s, 4H, 2 x -NCH2COO-), 3.37 (dd, J = 10.0, 5.5 Hz, 1H, -CHCOO-), 2.74-2.58 (m, 2H, HOOCCH2CH2-), 2.06-1.86 (m, 2H, HOOCCH2CH2-), 1.46-1.45 (2 x s, 27H, 3 x -OC(CH3)3).13C NMR (101 MHz, CDCl3) δC (ppm) 177.4 (HOOC-), 171.5 (-NCHCOO-), 170.7 (2 x -NCH2COO-), 81.8, 81.3 (-OC(CH3)3), 64.7 (-NCHCOO-), 54.1 (2 x -NCH2COO-), 31.1 (- CH2-), 28.3 (3 x -CH3), 28.2 (6 x -CH3), 25.4 (-CH2-). HRMS(ES): calcd. for C21H38NO8+: 432.2592; found: 432.2599. calcd. for C21H37NO8Na+: 454.2411; found: 454.2430. Compound 4.2 Rf(50% EtOAc in pentane) 0.37. P7115PC00 931H NMR (400 MHz, CDCl3) δH (ppm) 6.99 (d, 1H, -CONH-), 5.36 (s, 1H, -C=CH-), 5.23(d, 1H, -NHCOO-), 4.46 (bs, 1H, -CHO-), 3.41-3.30 (m, 11H, 2 x -OCONCH2-, -OCONHCH2-, 2 x -NCH2COO-, -CHCOO), 3.46-2.27 (m, 4H, -HNOCCH2CH2-,C=CCH2CO-), 2.04-1.81 (m, 8H, -HNOCCH2CH2-, cholesteryl protons), 1.59-0.84 (m,70H, cholesteryl protons, 4 x -O(CH3)3), 0.66 (s, 3H, cholesteryl -CH3).13C NMR (101 MHz, CDCl3) δC(ppm) 173.6 (-NHCO-), 171.9 (-NCHCOO-), 170.9 (2 x - NCH2COO-), 156.6 (bs, -NCOO-), 140.0 (-CH=C-), 122.5 (-CH=C-), 81.1, 80.7, 80.3 (- OC(CH3)3), 74.3 (-CHO-), 64.9 (-NCHCOO-), 56.8, 56.2, 54.4, 50.1, 47.2(*), 42.4, 39.9, 39.6, 38.7, 37.1, 36.7, 36.3, 35.9, 32.8, 32.0, 28.5 (3 x -CH3), 28.4, 28.3 (3 x -CH3), 28.2 (6 x -CH3), 28.1, 26.4, 24.4, 23.9, 23.0, 22.7, 21.2, 19.5, 18.8, 12.0.HRMS(ES): calcd. for C58H101N4O11+: 1029.7461; found: 1029.7515. calcd. forC58H100N4O11Na+: 1051.7281; found: 1051.7339. Peaks marked with (*) are broad peaks that split up due to rotamers of the BOC-group. HPLC: tr (4.2): 23.3 min Compound 4.3 Rf(40% EtOAc in pentane) 0.27.1H NMR (400 MHz, CDCl3) δH(ppm) 5.35 (bs, 1H, CH=C), 4.46 (bs, 1H, CH-O), 3.43- 3.12 (m, 17H, 7 x N-CH2, N-CH), 2.47-1.81 (m, 13H), 1.66-0.83 (m, 87H), 0.66 (s, 3H, CH3).13C NMR (101 MHz, CDCl3) δC (ppm) 173.3 (C(=O)N), 171.8 (C(=O)O), 170.8 (C(=O)O), 156.4 (NHC(=O)O), 140.2 (C=CH), 122.4 (C=CH), 81.6, 81.1, 79.5, 74.1, 65.0, 56.8, 56.2, 54.4, 50.1, 46.9, 44.2, 42.4, 39.8, 39.6, 38.7, 37.1, 36.7, 36.3, 35.9, 32.8, 32.0, 28.6, 28.3, 28.3, 28.2, 28.1, 26.5, 24.4, 23.9, 22.9, 22.7, 21.1, 19.4, 18.8, 12.0. HRMS(ES): calcd. for C69H122N5O13+H+: 1228.9034; found: 1228.9086. calcd. for C69H122N5O13+Na+: 1250.8853; found: 1250.8900 P7115PC00 94 Compound 5.3 Rf (30% EtOAc in pentane) 0.26.1H NMR (400 MHz, CDCl3) δH(ppm) 8.23 (d, J = 9.2 Hz, 2H, Ar-H), 7.32 (d, J = 9.2 Hz, 2H, Ar-H), 6.57 (bs, 1H, C(=O)NH), 5.48 (bs, 1H, C(=O)NH), 5.36 (bs, 1H, CH=C), 4.47 (bs, 1H, CH-O), 3.35-3.15 (m, 12H, 6 x N-CH2), 2.37-2.26 (m, 2H, CH2-CH=C), 2.04-0.85 (m, 64H, cholesteryl H), 0.67 (s, 3H, CH3).13C NMR (101 MHz, CDCl3) δC (ppm) 156.4 (NHC(=O)O), 153.4 (NHC(=O)O), 144.6 (C=CH), 125.2 (Ar C), 122.5 (C=CH), 122.1 (Ar C), 80.1 (OC(CH3)3), 74.3 (CH-O), 56.8, 56.2, 50.1, 46.9, 43.2, 42.4, 39.8, 39.6, 38.7, 37.6, 37.1, 36.7, 36.3, 35.9, 32.0, 32.0, 28.6 (OC(CH3)3), 28.4, 28.3, 28.1, 24.4, 23.9, 23.0, 22.7, 21.2, 19.5, 18.8, 12.0. HRMS(ES): calcd. for C55H89N5O9+H+: 980.6683; found: 980.6685

[0008] P7115PC00 95 Compound 6.3 Rf (EtOAc) 0.30.1H NMR (400 MHz, CDCl3) δH (ppm) 6.17 (bs, 1H, C(=O)NH), 6.17 (bs, 1H, C(=O)NH), 5.61 (bs, 1H, C(=O)NH), 5.34 (bs, 1H, CH=C), 4.46 (bs, 1H, CH-O), 3.67-2.56 (m, 46H), 2.34-2.25 (m, 3H), 2.09-0.84 (m, 157H), 0.66 (s, 3H, CH3).13C NMR (101 MHz, CDCl3) (broad peaks were observed for some carbons and somepeaks were missing because of being too low intensity). δC (ppm) 172.2-172.1 (m, C=O),170.7-170.5 (m, C=O), 156.4 (bs, C=O), 155.7 (bs, C=O), 81.1-80.4 (m, C(CH3)3), 64.5 (m, OOC-CH-N), 56.8, 56.2, 53.8-53.5 (m), 50.1, 46.9 (bs), 42.4, 39.8, 39.6, 38.7, 37.1, 36.7, 36.3, 35.9, 32.0 (m), 29.8, 29.5, 28.6-28.1 (m, C(CH3)3), 24.4, 23.9, 23.0, 22.8, 22.7, 21.1, 19.5, 18.8, 14.3, 12.0. HRMS(ES): calcd. for C122H213N11O28+2H+: 1141.7881; found: 1141.7857. calcd. for C122H213N11O28+H++Na+: 1152.7790; found: 1152.7759. calcd. for C122H213N11O28+2Na+: 1163.7700; found: 1163.7675.

[0009] P7115PC00 96monoNTA-CR2 (NR2). 1H NMR (400 MHz, CDCl3 / MeOD) δH(ppm) 8.26 (s, 0.69H, CH3COOH) 5.32 (s, 1H, CH=C), 4.04 (bs, 3H), 3.63-3.56 (m, 3H), 3.25-2.83 (m, 12H), 2.42-2.27 (m, 3H), 2.06- 1.81 (m, 13H), 1.53-0.82 (m, 35H), 0.65 (s, 3H, CH3). HRMS(ES): calcd. for C47H81N5O9+H+: 860.6107; found: 860.6136. calcd. for C47H81N5O9+2H+: 430.8090; found: 430.8101.

[0010] P7115PC00 97 triNTA-CR3 (triNR3) 1H NMR (400 MHz, DMSO-d6) δH(ppm) 9.37-7.74 (m, 5H, exchangeable with D2O, - COOH), 7.38-7.05 (m, 1H, exchangeable with D2O, C(=O)NH), 6.72-6.52 (m, 1H, exchangeable with D2O, C(=O)NH), 5.33 (bs, 1H, CH=C), 4.31 (bs, 1H, CH-O), 3.76- 2.73 (m, 35H*, 10 x CH2-NC(=O), 6 x N-CH2-COO, 3 x N-CH-COO), 2.40-0.69 (m, 74H), 0.65 (s, 3H, CH3). (*: A broad water peak at 3.42 ppm overlaps with the protons in this region, making precise integration not possible. The integral is estimated by integrating around the broad water peak, to obtain an approximate estimate of the integral). HRMS(ES): calcd. for C76H124N11O24-: 1574.8826; found: 1574.8828. calcd. for C76H123N11O242-: 786.9376; found: 786.9420. calcd. for C76H123N11O242-+ Na+: 1596.8645; found: 1596.8685.

[0011] P7115PC00 98 Maleimide-vc-MMAF. 1H NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 8.09 (d, J = 7.5 Hz, 1H), 7.81 (d, J = 8.5Hz, 1H), 7.58 (d, J = 7.6 Hz, 2H), 7.39–7.10 (m, 8H), 7.00 (s, 2H), 5.07–2.83 (m, 68H),2.19–0.75 (m, 68H).HRMS (ESI+) m / z calculated (calcd.) for C68H103N11O16 + K+: 1368,7532; found:1368,7126, calcd. for C68H103N11O16 + H++ K+: 684.8802; found: 684.8594 Conclusion Compounds according to the present disclosure were prepared and characterized. Example 2: Incorporation of synthetic receptors into cells AimTo demonstrate the ability of the cholesteryl carbamate synthetic receptors to beincorporated into cells. Materials and Methods Anti-fluorescein antibody (antiFITC) was purchased from ThermoFisher, Invitrogen cat.no 31242. Fluorescence microscopy was conducted on a Zeiss Observer.Z1 with a Plan- Achromat M27 objective (63x / 1.4 oil). Exposure time and gain were kept constant for all samples in each experiment. P7115PC00 99To MOLT-4 cells (4x105 cells / mL) in complete media was added CR1-CR4 (10 µM, from5 mM DMSO stocks) with a final DMSO content of 0.2%. To control cells only DMSO was added. The cells were incubated for 2 h at 37⁰C, 5% CO2, before the cells werewashed (2x, cold PBS / cold PBS + 2% FBS) and divided into two groups. To one-halfwas added antiFITC antibody (0.5 µM, in PBS with 2% FBS), which were kept on ice until visualization. The other half of the samples were stained with Hoechst (1:2000 in PBS) and incubated at room temperature for 15 min, before they were washed (2x, cold PBS + 2% FBS) and kept on ice until imaged on the Fluorescence Microscope. Results The results show that fluorescence from FITC can be observed on the cells (Figure 1A,top line). The addition of anti-fluorescein antibody (antiFITC) under 4 °C quenches thefluorescence of fluorescein only at the cell surface, as internalization is halted at those temperatures. Observation of non-quenched fluorescence inside the cells after antiFITC treatment (Figure 1A, bottom line) confirms the internalization of the compounds into intracellular compartments. Conclusion The compounds according to the present disclosure are able to incorporate into to the cell surface and internalize into the intracellular compartments.Example 3: Receptor-mediated internalization of anti-FITC antibody-drug conjugateand subsequent drug release AimTo demonstrate the ability of the cholesteryl carbamate synthetic compounds to act asreceptor mimics and to promote receptor-mediated endocytosis of extracellular proteins.Materials and MethodsAbbreviations. MMAF is the tubulin inhibitor cytotoxic compound Monomethyl AuristatinF. TCEP: tris(2-carboxyethyl)phosphine. DMSO: dimethylsulfoxide. PBS: phosphate buffered saline. ADC: antibody-drug conjugate. P7115PC00 100Fluorescence measurements. Were performed on a BioTek Synergy H1 microplatereader with hybrid monochromatic-based optics and filter-based optics. ADC preparation. AntiFITC antibody was buffer exchanged to PBS buffer (50 mM, 1 mM EDTA, pH 6) to a final protein concentration of >3 mg / mL. TCEP (stock 10 g / L, 100 eq.) was added to the AntiFITC antibody and the reaction mixture was incubated for 2 h at 20 °C. Subsequently, the reduced antibody was cooled to 4 °C before maleimide-vc- MMAF (5 g / L DMSO stock, 50 eq.) was added to the solution. The conjugation was incubated 3 h at 20 °C, before it was filtered and concurrently buffer exchanged to PBS(50 mM, pH 7.4) using an Amicon centrifugation spin filter (regenerated cellulose, 30 kDacutoff). Next, the sample was purified using a NAP5 column (Sephadex G-25 DNA grade). The ADC solution was concentrated using an Amicon filter (regenerated cellulose, 30 kDa cutoff) and the final ADC concentration was determined using UV-VIS λmax280 nm. The DAR was determined by MALDI-TOF spectrometry to be 2. The ADC thus comprises the cytotoxic drug MMAF conjugated to the antiFITC via a protease-sensitive linker (valine-citrulline).Cell viability. Cell viability was measured using PrestoBlue® cell assay according tomanufacturer instructions. Briefly, PrestoBlue reagent was added to the cell media in a 1:10 dilution and incubated for 1 h at 37⁰C, 5% CO2 before the samples were moved toa black bottom 96-well plate and measured on the Plate Reader (^^^554 / ^^^590). Cellviability is calculated as the % of fluorescence intensity between samples and negative controls.Dose-response curves. Cell viability data were prepared by making an average of thetechnical replicates, subtracting the background (media only) from the raw data and normalizing to the independent viability control. The viability was then plotted as a function of the logarithm of the concentration. The independent IC50 values were estimated by fitting them to a non-linear regression, sigmoidal curve (four parameters, variable slope).Test. To MOLT-4 cells (3x105 cells / mL) in complete media was added CR1-CR4 (10 µM,from 5mM DMSO stocks) with a final DMSO content of 0.2%. To control cells only DMSO was added. The cells were incubated for 2 h at 37⁰C, 5% CO2, before all samples werewashed (1x, PBS) and resuspended in complete media (2.2x105 cells / mL). A dilutionseries of the ADC described above (payload: MMAF) was (prepared in PBS) added to P7115PC00 101 the samples and the cells were incubated for 72 h at 37⁰C, 5% CO2. At that time, cellviability was calculated as using the PrestoBlue® assay as described above. Theexperiment was run in triplicates, with three independent experiments (n = 3, N =3).Effect of time. Compounds CR1-CR4 were added to MOLT-4 cells as described above,followed by two times washing to remove the excess compound, and then cells wereresuspended in media. To a the first group of samples, ADC (prepared as describedabove, payload: MMAF) was added at that time to achieve a final ADC concentration of10 or 150 nM. To a second group of samples, ADC was added after incubation for an additional 24 h to achieve a final concentration of 10 or 150 nM. Cells were incubated for72 h upon which viability was measured using the PrestoBlue® assay as describedabove (n=2, N=3).The experiment to study the effect of time was repeated as described above withreceptors R1 (compound from Monge et al.), CR1-CR4 in three independentexperiments. Results As shown in the dose-response curves in Figure 2, all compounds facilitated theinternalization of the ADC and degradation of the linker to release the cytotoxic drugMMAF. Samples containing compounds CR1-CR4 and ADC demonstrated an IC50 in therange of 3 to 15 nM. In contrast, samples treated with MMAF (the free payload of theADC) demonstrated an IC50 of 464 nM, which is two orders of magnitude higher than samples containing only MMAF (the payload of the ADC). MMAF is a molecule with low membrane permeability (Doronina et al.), however, once it is internalized it exhibits cytotoxicity with high potency. Thus, this data demonstrates thatcompounds CR1-CR4 produce receptor-mediated internalization of the ADC. Uponinternalization, the ADC is degraded in the intracellular compartments to release MMAFby proteolytic cleavage of the ADC linker – thereby exhibiting potent cytotoxic effects.Samples treated only with ADC did not demonstrate any decrease in cell viability,indicating that compounds CR1-CR4 were the mediators of the internalization andcytotoxic effects of the ADC. The time-resolved experiment demonstrated that compounds CR2-CR4, all of whichcomprise a secondary amine in the linker, enhance the functional internalization of theADC compared to compound CR1, which has no amine in the linker. As shown in Figure P7115PC00 1023, compound CR1 produced a minor decrease in viability than compounds CR2-CR4when targeted with the ADC immediately after incorporation of the compounds (Figure3A). When the ADC was added to the cells after 24 hours, the CR1 group did notdemonstrate toxicity, while the CR2-CR4 groups demonstrated higher cytotoxicity inunder the same conditions (Figure 3B).As shown in Figure 4B, CR2-CR4 showed under the same conditions improved effectscompared to R1, a cholesterylamine receptor disclosed in Monge et al. Conclusion Compounds according to the present disclosure are able to promote receptor-mediated endocytosis and degradation of extracellular target molecules. The presence of amines in the linker increases the efficiency of receptor-mediated internalization. Example 4: Depletion of extracellular IgG using synthetic receptors in HepG2 cells. Aim To demonstrate the ability of the cholesteryl carbamate compounds of the present disclosure to act as receptor mimics and to promote receptor-mediated endocytosis of extracellular proteins in hepatic cell lines. Materials and methodsTest. HepG2 cells were seeded in a 96-well plate at the 104 cells / well, and cultivated for72 hours at 37 ^C and 5% CO2. Complete media was renewed and 10µM synthetic r wasadded from a 100 µM stock (final DMSO % = 0.2), control cells received equivalent DMSO only. The samples were incubated for 2 hours at 37 ^C and 5% CO2 and washedtwice in PBS. Cy-5 labelled Mouse IgG1 monoclonal antiFITC antibody was added to afinal concentration of 200 nM, 0.03 g / L (unless otherwise stated). All samples were mixed well and extracellular media samples were taken out and different time points. The IgG1content was quantified using a commercial Mouse IgG1 ELISA kit (Thermofisher, REF.:88-50410-22). Results The results are shown in Figure 5, demonstrating depletion of IgG from the extracellularmedium in samples treated with receptors CR2-CR3 in HepG2 cells. Under theseconditions, compound CR3 produced a stronger statistically significant effect compared P7115PC00 103to control (no receptor) in comparison to the effect of R1 compared to control (noreceptor). ConclusionThe synthetic receptors can be used for selective capture and elimination ofextracellular target proteins in hepatocytes. Example 5: Effect of the presence of LDL AimInvestigating the effect of the presence of LDL in the performance of syntheticreceptors. Materials and MethodsPreparation of LDL-bound receptor samples. CR1-CR4 and R1 (from DMSO stock,5 mM) were mixed with LDL (Sigma Aldrich, LP2-2MG, 4.96 mg / mL stock, lot no.:4025970 or 4055454) to a final concentration of 382 μM receptor and 4.6 mg / mL LDL. For the control, the corresponding receptors were mixed with PBS. The samples wereincubated for 2 h at 37 oC, before the sample containing LDL was purified by CentriPureMINI spin Desalt Z-25 columns. The receptor / LDL ratio was determined before and after purification by UV-VIS at 280 nm and 490 nm. If the samples were prepared in advance, the purified samples were stored at 4⁰C in the dark until administration.Administration of receptors with LDL to HEPG2 cells and protein capture. HepG2cells were seeded in a 96-well plate (25.000 cells / well or 5.000 cells / well) and incubated for 24 or 72 h, respectively. The media was exchanged with media containing CR1-CR4and R1 with and without LDL (final concentration was estimated based on UV-VIS at 280nm and 490 nm before and after SEC purification). To control cells were added DMSO in PBS (final DMSO concentration approx.0.2 %). The cells were incubated for 2 h at 37⁰C and 5% CO2 before they were washed (2x PBS) and detached with trypsin (0.025%, 25-30 μL for 5 min at 37⁰C, 5% CO2). For the rest of the preparation, the cells were kept at 4oC. The media was exchanged with cold PBS + 2% FBS containing 0.5 μM antiFITC- Ab and 1 μg / mL PI stain. The cells were incubated on ice for 30 min before being measured on the Quanteon flow cytometer. P7115PC00 104 Estimated concentrations of compounds in experiments: The experiment for selective protein capture in HepG2 cells was carried out as describedin Example 4, with the only change being that the + LDL samples received receptor incombination with LDL particles.% in surface. HepG2 cells were seeded in a 96-well plate (25.000 cells / well or 5.000cells / well) and incubated for 24 or 72 h, respectively. The media was exchanged withmedia containing CR1-CR4 and R1 with and without LDL (final concentration wasestimated based on UV-VIS at 280 nm and 490 nm before and after SEC purification. To control cells were added DMSO in PBS (final DMSO concentration approx.0.2 %). The cells were incubated for 2 h at 37 ⁰C and 5% CO2before they were washed (2x PBS) and detached with trypsin (0.025%, 25-30 μL for 5 min at 37 ⁰C, 5% CO2). For the rest of the preparation, the cells were kept at 4oC. The media was exchanged with cold PBS + 2% FBS containing 0.5 μM antiFITC-Ab and 1 μg / mL PI stain. The cells were incubatedon ice for 30 min before being measured on the Quanteon flow cytometer. The % ofsurface receptors was estimated by the percentage of quenched fluorescence in thesamples where antiFITC-Ab was added. Results For all compounds it was shown that the presence of LDL did not impede theincorporation onto the cells. The cell’s fluorescence was significantly higher when thesynthetic receptor molecules were administered onto cells in their complexes with LDL,compared to the administration of receptors without LDL. In addition, a high fraction ofthe fluorescence could be quenched by the antiFITCantibody, which means that asignificant fraction of the compounds was localized at the cell surface, and this fractionwas very similar regardless of incorporation with or without LDL particles (Figure 6A,B). P7115PC00 105An additional study of protein depletion mediated by CR2 and CR3 showed that themolecules were equally well suited for antibody capture and removal upon incorporation with or without LDL (Figure 6C). Conclusion Compounds of the present disclosure can be incorporated into cells and used for proteincapture in the presence of LDL. This is important for the prospect of in vivo use of thesecompounds for capturing extracellular target molecules. This result is also important for the targeting of liver and liver cells for delivery of payloads in vivo. Example 6: Depletion of proteins over multiple rounds of extracellular protein addition Aim To study the ability of the receptor to capture extracellular target molecules over several rounds of exposure. Materials and MethodsThe experiment for selective protein capture in HepG2 cells was carried out as describedin Example 4. Receptor CR3 was used and starting concentration of the IgG was 20 nM.After 24 hours of incubation, samples were taken out for IgG content analysis and thecomplete media was removed and fresh media having 20 nM of IgG was added again.After an additional 24 hours, samples were taken out for IgG content analysis using the commercial Mouse IgG1 ELISA Kit (Thermofisher, REF.: 88-50410-22). Results The results show that the compound allows for the capture and elimination of the targetprotein over multiple rounds (Figure 7). The second round of selective protein removalwas as efficacious as the 1stround. Conclusion Compounds according to the present disclosure allow for elimination of target proteins over multiple rounds of exposure. P7115PC00 106 Example 7: Co-localization study of anti-FITC Ab and lysosome tracker. Materials and MethodsCy-5 IgG preparation. Monoclonal AntiFITC antibody (Sigma REF: A16068, LOT: 70-118-121719) was buffer exchanged to a 0.1 M Sodium Bicarbonate buffer pH 8.3 using an Amicon® spin filter (cutoff 10kDa). The antibody concentration was determined using UV-vis (A280). Cyanine 5 (Cy-5) NHS Ester (Thermofisher Scientific, REF: A37574) was dissolved in DMSO to 5 g / L and added to the antibody solution in an excess of 10 molarequivalents. The reaction was left at room temperature for 1 hour with gentle shaking(800 rpm). The Cy-5 labeled antibody was purified and the buffer was exchanged to a50 mM PBS pH 7.4 using an Amicon® Ultra centrifugation filter (Regenerated Cellulose,10kDa cutoff). The final protein concentration and the DOL were determined with UV-vis(A280 and A491) measurements. The DOL for Cy-5 AntiFITC antibody was estimated to be1,5. HepG2 cells were seeded at 1x104cells / mL in a ibidi® µ-Slide 8 well high plate and incubated for 72 h at 37°C, 5% CO2 until cells were 70 % confluent. Fresh media wasadded to the cells with or without 10 µM CR3 from a 5 mM stock in DMSO. The cellswere then incubated for 2 h at 37°C, 5% CO2, and washed twice in Hanks’ Balanced Salt Solution (HBSS) (Sigma, ref.: H264) before complete cell media containing 200 nM ofthe cy-5 labeled anti-FITC-Ab from a PBS stock and / or 75 nM Lysotracker Blue DND22(Invitrogen, ref.: L7525) and incubated for 2 h 37°C, 5% CO2. All samples were washed three times in HBSS before 100 µL live imaging cell solution (thermofisher, ref.: A59688DJ) was added including a 1:100 dilution of prolong Live Antifade Reagent, for live cell imaging (Thermofisher, ref.: P36975). Single stain controls were included as well. Images were conducted on a Zeiss CLSM 800. Confocal imaging was performed using a CLSM 800 inverted laser scanning confocal microscope (Zeiss, Oberkochen) with a GaAsP detector. A PlanApochromat 63x / 1.4 oil DIC objective was used. Lysotrackerblue-DND-22 was excited using the 405 nm diode laser line at 2.0 % intensity and detected at 400 nm to 640 nm wavelengths. Cyanine5 was excited using the 640 nm diode laser at 0.05 % and detected at 650 nm to 700 nm wavelengths. Images were obtained using the ZEN black, Zeiss, Oberkochen Germany, and data processing was performed using Zeiss Zen 3.2, Blue edition. P7115PC00 107 Results The results are displayed in Figure 8. It can be seen that the fluorescent signal of the anti-FITC antibody (target protein) and of the lysotracker channel overlay in the samespots. This demonstrates a clear co-localization of the internalized protein and thelysotracker, confirming the lysosomal location of the internalized target protein. Conclusion The compounds of the present disclosure mediate protein internalization into the degrading lysosomal compartments. Example 8: Cytotoxicity screen for nitrilotriacetic acid (NTA) cholesteryl carbamate receptors Aim To test the in vitro toxicity of NTA-cholesteryl carbamate receptors. Materials and MethodsStock solutions. Solutions of receptors monoNTA-CR2 (NR2) (8.53 mM) andmonoNTA-CR3 (NR3) (15 mM) in a 1:1 MeOH:CHCl3 mixture were prepared. Thesolutions were sonicated for 45 min until completely dissolved. A stock of methyl-^-cyclodextrin (Sigma, Ref.: C4555) was prepared in 20 mM HEPES pH 7.4 to a concentration of 50 g / L in a 5 mL pointy glass vial. The vial containing the cyclodextrin solution was heated to 80°C under stirring before the receptor-NTA solution was addedusing a Hamilton pipette. The heat was then turned off and the solution was cooled downunder stirring. The final concentration of the NR2 and NR3 stocks with 1:10 cyclodextrinwere 1.54 and 2.75 mM respectively. The stocks were aliquoted and stored in the freezer. The triNTRA-CR3 receptor (triNR3) receptor was dissolved in DMSO at a final concentration of 5 mM and stored as aliquots at -20 °C. Right before use, the triNR3 stocks were unfrozen and mixed in 1:10 with Methyl-^-cyclodextrin (Sigma, Ref.: C4555)in PBS and diluted in media to the final concentration (10 µM) which was added directlyto the cells. Cytotoxicity screen. HepG2 cells were seeded at 104cells / well in a Nunc delta-treated 96-well plate and cultivated for 72 h at 37°C, 5% CO2until 70 % confluence. Completemedia was renewed, and NR2, NR3 or triNR3 was added in a final concentration of 10 P7115PC00 108 µM from the 1:10 cyclodextrin stocks (see preparation above). The cells were incubated for 2 h at 37°C, 5% CO2, and washed twice in DPBS before media containing 100 µM NiCl2, CoCl2, MgCl2, and ZnCl2was added from 2.5 mM stocks in MiliQ water. The samples were incubated for 72 h at 37°C, 5% CO2and the cell viability was assayed using presto blue assay® according to the commercial protocol. Positive control received no receptor, while a negative (death CNTRL) control was cells receiving DMSO (37 %), and media only was used for background subtraction. The data was plotted relative to the positive cell-only sample representing 100 % viability. The data was reproduced in three independent replicates with technical triplicates and represented as mean ± standard deviation. ResultsThe results are shown in Figure 9. No significant changes in cell viability were observedin the presence of NR2, NR3, or triNR3 receptors alone nor when they were combinedwith the divalent metal cations Ni2+, Zn2+, Co2+and Mg2+. ConclusionThere were no observed signs of cytotoxicity of the NTA-cholesteryl carbamate receptorscaffold or divalent metal ions.Example 9: Cellular internalization of oligohistidine-labelled proteins mediated by NTA-cholesteryl carbamate receptors. Materials and Methods HepG2 cells were seeded at 1x104cells / well in a nunc delta-treated 96-well U-bottom plate and incubated at 37°C, 5% CO2 until cells were 70% confluent. Fresh media wasadded to the cells with or without 10 µM NR2, NR3 from stock with cyclodextrins (seeExample 8). The cells were then incubated for 2 h at 37°C, 5% CO2, and washed twice with PBS. Complete cell media containing 100 nM of oligohistidine-labelled redfluorescence protein (RFP-His6) (Abcam, ref.: ab268931) was added to the cells, alonga final concentration of 100 µM NiCl2, CoCl2, MgCl2, or ZnCl2 from a 2.500 mM stock in MiliQ water. The cells were then incubated for 2 h at 37°C, 5% CO2, washed twice with DPBS, and stained Near-IR live / dead stain (Thermofisher, Ref.: L34975) for 20 min. at room temperature. The cells were then washed one time in DPBS, and trypsinated using 0.25 mM trypsin with EDTA. The unattached cells were then spun down (300 g 5 min.) and dissolved in DPBS with 2 % FBS before being analyzed using a quanteon flow P7115PC00 109 cytometer. Live cells were gated based on near-IR live / dead stain and the fluorescence of RFP was monitored using the 561 nm laser for excitation and emission filter 586 / 20. A similar test was performed using oligohistidine-labelled green fluorescent protein(GFP-His6 (Thermofisher, ref.: A42613)) to test internalization mediated by NR2, NR3 ortriNR3. The conditions were the same as above, but GFP-His6 was added at 1.4 µM tothe cells along with 100 µM NiCl2 or ZnCl2 from a 2.5 mM stock in MiliQ water. Thefluorescence of GFP was monitored using the 488 nm laser for excitation and emission filter 530 / 30.Estimation of internalized target protein. A GFP-His6 internalization experimentincorporating a further wash with excess NTA to estimate the extent of internalized protein was performed. The conditions were as described above and testedinternalization of NR2 in HAP1 cells and triNR3 in HepG2 cells. A set of samples werefurther incubated with 400 µM Na2-NTA for 30 min and posteriorly washed before measuring fluorescence. The free NTA moiety at higher concentrations would outcompete any surface bound GFP-His6, thus leaving only internalized GFP-His6. The percentage of outcompeted GFP-His6 was calculated as the as the percentage change of mean fluorescence intensity (MFI) upon NTA washing. ResultsSignificant internalization of both GFP-His6 and RFP- His6 is observed in the presence ofNi2+ ions for NR2, NR3 (Figure 10 and Figure 11). The triNR3 compound producedhigher overall fluorescence compared to NR2 or NR3 (Figure 10), and demonstratedsignificant signal for Ni, Co and Zn ions, highlighting the higher efficacy of this scaffold.This is in agreement with literature stated KD of 10 µM vs. 20 nM for mono and tri-NTArespectively (Lata et al. 2005) . Furthermore, the histogram demonstrated that the fullcell population has enhanced fluorescence and not only a subset of the live cell population (data not shown).After washing with 400 µM Na2-NTA (Figure 12), it is seen that ~ 80% of the GFP-His6had been internalized by triNR3 (7-22% outcompeted fluorescence) and ~ 50% (48%outcompeted fluorescence) by NR2. In similar conditions, Peterson et al.(Boonyarattanakalin et al. 2006) observed a 90% decrease in fluorescence upon washing with NTA, indicating that only about 10% of the protein was internalized. Thus, it is seen that the receptor design according to the present disclosure promotes higher P7115PC00 110 internalization efficiency compared to previously reported N-alkyl derivatives of cholesteryl amine.The results on RFP- His6 (Figure 11) also demonstrated internalization mediated by thetested compounds. These tests were done with nanomolar concentration of the target protein, which is below the dissociation constant between metal-NTA groups and theoligohistidine (KD ≈ 10 µM ). Even in this suboptimal conditions of low concentration oftarget protein, it is confirmed that tris(nitrilotriacetic)acid (NTA) based receptors promotereceptor-mediated endocytosis. Furthermore, the flow cytometry histogram highlightsthat the full cell population has enhanced fluorescence and not only a subset of the livecell population (data not shown).Conclusions The tris(nitrilotriacetic)acid based receptors according to the present disclosure promote receptor-mediated endocytosis of oligohistidine based target proteins. Example 10: Confocal imaging confirming receptor-mediated internalization of GFP-His6 Materials and Methods HepG2 cells were seeded at 1x104cells / mL in an ibidi® µ-Slide 8 wellhighplate andincubated for 72 h at 37°C, 5% CO2 until cells were 70 % confluent. Fresh media wasadded to the cells with or without 10 µM NR2 or Tri-NR3 from a 100 µM stock withcyclodextrins (see preparation above, section 6). The cells were then incubated for 2 h at 37°C, 5% CO2, and washed twice with PBS before complete cell media containing 1.4µM GFP-His6 (Thermofisher, ref.: A42613) was added to the cells, along with a finalconcentration of 100 µM NiCl2 from a 2.5 mM stock in MiliQ water. The cells were then incubated for 2 h at 37°C, 5% CO2, and washed once with DPBS. The nuclei werestained with 0.01 mM Hoechst 33342 in DPBS for 10 min. from a 20 mM stock in DMSO(Thermofisher ref.: 62249) and washed 3 times in PBS before imaging was conducted on a Zeiss CLSM 800. Single stain controls were included.Confocal imaging was performed using a CLSM 800 inverted laser scanning confocalmicroscope (Zeiss, Oberkochen) with a GaAsP detector. A PlanApochromat 63x / 1.4 oilDIC objective was used. Hoechst 33342 was excited using the 405 nm diode laser lineat 2.0 % intensity and detected at 400 nm to 470 nm wavelengths. FITC was excitedusing the 488 nm diode laser at 1.0 % and detected at 495 nm to 700 nm wavelengths. P7115PC00 111 Images were obtained using the ZEN black, Zeiss, Oberkochen Germany, and data processing was performed using Zeiss Zen 3.2, Blue edition. Results The results are shown in Figure 12. In addition to the above experiments, internalization is confirmed by the fluorescent signal observed inside the cells. Conclusion The tris(nitrilotriacetic)acid based receptors according to the present disclosure promote receptor-mediated endocytosis of oligohistidine based target proteins. ReferencesBoonyarattanakalin et al. “Endocytic Delivery of Vancomycin Mediated by a SyntheticCell Surface Receptor:  Rescue of Bacterially Infected Mammalian Cells and TissueTargeting In Vivo” J. Am. Chem. Soc. 2007, 129, 2, 268–269.Doronina, S. O.; Mendelsohn, B. A.; Bovee, T. D.; Cerveny, C. G.; Alley, S. C.; Meyer, D. L.; Oflazoglu, E.; Toki, B. E.; Sanderson, R. J.; Zabinski, R. F.; Wahl, A. F.; Senter, P. D., Enhanced activity of monomethylauristatin F through monoclonal antibody delivery: effects of linker technology on efficacy and toxicity, Bioconjug. Chem., 2006, 17, 114-24.Blake R. Peterson. “ Synthetic mimics of mammalian cell surface receptors: prostheticmolecules that augment living cells”. Org. Biomol. Chem., 2005,3, 3607-3612 Sun, X., et al., PROTACs: great opportunities for academia and industry. Signal Transduct Target Ther, 2019.4: p.64. Monge et al.2020 “Chemical Artificial Internalizing Receptors for Primary T Cells” Adv.Sci. 2020, 7, 2001395.Boonyarattanakalin, S., Athavankar, S., Sun, Q., & Peterson, B. R. (2006). Synthesis of an artificial cell surface receptor that enables oligohistidine affinity tags to function asmetal-dependent cell-penetrating peptides. Journal of the American ChemicalSociety, 128(2), 386–387. https: / / doi.org / 10.1021 / ja056126jLata et al.2005 High-Affinity Adaptors for Switchable Recognition of Histidine-TaggedProteins. Journal of the American Chemical Society 2005127 (29), 10205-10215 DOI:10.1021 / ja050690c

Claims

P7115PC00 112 Claims1. A compound according to formula (I):acceptable salt thereof, wherein N Xis a linker, said linker X comprises at least one groupH, andRTcomprises a moiety that binds an extracellular target molecule, for use in a method of internalization of the extracellular target molecule into a cell.

2. The compound for use according to claim 1, wherein the method comprises:a) providing the compound of formula (I);b) contacting a cell having a cell surface with the compound in step a), therebyobtaining a cell comprising the compound of formula (I) bound to the cell surface; c) contacting the cell of step b) with an extracellular target molecule, whereinsaid extracellular target molecule binds the compound of step a); thereby internalizing the extracellular target molecule into the cell.

3. The compound for use according to claim 2, wherein the cell is an isolated cell.

4. The compound for use according to any one of claims 2 to 3, wherein in step c),said extracellular target molecule binds the compound of formula (I) simultaneously or sequentially to the compound of formula (I) binding the cell surface.P7115PC00 1135. The compound for use according to any on of claims 1 to 4 wherein the compoundis according to.

6. The compound for use according to any one of the preceding claims, wherein Xcomprises or consists of a linear bivalent, saturated or unsaturated, C1-C200hydrocarbon chain wherein one or more methylene groups are individually and optionally replaced by one or more of the groups selected from: -O-, -N(H)-, -N(RL1)-, -C(=O)O-, -C(=O)-, -N(H)C(=O)-, -N(RL1)C(=O)-, -NHC(=O)NH-, - NHC(=S)NH- , -S-, -S(=O)-, -S(=O)2-, -N(RL1)S(=O)2-, -S(=O)2N(RL1)-; an optionally substituted aromatic group; an optionally substituted carbocycle; an optionally substituted heterocycle; an optionally substituted aromatic heterocycle, wherein RL1is C1-5alkyl.

7. The compound for use according to any one of the preceding claims, wherein Xcomprises or consists of a linear bivalent, saturated or unsaturated, C1-C180hydrocarbon chain, such as a C1-C160, C1-C140, C1-C120, C1-C100, C1-C80, C1-C60, C1-C40, or C1-C20 hydrocarbon chain.

8. The compound for use according to any one of the preceding claims, wherein Xcomprises or consists of a linear bivalent, saturated or unsaturated, C5-C20hydrocarbon chain, such as a C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C13, C14, C15, C16, C17, C18, C19, or C20hydrocarbon chain.

9. The compound for use according to any one of the preceding claims, wherein oneor more methylene groups in X are individually and optionally replaced by one or more of the groups selected from: -O-, -N(H)-, -C(=O)-, -N(H)C(=O)-, -N(RL1)C(=O)- ,-NHC(=O)NH-, -NHC(=S)NH- , -S-, -S(=O)-, -S(=O)2-, -N(RL1)S(=O)2-, -S(=O)2N(RL1)-, an optionally substituted carbocycle, an optionally substituted heterocycle, wherein RL1is C1-5 alkyl.P7115PC00 11410. The compound for use according to any one of the preceding claims, wherein oneor more methylene groups in X are individually and optionally replaced by one or more of the groups selected from: -O-, -N(H)-, -C(=O)-, -N(H)C(=O)-, -N(RL1)C(=O)- ,-NHC(=O)NH-, -NHC(=S)NH-, wherein RL1 C1-5 alkyl.

11. The compound for use according to any one of claims 1 to 10, wherein X comprises1 to 5 secondary amine groups, such as 1, 2, 3, 4, or 5 secondary amine groups.

12. The compound for use according to claim 11, wherein X comprises 1 to 5 groups, .

13. The compound for use according to any one of the preceding claims, wherein Xcomprises at least two secondary amine groups.

14. The compound for use according to claim 13, wherein X comprises at least twogroups.

15. The compound for use according to any one of the preceding claims, wherein Xcomprises at least three groups .

16. The compound for use according to any one of claims 1 to 11, wherein Xcomprises or consists of any one selected from:.P7115PC00 11517. The compound for use according to any one of claims 1 to 11, wherein Xcomprises or consists of any one selected from:.

18. The compound for use according to any one of the preceding claims, wherein Xcomprises, wherein n is an integer from 1 to 70.

19. The compound for use according to claim 18, wherein n is an integer from 1 to 60,1 to 50, 1 to 40, 1 to 30, 1 to 20, 1 to 10, such as n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

20. The compound for use according to any one of the preceding claims, wherein Xcomprises one or more groups .

21. The compound for use according to any one of the preceding claims, wherein Xcomprises, wherein m1 is an integer from 1 to 10, such as an integer from 1 to 5, such as 1, 2, 3, 4, or 5.

22. The compound for use according to any one of the preceding claims, wherein Xcomprises, wherein m2 is an integer from 1 to 10, such as aninteger from 1 to 5, such as 1, 2, 3, 4, or 5.

23. The compound for use according to any one of the preceding claims, wherein Xcomprises; wherein m3 is 1 to 10.P7115PC00 11624. The compound for use according to any one of the preceding claims, wherein Xcompriseswherein m4 is 1 to 10, L1is -NH-, -C(=O)-, - C(=O)NH-, or -O-.

25. The compound for use according to any one of the preceding claims, wherein Xcompriseswherein moiety A comprises or consists of any monocyclic or polycyclic carbocycle or heterocycle.

26. The compound for use according to claim 25, wherein X comprises, wherein Ax is either -CH- or N.

27. The compound for use according to any one of the preceding claims, wherein Xcomprises one or more branches, wherein each branch is optionally and individually a C1-C5alkyl, C1-C5alkoxy, or C3-C7cycloalkyl, each of which may optionally have one or more substituents.

28. The compound for use according to any one of claims 1 to 27, wherein X does notcomprise a branch.

29. The compound for use according to any one of the preceding claims, wherein Xcomprises one or more substituents selected from: -OH, -NH3, -C(=O)NH2, or an alkylamine.

30. The compound for use according to any one of the preceding claims, wherein RT isspecifically adapted to bind the extracellular target molecule.P7115PC00 11731. The compound for use according to any one of the preceding claims, wherein RTcomprises a moiety able to bind an antibody, or an antigen-binding antibody fragment.

32. The compound for use according to any one of the preceding claims, wherein RTcomprises a group derived from fluorescein.

33. The compound for use according to any one of the preceding claims, wherein RTcomprises or consists of any one of formulas (F-Ia), (F-IIa), (F-Ib), and (F-IIb):or any tautomer, or acid-base form thereof, wherein RFis absent or a C1-C5 hydrocarbon chain, wherein one or more methylene groups is optionally and individually replaced by -O-, -N(H)-, -C(=O)-, -N(H)C(=O)- ,-N(RL1)C(=O)-, -NHC(=O)NH-, -NHC(=S)NH-, an optionally substitutedcarbocycle, an optionally substituted heterocycle; wherein RL1is C1-5 alkyl.

34. The compound for use according claim 33, whereinRFis a C1-C5 hydrocarbon chain, wherein one or more methylene groups is optionally and individually replaced by -O-, -N(H)-, -C(=O)-, -N(H)C(=O)- ,-N(RL1)C(=O)-, -NHC(=O)NH-, -NHC(=S)NH-, an optionally substitutedcarbocycle, an optionally substituted heterocycle; wherein RL1is C1-5 alkyl.P7115PC00 11835. The compound for use according claim 33, wherein RF is-NHC(=S)NH-.

36. The compound for use according for use according claim 33, wherein RF is absent.

37. The compound for use according to any one of claims 1 to 11 and 18 to 36,wherein the compound isor a pharmaceutically acceptable salt thereof.P7115PC00 11938. The compound for use according to claim 37, wherein the compound is39. The compound for use according to claim 37, wherein the compound is(CR3).

40. The compound for use according to claim 37, wherein the compound is41. The compound for use according to any one of claims 1 to 30, wherein RTcomprises a moiety able specifically adapted to bind an oligohistidine group.

42. The compound for use according to any one of claims 1 to 30 and 41, wherein RTcomprises one or more moieties derived from nitrilotriacetic acid (NTA) , or a derivative thereof.P7115PC00 12043. The compound for use according to any one of claims 1 to 30 and 41 to 42,wherein RTcomprises or consists of 1 to 3 moieties derived from nitrilotriacetic acid (NTA) , or a derivative thereof, such as 1, 2, or 3 moieties derived from nitrilotriacetic acid (NTA).

44. The compound for use according to any one of claims 1 to 30 and 41 to 43,wherein RTcomprises 1 to 3 units of formula (N-I), such as 1, 2 or 3 units of formula (N-I):

45. The compound for use according to any one of claims 1 to 30 and 41 to 44,wherein RTcomprises 1 to 3 units of formula (NI-a), such as 1, 2 or 3 units of formula (N-Ia)wherein RX is a C1-C20 hydrocarbon chain, wherein one or more methylene groupsis optionally and individually replaced by -O-, -N(H)-, -C(=O)-, -N(H)C(=O)- ,-N(RL1)C(=O)-, -NHC(=O)NH-, -NHC(=S)NH-, an optionally substitutedcarbocycle, or an optionally substituted heterocycle; and formula (N-Ia) is attached to X via RX.

46. The compound for use according to claim 45, wherein RX comprises or consist of, wherein k is an integer form 1 to 5.

47. The compound for use according to claim 46, wherein k is 1, 2, 3, 4, or 5.

48. The compound for use according to any one of claims 46 to 47, wherein k is 2.P7115PC00 12149. The compound for use according to any one of claims 1 to 30 and 41 to 47,wherein the compound is according to formula (N-IIa) or (N-IIb):wherein Xis as defined in any one of claims 1 to 29,each instance of RX, RX1, RX2and RX3is individually and independently selected from a C1-C20 hydrocarbon chain, wherein one or more methylene groups isoptionally and individually replaced by -O-, -N(H)-, -C(=O)-, -N(H)C(=O)- ,-N(RL1)C(=O)-, -NHC(=O)NH-, -NHC(=S)NH-, an optionally substitutedcarbocycle, or an optionally substituted heterocycle.P7115PC00 12250. The compound according to claim 49, wherein the compound is according toformula (N-IIc):heterocycle, such as a 4-18, or 11 to 16 membered heterocycle, andRY1, RY2, and RY3are individually and independently selected form a C1-C5 linear hydrocarbon chain, wherein one or more methylene group(s) is optionally andindividually replaced by -O-, -N(H)-, -C(=O)-, -N(H)C(=O)-, -N(RL1)C(=O)-, - NHC(=O)NH-, or -NHC(=S)NH-; wherein RL1is C1-5 alkyl.P7115PC00 12351. The compound according to claim 50, wherein the compound is according toformula (N-IId):wherein each instance of RY1, RY2, and RY3 is individually and independently selected form aC1-C5 linear hydrocarbon chain, wherein one or more methylene groups is optionally and individually replaced by -O-, -N(H)-, -C(=O)-, -N(H)C(=O)-, -N(RL1)C(=O)-, -NHC(=O)NH-, or -NHC(=S)NH-; wherein RL1is C1-5 alkyl.

52. The compound for use according to any one of claims 1 to 30, and 41 to 49,pharmaceutically acceptable salt thereof.P7115PC00 12453. The compound for use according to any one of claims 1 to 30 and 41 to 49,wherein the compound is(NR3), or a pharmaceutically acceptable salt thereof.

54. The compound according to any one of claims 1 to 30 and 41 to 51, wherein thecompound is(triNR3), or a pharmaceutically acceptable salt thereof.

55. The compound for use according to any one of claims 1 to 30 and 41 to 54,wherein RTcomprises a complex with a metal.

56. The compound for use according to any one of claims 1 to 30 and 41 to 55,wherein RTcomprises a 1, 2 or 3 metal complexes of nitrilotriacetic acid with Co2+, Ni2+, or Zn2+.

57. The compound for use according to any one of claims 1 to 30 and 41 to 56,wherein RTcomprises a metal complex of Co2+.

58. The compound for use according to any one of claims 1 to 30 and 41 to 56,wherein RTcomprises a metal complex of Ni2+.P7115PC00 12559. The compound for use according to any one of claims 44 to 54, wherein each unitof formula (N-I) or (N-Ia) is forming a metal complex with one selected from: Co2+, Ni2+, and Zn2+.

60. The compound according to claim 59, wherein each unit of formula (N-I) or (N-Ia)is forming a metal complex with Co2+.

61. The compound according to claim 59, wherein each unit of formula (N-I) or (N-Ia)is forming a metal complex with Ni2+.

62. The compound according to any one of claims 1 to 40, wherein the compoundcomprises only one group derived from63. The compound according to any one of the preceding claims, wherein thecompound comprises only one cholesteryl unit. The compound according to any one of the preceding claims, wherein RTdoes not comprise or consist of a lipid moiety.

64. The compound for use according to any one of claims 1 to 63, wherein, whereintarget molecule is degraded upon internalization.

65. The compound for use according to any one of claims 1 to 63, wherein the targetmolecule is stored in the intracellular compartments.

66. The compound for use according to any one of claims 1 to 65, wherein the cell is aneukaryotic cell.

67. The compound for use according to claim 66, wherein the cell is a lymphocyte, suchas a T cell, or a hepatocyte.

68. The compound for use according to any one of claims 1 to 67, wherein thecompound binds the extracellular surface of the cell.

69. The compound for use according to any one of claims 1 to 68, wherein thecompound binds the cell membrane.P7115PC00 12670. The compound for use according to any one of claims 1 to 69, wherein thecompound binds to the extracellular surface of a cell and to the extracellular target molecule at the same time.

71. The compound for use according to any one of claims 1 to 70, wherein uponbinding of the compound to a cell membrane and binding of RTto the extracellular target molecule, the extracellular target molecule is internalized into the cell.

72. The compound for use according to claim 71, wherein the target molecule isdegraded upon internalization into the cell.

73. The compound for use according to claim 71, wherein the extracellular targetmolecule is stored in the intracellular compartments.

74. The compound for use according to any one of claims 1 to 73, wherein theextracellular target molecule is a peptide, a protein, a carbohydrate, a smallmolecule, or a nucleic acid.

75. The compound for use according to any one of claims 1 to 74, wherein theextracellular target molecule is a protein.

76. The compound for use according to claim 75, wherein the extracellular targetmolecule is a therapeutic protein.

77. The compound for use according to any one of claims 75 to 76, wherein theextracellular target molecule is a cytokine.

78. The compound for use according to any one of claims 74 to 77, wherein theextracellular target molecule comprises a oligohistidine group.

79. The compound for use according to claim 78, wherein the extracellular targetmolecule is a protein or peptide comprising a oligohistidine group at the N- orC- terminus.

80. The compound for use according to any one of claims 78 to 79, wherein theoligohistidine group comprises at least 6 sequential histidine groups, such as 7, 8, 9, 10, 11, 12, 13, 14 or 15 sequential histidine groups.

81. The compound for use according to any one of claims 78 to 80, wherein theoligohistidine group comprises 6 to 12 sequential histidine groups.P7115PC00 127 82. The compound for use according to any one of claims 78 to 81, wherein theoligohistidine group is according to formula (H-I):wherein formula (H-I) is attached to the N-, or C- terminus of the extracellular target protein,wherein p is an integer from 6 to 15.

83. The compound for use according to any one of claims 78 to 82, wherein thecompound is as defined in any one of claims 41 to 61.

84. The compound for use according to any one of claims 75 to 76, wherein theextracellular target molecule is an antibody, or an antigen-binding antibody fragment.

85. The compound for use according to claim 84, wherein the extracellular targetmolecule is according to formula (II): Ab-LX-RP(II), wherein Ab is an antibody, or an antigen-binding antibody fragment, LXis a linker, and RPis a therapeutic agent.

86. The compound for use according to any one of claims 84 to 85, wherein LX is anon-cleavable linker.

87. The compound for use according to any one of claims 84 to 85, wherein LX is acleavable linker.

88. The compound for use according to claim 87, wherein LX is a protease-cleavablelinker, such as a cathepsin cleavable linker.P7115PC00 12889. The compound for use according to any one of claims 87 to 88, wherein LXcomprises90. The compound for use according to any one of claims 87 to 89, wherein LXcomprises91. The compound for use according to any one of claims 87 to 90, wherein LXcomprises.

92. The compound for use according to any one of claims 85 to 91, wherein RP is ananticancer agent.

93. The compound for use according to any one of claims 85 to 91, wherein RP is anantimitotic agent, such as a tubulin inhibitor.

94. The compound for use according to any one of claims 85 to 91, wherein RP ismonomethyl auristatin E (MMAE) or monomethyl auristatin F (MMAF).P7115PC00 12995. The compound for use according to any one of claims 85 to 91, wherein RP is.

96. The compound for use according to any one of claims 85 to 91, wherein RP is.

97. The compound for use according to any one of claims 84 to 96, wherein theantibody or antibody fragment binds a non-endogenous moiety.

98. The compound for use according to any one of claims 84 to 97, wherein theantibody is an anti-fluorescein antibody (antiFITC).

99. The compound for use according to any one of claims 84 to 97, wherein thecompound is as defined in any one of claims 31 to 40.

100. A compound according to formula (I):acceptable salt thereof, whereinX is a linker, said linker X comprises at least one group , andP7115PC00 130 RT comprises a moiety that binds an extracellular target molecule, for use intreatment of a disease or disorder, wherein said treatment comprises a step of internalizing an extracellular target molecule into a cell.

101. The compound for use according to claim 100, wherein said disease is cancer.

102. The compound for use according to any one of claims 100 to 101, wherein theextracellular target molecule is an antibody-drug conjugate.

103. The compound for use according to any one of claims 100 to 102, wherein theextracellular target molecule is as defined in any one of claims 85 to 98.

104. The compound for use according to any one of claims 100 to 103, wherein thecompound is as defined in any one of claims 1 to 40.

105. A compound according to formula (I):formula (I), or a pharmaceutically acceptable salt thereof, whereinX is a linker, said linker X comprises at least one group , and RTcomprises a moiety specifically adapted to bind an extracellular target molecule, for use in diagnosis.

106. The compound for use according to claim 105, wherein the compound is for use inin vivo diagnosis of diseases.

107. The compound for use according to claim 105, wherein the compound is for use inex vivo diagnosis.

108. The compound for use according to any one of claims 105 to 107, wherein saiduse comprises a step internalizing an extracellular target molecule into a cell.P7115PC00 131 109. The compound for use according to any one of claims 105 to 108, wherein theextracellular molecule is as defined in any one of claims 78 to 82.

110. The compound for use according to any one of claims 105 to 108, the compoundis as defined in any one of claims 41 to 61.

111. An isolated cell comprising a compound as defined in any one of claims 1 to 99.

112. The isolated cell according to claim 111, wherein the compound is located at thecell surface.

113. The isolated cell according to any one of claims 111 to 112, wherein the cell is aneukaryotic cell.

114. The isolated cell according to claim 113, wherein the cell is a lymphocyte, such asa T cell, or a hepatocyte.

115. A compound according to formula (I):formula (I), or a pharmaceutically acceptable salt thereof, whereinX is a linker, said linker X comprises at least two groups , and RTcomprises a moiety that is specifically adapted to bind an extracellular target protein.

116. The compound according to claim 115, wherein X is as defined in any one ofclaims 4 to 10, 17 to 29.P7115PC00 132117. The compound according to any one of claims 115 to 116, wherein RT comprisesor consists of any one of formulas (F-Ia), (F-IIa), (F-Ib), and (F-IIb):or any tautomer, or acid-base form thereof, wherein RFis absent or a C1-C5hydrocarbon chain, wherein one or more methylene groups is optionally and individually replaced by -O-, -N(H)-, -C(=O)- ,-N(H)C(=O)-, -N(RL1)C(=O)-, -NHC(=O)NH-, -NHC(=S)NH-, an optionallysubstituted carbocycle, an optionally substituted heterocycle; wherein RL1is C1-5 alkyl.

118. The compound according to any one of claims 115 to 116, wherein RT is asdefined in any one of claims 32 to 36.P7115PC00 133119. The compound according to any one of claims 115 to 118, wherein thecompound is, or a pharmaceutically acceptable salt thereof.

120. The compound according to any one of claims 115 to 116, wherein RTcomprises 1 to 3 units of formula (N-Ia), such as 1, 2 or 3 units of formula (N- Ia):Ia) wherein RX is a C1-C20 hydrocarbon chain, whereinone or more methylene groups is optionally and individually replaced by -O-, - N(H)-, -C(=O)-, -N(H)C(=O)-, -N(RL1)C(=O)-, -NHC(=O)NH-, -NHC(=S)NH-, anoptionally substituted carbocycle, or an optionally substituted heterocycle; and formula (N-Ia) is attached to X via RX.

121. The compound according to any one of claims 115 to 116, wherein RT is asdefined in any one of claims 41 to 61.P7115PC00 134122. The compound according to any one of claims 115-116 and 120-121,wherein the compound is(triNR3), or a pharmaceutically acceptable salt thereof, or a complex thereof with Co2+, Ni2+, or Zn2+, preferably with Ni2+.

123. A composition comprising a compound as defined in any one of claims 115 to 122and a pharmaceutically acceptable excipient or carrier.

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