Newly synthesized boron-nitrogen heterocycles and their conjugates with pharmaceutically utilizable substances

Abstract

The present invention relates to H2O2-sensitive compounds comprising a boron-nitrogen- heterocycle and their therapeutic applications. Moreover, the present invention relates to H2O2-sensitive compounds comprising a boron-nitrogen heterocycle for the targeted and controllable release of an active substance / dye / fluorophore in tissues. The present invention further relates to H2O2-sensitive compounds comprising a boron-nitrogen heterocycle that may be coupled to said substance / dye / fluorophore, optionally via a linker, preferably via a self-immolative linker. The present invention further relates to a kit of pharmaceutical ingredients that comprises said compound and a peptide or a protein that enhances the release, distribution and / or the half-life of the active substance / dye / fluorophore in target tissues. Moreover, the present invention relates to a method for the diagnosis, prevention and / or treatment of a disease, such as a proliferative disease, a neurodegenerative disease, a viral infection, and / or a non-viral infection, comprising the administration of said compound or said kit to a subject in need thereof.

Description

[0001] Julius-Maximilians-Universitat Wurzburg

[0002] Newly synthesized boron-nitrogen heterocycles and their conjugates with pharmaceutically utilizable substances

[0003] FIELD OF THE INVENTION

[0004] The present invention relates to the general field of drug delivery systems. In particular, the present invention relates to H202-sensitive compounds comprising a boron-nitrogen heterocycle and their therapeutic applications. Moreover, the present invention relates to H202-sensitive compounds comprising a boron-nitrogen heterocycle for the targeted and controllable release of an active substance / dye / fluorophore in tissues.

[0005] BACKGROUND OF THE INVENTION

[0006] A major problem in the effective treatment of diseases is the undesirable side effects caused by the non-targeted effectiveness of the active substance used. For example, commercially used chemotherapeutic agents not only attack diseased cells but also healthy cells. Drug delivery systems (DDS) are frequently used in the pharmaceutical industry to minimize the side effects of active ingredients as much as possible. By activating these systems in the diseased tissue, the targeted release and mode of action of the previously bound and thus (partially) inactive active ingredients is made possible (activity on demand concept, AoD). Thus, these systems are intended to keep the concentration of active substances used in diseased tissue as constant as possible over a longer period of time, whereas the concentration of active substances in healthy tissue should be as low as possible.

[0007] In 1952, the first formulation that specifically released active ingredients was developed. Based on this, oral and transdermal drug delivery systems were developed in the first generation of drug delivery. Mechanisms for targeted drug release were also investigated. Second-generation drug delivery systems are based on long-term depot formulations and nanotechnology-based systems, among other things. The release or activation is triggered by pathophysiological differences such as pH, temperature, light, proteases and ROS between healthy and diseased tissue.

[0008] However, despite significant advancements in the field of targeted drug delivery, there remains a critical need for further improvement in targeted drug release systems. Current methods, while promising, often face challenges such as limited specificity, suboptimal drug release kinetics, and potential off-target effects. These limitations can result in reduced therapeutic efficacy and increased side effects, undermining the need for improved of targeted therapies. Additionally, the complexity of biological environments and the heterogeneity of diseases, particularly cancer, necessitate the development of more sophisticated and adaptable drug delivery systems. By enhancing the precision, efficiency, and safety of targeted drug release, it would be possible to improve patient outcomes, minimize adverse effects, and expand the applicability of these therapies to a broader range of conditions.

[0009] To this day, the development of drug delivery systems is a key area of research in the pharmaceutical industry, as in addition to the expected minimization of undesirable side effects, the drug dose can also be significantly reduced in many cases.

[0010] Therefore, there is a need for compounds or pharmaceutically acceptable salts thereof that enable the targeted and controllable release of an active substance / dye / fluorophore in tissues. Also, there is a need for compounds that enable the finetuning of said targeted and controllable release of the active substance / dye / fluorophore in (diseased) tissues. Moreover, there is a need for a kit of pharmaceutical ingredients that comprises said compound and a peptide or a protein that enhances the release, distribution and / or the half-life of the active substance / dye / fluorophore in target tissues. Furthermore, there is a need for a method for the diagnosis, prevention and / or treatment of a disease, such as a proliferative disease, a neurodegenerative disease, a viral infection, and / or a non-viral infection, comprising the administration of said compound or said kit to a subject in need thereof.

[0011] SUMMARY OF THE INVENTION

[0012] In the following, the elements of the invention will be described. These elements are listed with specific embodiments, however, it should be understood that they may be combined in any manner and in any number to create additional embodiments. The variously described examples and preferred embodiments should not be construed to limit the present invention to only the explicitly described embodiments. This description should be understood to support and encompass embodiments which combine two or more of the explicitly described embodiments or which combine the one or more of the explicitly described embodiments with any number of the disclosed and / or preferred elements. Furthermore, any permutations and combinations of all described elements in this application should be considered disclosed by the description of the present application unless the context indicates otherwise.

[0013] In a first aspect, the present invention relates to a compound having a general formula of any one of formulas (I) to (VII)

[0014] 5 wherein

[0015] R1is or comprises, at each occurrence, independently a drug or a reporter, or R1is, at each occurrence, independently selected from a group comprising N(RX5)2, Ci-C5alkyl, Ci-C20alkoxycarbonyl, alkyne, aryl, alkene, and heteroaryl, wherein at least one R1is or comprises a drug or a reporter, optionally wherein the drug or the reporter is coupled and / or is attached to at least one boron atom of the compound via a linker, wherein the linker is preferably a self-immolative linker, such as an alkyl -based linker or an aryl -based linker, and / or a linker comprising an ether and / or an ester group,

[0016] R2to R9are, at each occurrence, independently selected from a group comprising H, OH, OR15, N(RX5)2, N02, S02, P(R16)3-5, halogen, Ci-C5alkyl, Ci-C20alkoxycarbonyl, alkyne, aryl, alkene, and heteroaryl, wherein said aryl or said heteroaryl is optionally substituted with one or more of R18, preferably one or two of R18, X is O, NR'5, S, SO, or S02,

[0017] R15is, at each occurrence, independently selected from a group comprising H, OH, halogen, C1-C10 alkyl, aryl, heteroaryl, and (C=0)R19,

[0018] R16is, at each occurrence, independently O or OR17,

[0019] R17is, at each occurrence, independently selected from a group comprising P, C1-C10 alkyl, Ci-

[0020] Cio aryl, Ci-C 10 heteroaryl, and ribose,

[0021] R18is, at each occurrence, independently H or C1-C5 alkyl, and

[0022] R19is, at each occurrence, independently C3-Ci0alkyl, optionally substituted with a maleimide group, or a pharmaceutically acceptable salt thereof.

[0023] In one embodiment, the compound has a general formula of formula (Va)

[0024] In one embodiment, at least one boron atom or nitrogen atom of the compound is chemically modified.

[0025] In one preferred embodiment, at least one boron atom of the compound is chemically modified.

[0026] In one embodiment, the linker, preferably the self-immolative linker, has a general formula of any one of formulas (A) to (F):

[0027] wherein R10, R11, R12and R13are each independently selected from a group comprising H, OH, OR15, halogen, Ci-C io alkyl, aryl, and heteroaryl, and wherein R14is or comprises a drug or a reporter.

[0028] In one preferred embodiment, the compound does not comprise a boronic acid function and / or borin group (B-OH) at either of the boron atoms of the heterocycle.

[0029] In one embodiment, the compound comprises one or more further moieties, wherein the one or more further moiety / moieties is / are preferably a polymer or polymer conjugate, more preferably polyethylene glycol (PEG) or Dibenzocyclooctyne-PEG (DBCO- PEG), wherein said polymer or polymer conjugate is preferably attached to the compound having a general formula of any one of formulas (I) to (VII) at any of R2to R9, more preferably at any of R3to R9, and / or wherein the one or more further moiety / moieties is / are preferably a peptide or a protein, such as a peptide or a protein which increases the level of reactive oxygen species (ROS), for example an antibody or an enzyme which increases the level of ROS, preferably an L-amino acid oxidase, such as Aplysia punctata ink toxin (APIT), which comprises or consists of an amino acid sequence which is at least 90% identical, preferably at least 95% identical, more preferably at least 98% identical, even more preferably at least 99% identical, optionally identical, to the amino acid sequence of SEQ ID NO. 1, wherein said peptide or protein is attached, preferably covalently attached, to the compound having a general formula of any one of formulas (I) to (VII) at any of R2to R9, more preferably at any of R to R .

[0030] In one embodiment, one or more of the further moieties are attached to the compound having a general formula of any one of formulas (I) to (VII) via a linker.

[0031] In one embodiment, the compound having a general formula of any one of formulas (I) to (VII) comprises at any of R2to R9a combination of two or more further moieties that are attached to each other, such as a combination of a polymer or polymer conjugate, preferably polyethylene glycol (PEG) or DBCO-PEG, and a peptide or a protein, such as a peptide or a protein which increases the level of reactive oxygen species (ROS), wherein, optionally, said combination is attached to the compound having a general formula of any one of formulas (I) to (VII) via a linker.

[0032] In one embodiment, said combination of a polymer or polymer conjugate, preferably polyethylene glycol (PEG) or DBCO-PEG, and a peptide or a protein, such as a peptide or a protein which increases the level of reactive oxygen species (ROS) is attached to the compound having a general formula of any one of formulas (I) to (VII) via a linker.

[0033] In one embodiment, said linker between the one or more of the further moieties and the compound is selected from a group comprising Amide bonds, enzyme-cleavable (such as peptide linkers like Val-Cit or Val-Ala, often with self-immolative p-aminobenzyl carbamate spacers); Thioether bonds, non-cleavable (such as succinimidyl-4-(N- maleimidomethyl)cyclohexane-i-carboxylate, SMCC); Disulfide bonds, redox-cleavable (such as hindered alkyl or aryl disulfides with gem-dimethyl substitution); Hydrazone bonds, acid- labile (such as 4-(4-acetylphenoxy)butanoic hydrazone); Carbamate bonds, enzyme- or pH- cleavable (such as p-aminobenzyl carbamate, PABC); Ester bonds, enzymatically cleavable (such as alkyl or aryl esters and carbonates); P-Glucuronide bonds, enzyme-cleavable (such as aromatic P-glucuronide carbamates); Aryl or alkyl linkers, non-cleavable hydrophobic spacers (such as phenylene, benzyl, or hexyl chains providing distance and flexibility between payload and antibody).

[0034] In one embodiment, said polymer or polymer conjugate is coupled to a peptide or a protein, such as a peptide or a protein which increases the level of reactive oxygen species (ROS), for example an antibody or an enzyme which increases the level of ROS, preferably an L-amino acid oxidase, such as Aplysia punctata ink toxin (APIT), which comprises or consists of an amino acid sequence which is at least 90% identical, preferably at least 95% identical, more preferably at least 98% identical, even more preferably at least 99% identical, optionally identical, to the amino acid sequence of SEQ ID NO. 1.

[0035] In one embodiment, the compound comprises one or more further moieties, wherein the one or more further moiety / moieties is / are preferably a polymer or polymer conjugate, more preferably polyethylene glycol (PEG) or DBCO-PEG, wherein said polymer or polymer conjugate is preferably attached to the compound having a general formula of any one of formulas (I) to (VII) at R2.

[0036] In one embodiment, the compound having a general formula of any one of formulas (I) to (VII) comprises a polymer or polymer conjugate, preferably a polymer conjugate, at R2, wherein said polymer or polymer conjugate is coupled to a peptide or a protein, such as a peptide or a protein which increases the level of reactive oxygen species (ROS), for example an antibody or an enzyme which increases the level of ROS, preferably an L-amino acid oxidase, such as Aplysia punctata ink toxin (APIT), which comprises or consists of an amino acid sequence which is at least 90% identical, preferably at least 95% identical, more preferably at least 98% identical, even more preferably at least 99% identical, optionally identical, to the amino acid sequence of SEQ ID NO. 1.

[0037] In one embodiment, the compound comprises one or more further moieties, wherein the one or more further moiety / moieties is / are preferably a polymer or a polymer conjugate, more preferably polyethylene glycol (PEG) or DBCO-PEG, wherein said polymer or polymer conjugate is preferably attached to the compound having a general formula of any one of formulas (I) to (VII) at any of R3to R9, and / or wherein the one or more further moiety / moieties is / are preferably a peptide or a protein, such as a peptide or a protein which increases the level of reactive oxygen species (ROS), for example an antibody or an enzyme which increases the level of ROS, preferably an L-amino acid oxidase, such as Aplysia punctata ink toxin (APIT), which comprises or consists of an amino acid sequence which is at least 90% identical, preferably at least 95% identical, more preferably at least 98% identical, even more preferably at least 99% identical, optionally identical, to the amino acid sequence of SEQ ID NO. 1, wherein said peptide or protein is preferably covalently attached to the compound having a general formula of any one of formulas (I) to (VII) at any of R3to R9. In one embodiment, if the compound comprises more than one further moiety, such as at least two further moieties, the further moieties may either be identical or the moieties may be different from each other. The more than one further moieties may be attached to the to different positions selected from positions at any of R2to R9or two or more of the further moieties may be attached to the same position at any of R2to R9, wherein a first further moiety is attached to the BNN heterocycle, optionally via a linker, and a second further moiety is attached to the first further moiety either directly or indirectly.

[0038] In one embodiment, R1or R14is or comprises a drug which is selected from a group comprising anti-cancer drugs, such as antimetabolites (e.g., methotrexate), alkylating drugs, such as chlorambucil or cylcophosphamid, topoisomerase blockers, such as etoposide, enzymes, such as asparaginase, hormonal antagonists, such as tamoxifen, mitose blockers, such as vinca alkaloids, camptothecin, anthracyclines, such as doxorubicin, kinase inhibitors, such as erlotinib, gefitinib, imatinib, or lapatinib, hormones, such as estrogens or antiestrogens (e.g., estramustin), fulvestrant, gemcitabine, cytarabine, or proteasome inhibitors, such as bortezomib, anti-inflammatory drugs, such as nonsteroidal anti-inflammatory drugs (e.g. naproxen and diclofenac), corticosteroids, colchicine, and antihistamines, virustatics, such as nucleosides (e.g., emitricitabin), nucleotides, such as tenofovir, or non-nucleosides, such as nevirapine, ribavirin, ganciclovir, vidarabine, acyclovir, penciclovir, zalcitabine, protease inhibitors, such as lopinavir, blockers of the integrase, such as raltegravid, entry inhibitors, such as enfuvirtide, or amantadine, and antibiotics, such as betalactam antibiotics, penicillins, aminopenicillins, acylaminopenicillins, cephalosporins, cabapenems, monobactams, aminoglycosides, streptomycin, kanamycins, tetracyclines, macrolides and their analoga, streptogramines, oxazolidones, such as linezolid, benzochinon ansamycins, such as geldanamycin, chloramphenicol, fusidic acid, mupirocin or retapamulin, gyrase inhibitors, such as fluorochinolones, folic acid antagonists, such as sulfonamides, fidaxomicin, cyclic lipopeptids, such as daptomycin, polypeptides, such as polymyxin or colistin, and antitubercular medications, such as isoniazid, pyrazinamide, or ethambutol, RNA polymerase inhibitors, such as rifampicin, or clofazimin drugs, and antimycotic drugs, such as azol-antimycotics (e.g. voriconazole or posaconazole), polyen-antimycotics, such as amphotericin B, nystatin, or natamycin, echinocandines, such as caspofungin, anidulafungin, or micafungin. In one embodiment, R1or R14is or comprises a reporter which is selected from a group comprising fluorescence dyes, such as near infrared (NIR) dyes, e.g. resorufin or 2-[2-(2,3- Dihydro-6-hydroxy-iH-xanthen-3-yl)ethenyl]-i-ethyl-3,3-dimethyl-3H-indolium, diagnostic macromolecules, mass reporters, and chemoluminescence dyes.

[0039] In one embodiment, the coupling and / or attaching of the drug or the reporter to a boronnitrogen heterocycle backbone of a compound having a general formula of any one of formulas (I) to (VII) inactivates the drug or the reporter, such as partially and / or temporarily inactivates the drug or the reporter, optionally wherein an active drug and / or an active reporter is released in presence of a reactive oxygen species (ROS), such as hydrogen peroxide (H202).

[0040] In one embodiment, the drug or the reporter is inactive when coupled to a boron-nitrogen heterocycle backbone of a compound having a general formula of any one of formulas (I) to (VII), preferably via a linker; wherein, when the drug or reporter is released from the compound, preferably in the presence of ROS, the drug or reporter becomes active upon release.

[0041] In preferred embodiments, the compound according to the present invention is pharmacologically and / or physiologically inactive after the drug or reporter is released from the compound.

[0042] In one embodiment, the release of an active drug and / or an active reporter is directly dependent on the sensitivity of the compound to ROS, such as to H202, wherein a higher sensitivity of the compound to ROS, such as to H202, results in a faster release of an active drug and / or an active reporter and / or a lower sensitivity of the compound to ROS, such as to H202, results in a slower release of an active drug and / or an active reporter.

[0043] In one embodiment, the sensitivity of the compound to ROS, such as to H202, is dependent on steric and / or electronic characteristics of the linker, wherein the linker is preferably a self- immolative linker, wherein the release of an active drug and / or an active reporter in presence of ROS, such as H202, is faster when the linker is (a) small and / or sterically less demanding compared to the release of an active drug and / or an active reporter in presence of ROS, such as H202, when the linker is (b) large and / or sterically demanding, and / or wherein the release of an active drug and / or an active reporter in presence of ROS, such as H202, is slower when the linker is (a) large and / or sterically demanding compared to the release of an active drug and / or an active reporter in presence of ROS, such as H202, when the linker is (b) small and / or sterically less demanding.

[0044] In one embodiment, the sensitivity of the compound to ROS, such as to H202, is dependent on R2, such as is dependent on steric and / or electronic characteristics of R2, wherein the release of an active drug and / or an active reporter in presence of ROS, such as H202, is faster when R2is (i) small and / or sterically less demanding compared to the release of an active drug and / or an active reporter in presence of ROS, such as H202, when R2is (ii) large and / or sterically demanding, and / or wherein the release of an active drug and / or an active reporter in presence of ROS, such as H202, is slower when R2is (ii) large and / or sterically demanding compared to the release of an active drug and / or an active reporter in presence of ROS, such as H202, when R2is (i) small and / or sterically less demanding, optionally wherein R2is (i) small and / or sterically less demanding if R2is H, OH, OR15, N(RX5)2, N02, S02, P(R16)3-5, halogen, Ci-C5alkyl, Ci-C5alkoxycarbonyl, alkyne, or alkene, R15is H, OH, halogen, and R16is O, further optionally wherein R2is (ii) large and / or sterically demanding if R2is OR15, N(RX5)2, P(R16)3-5, C6-C2Oalkoxycarbonyl, aryl, or heteroaryl, wherein said aryl or said heteroaryl is optionally substituted with one or more of R18, preferably one or two of R18, R' is C1-C10 alkyl, aryl, or heteroaryl, R16is OR1',

[0045] R'7is P, C1-C10 alkyl, C1-C10 aryl, C1-C10 heteroaryl, or ribose, and

[0046] R18is, at each occurrence, independently selected from H or Ci-C5alkyl, such as wherein R2is (ii) large and / or sterically demanding if R2is phenyl, 2-methylphenyl, 2,6-dimethylphenyl, or 2,6-diisopropylphenyl.

[0047] In one embodiment, at least one of R2-9is 6-Maleimidohexanamide.

[0048] In one embodiment, R5is 6-Maleimidohexanamide.

[0049] In one embodiment, at least one of R2-9is a 6-Maleimidohexanamide moiety.

[0050] In one embodiment, R5is a 6-Maleimidohexanamide moiety. In one embodiment, said 6-Maleimidohexanamide moiety makes it possible to connect the compound with a further macromolecule, such as a peptide or a protein, such as a peptide or a protein which increases the level of reactive oxygen species (ROS), for example an antibody or an enzyme which increases the level of ROS.

[0051] In one embodiment, the sensitivity of the compound to ROS, such as to H202, can be tuned by exchange and / or modification of the linker, preferably by changing the steric and / or electronic characteristics of the linker, wherein the release of an active drug and / or an active reporter in presence of ROS, such as H202, is faster when the linker is (a) small and / or sterically less demanding compared to the release of an active drug and / or an active reporter in presence of ROS, such as H202, when the linker is (b) large and / or sterically demanding, and / or wherein the release of an active drug and / or an active reporter in presence of ROS, such as H202, is slower when the linker is (a) large and / or sterically demanding compared to the release of an active drug and / or an active reporter in presence of ROS, such as H202, when the linker is (b) small and / or sterically less demanding.

[0052] In one embodiment, the sensitivity of the compound to ROS, such as to H202, can be tuned by exchange and / or modification of R2, preferably by changing the steric and / or electronic characteristics of R2, wherein the release of an active drug and / or an active reporter in presence of ROS, such as H202, is faster when R2is (i) small and / or sterically less demanding compared to the release of an active drug and / or an active reporter in presence of ROS, such as H202, when R2is (ii) large and / or sterically demanding, and / or wherein the release of an active drug and / or an active reporter in presence of ROS, such as H202, is slower when R2is (ii) large and / or sterically demanding compared to the release of an active drug and / or an active reporter in presence of ROS, such as H202, when R2is (i) small and / or sterically less demanding, optionally wherein R2is (i) small and / or sterically less demanding if R2is H, OH, OR15, N(RX5)2, N02, S02, P(R16)3-5, halogen, Ci-C5alkyl, Ci-C5alkoxycarbonyl, alkyne, or alkene, R15is H, OH, halogen, and R16is O, further optionally wherein R2is (ii) large and / or sterically demanding if R2is OR15, N(RX5)2, P(R16)3-5, C6-C2Oalkoxycarbonyl, aryl, or heteroaryl, wherein said aryl or said heteroaryl is optionally substituted with one or more of R18, preferably one or two of R18, R15is C1-C10 alkyl, aryl, or heteroaryl, R16is OR17, R17is P, C1-C10 alkyl, C1-C10 aryl, C1-C10 heteroaryl, or ribose, and

[0053] R18is, at each occurrence, independently selected from H or C1-C5 alkyl, such as wherein R2is (ii) large and / or sterically demanding if R2is phenyl, 2-methylphenyl, 2,6-dimethylphenyl or 2,6-diisopropylphenyl.

[0054] In one preferred embodiment, the compound is a functionalized compound.

[0055] In one embodiment, the sensitivity of the compound to ROS, such as to H202, can be tuned by adjusting the ring size and / or the placement of the heteroatoms in the boron-nitrogen heterocycle of the compound; wherein the release of an active drug and / or an active reporter in presence of ROS, such as H202, is faster when the placement of the heteroatoms in the boron-nitrogen heterocycle is in an BNN configuration (i.e. when one nitrogen atom is placed between a boron atom and a nitrogen atom in the heterocycle, such as in compounds of any of the general formula (I) to (VI)) compared to the release of an active drug and / or an active reporter in presence of ROS, such as H202, when the placement of the heteroatoms in the boron-nitrogen heterocycle is in an NBN configuration (i.e. when one boron atom is placed between two nitrogen atoms in the heterocycle, such as in compounds of any of the general formula (VII)); and / or wherein the release of an active drug and / or an active reporter in presence of ROS, such as H202, is slower when the placement of the heteroatoms in the boron-nitrogen heterocycle is in an NBN configuration compared to the release of an active drug and / or an active reporter in presence of ROS, such as H202, when the placement of the heteroatoms in the boron- nitrogen heterocycle is in an BNN configuration.

[0056] In one aspect, the present invention relates to a kit of pharmaceutical ingredients comprising

[0057] (1) a peptide or a protein which increases the level of reactive oxygen species (ROS), for example an antibody or an enzyme, preferably an L-amino acid oxidase, such as Aplysia punctata ink toxin (APIT), which preferably comprises or consists of an amino acid sequence which is at least 90% identical, preferably at least 95% identical, more preferably at least 98% identical, even more preferably at least 99% identical, optionally identical, to the amino acid sequence of SEQ ID NO. 1, and

[0058] (2) a compound according to any one of the foregoing aspects and embodiments.

[0059] In one aspect, the present invention relates to the use of a compound according to the present invention, or a kit according to the present invention, as a drug delivery system (DDS), in particular a DDS that releases an (active) drug and / or an (active) reporter in presence of reactive oxygen species (ROS), such as hydrogen peroxide (H202). In one aspect, the present invention relates to a compound according to the present invention, or a kit according to the present invention, for use in medicine.

[0060] In one aspect, the present invention relates to a compound according to the present invention, or a kit according to the present invention for use in a method of diagnosis, prevention and / or treatment of a disease, such as a proliferative disease, an inflammatory disease, a neurodegenerative disease, a viral infection, and / or a non-viral infection in a subject in need thereof.

[0061] In one preferred embodiment, the disease to be diagnosed, prevented and / or treated is associated with increased ROS levels in a diseased tissue compared to healthy tissue.

[0062] In one embodiment, the proliferative disease is cancer, preferably a cancer with solid tumor(s).

[0063] In one embodiment, the viral infection is an infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) and / or hepatitis C virus (HCV).

[0064] In one embodiment, the non-viral infection is a microbial infection.

[0065] In one embodiment, the subject is a mammal, such as an animal or a human, preferably a human.

[0066] In one aspect, the present invention relates to a method for the diagnosis, prevention and / or treatment of a disease, such as a proliferative disease, an inflammatory disease, a neurodegenerative disease, a viral infection, and / or a non-viral infection, comprising the administration of a therapeutically effective amount of the compound according to the present invention, i.e. according to any one of the foregoing aspects and embodiments, or the kit according to the present invention, i.e. according to any one of the foregoing aspects and embodiments, to a subject in need thereof.

[0067] In one embodiment, the proliferative disease is cancer, preferably a cancer with solid tumor(s).

[0068] In one embodiment, the inflammatory disease is selected from a group comprising Rheumatoid arthritis; Psoriatic arthritis; Ankylosing spondylitis; Ulcerative colitis; Crohn’s disease; Systemic lupus erythematosus (SLE); Systemic sclerosis (scleroderma); ANCA- associated vasculitis; Giant cell arteritis; Cryopyrin-associated periodic syndromes (CAPS); Tumor necrosis factor receptor-associated periodic syndrome (TRAPS); Hyperimmunoglobulin D syndrome (HIDS) / Mevalonate kinase deficiency; Familial Mediterranean fever (FMF); Still’s disease; Idiopathic pulmonary fibrosis (IPF); Chronic fibrosing interstitial lung diseases with a progressive phenotype; Systemic sclerosis-associated interstitial lung disease (SSc-ILD); Liver fibrosis (including cirrhosis due to nonalcoholic steatohepatitis, viral hepatitis, or primary biliary cholangitis); Chronic kidney disease with renal fibrosis; Intestinal fibrosis / stricturing Crohn’s disease; Cutaneous fibrosis in systemic sclerosis; Chronic pancreatitis with pancreatic fibrosis; Cardiac fibrosis and post-myocardial infarction remodeling.

[0069] In one embodiment, the subject is a mammal, such as an animal or a human, preferably a human.

[0070] In one embodiment, the viral infection is an infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) and / or hepatitis C virus (HCV).

[0071] In one embodiment, the non-viral infection is a microbial infection.

[0072] In one embodiment, the compound or the kit is administered via oral, intravenous and / or intratumoral administration.

[0073] In one aspect, the present invention relates to the use of the compound according to the present invention, or the kit according to the present invention for the manufacture of a medicament for the diagnosis, prevention and / or treatment of a disease, such as a proliferative disease, an inflammatory disease, a neurodegenerative disease, a viral infection, and / or a non-viral infection.

[0074] According to this aspect, the compound, the kit, the subject, the proliferative disease, the inflammatory disease, the neurodegenerative disease, the viral infection and the non-viral infection are as defined herein.

[0075] DETAILED DESCRIPTION

[0076] The terms “of the [present] invention”, “in accordance with the invention”, “according to the invention” and the like, as used herein are intended to refer to all aspects and embodiments of the invention described and / or claimed herein. As used herein, the term “comprising” is to be construed as encompassing both “including” and “consisting of’, both meanings being specifically intended, and hence individually disclosed embodiments in accordance with the present invention. Where used herein, “and / or” is to be taken as specific disclosure of each of the two specified features or components with or without the other. For example, “A and / or B” is to be taken as specific disclosure of each of (i) A, (ii) B and (iii) A and B, just as if each is set out individually herein. In the context of the present invention, the terms “about” and “approximately” denote an interval of accuracy that the person skilled in the art will understand to still ensure the technical effect of the feature in question. The term typically indicates deviation from the indicated numerical value by ±20%, ±15%, ±10%, and for example ±5%. As will be appreciated by the person of ordinary skill, the specific such deviation for a numerical value for a given technical effect will depend on the nature of the technical effect. For example, a natural or biological technical effect may generally have a larger such deviation than one for a man-made or engineering technical effect. Where an indefinite or definite article is used when referring to a singular noun, e.g. "a", "an" or "the", this includes a plural of that noun unless something else is specifically stated.

[0077] In one embodiment, the terms “subject” or “patient”, as used herein, relates to a mammal, such as an animal or a human, preferably a human.

[0078] The term “drug”, as used herein, refers to any chemical substance, molecule, compound, or biologic agent that is intended for use in the diagnosis, treatment, cure, mitigation, or prevention of a disease, disorder, or medical condition in a subject, including humans and animals. The term encompasses substances that exert a pharmacological, immunological, or metabolic effect, and includes both prescription and non-prescription (over-the-counter) agents. In the context of this invention, the drug is preferably selected from a group comprising anti-cancer drugs, such as antimetabolites (e.g., methotrexate), alkylating drugs, such as chlorambucil or cylcophosphamid, topoisomerase blockers, such as etoposide, enzymes, such as asparaginase, hormonal antagonists, such as tamoxifen, mitose blockers, such as vinca alkaloids, camptothecin, anthracyclines, such as doxorubicin, kinase inhibitors, such as erlotinib, gefitinib, imatinib, or lapatinib, hormones, such as estrogens or antiestrogens (e.g., estramustin), fulvestrant, gemcitabine, cytarabine, or proteasome inhibitors, such as bortezomib, anti-inflammatory drugs, such as nonsteroidal anti-inflammatory drugs (e.g. naproxen and diclofenac), corticosteroids, colchicine, antihistamines, and other agents with antiinflammatory properties, virustatics, such as nucleosides (e.g., emitricitabin), nucleotides, such as tenofovir, or non-nucleosides, such as nevirapine, ribavirin, ganciclovir, vidarabine, acyclovir, penciclovir, zalcitabine, protease inhibitors, such as lopinavir, blockers of the integrase, such as raltegravid, entry inhibitors, such as enfuvirtide, or amantadine, and antibiotics, such as betalactam antibiotics, penicillins, aminopenicillins, acylaminopenicillins, cephalosporins, cabapenems, monobactams, aminoglycosides, streptomycin, kanamycins, tetracyclines, macrolides and their analoga, streptogramines, oxazolidones, such as linezolid, benzochinon ansamycins, such as geldanamycin, chloramphenicol, fusidic acid, mupirocin or retapamulin, gyrase inhibitors, such as fluorochinolones, folic acid antagonists, such as sulfonamides, fidaxomicin, cyclic lipopeptids, such as daptomycin, polypeptides, such as polymyxin or colistin, and antitubercular medications, such as isoniazid, pyrazinamide, or ethambutol, RNA polymerase inhibitors, such as rifampicin, or clofazimin drugs, and antimycotic drugs, such as azol-antimycotics (e.g. voriconazole or posaconazole), polyen-antimycotics, such as amphotericin B, nystatin, or natamycin, echinocandines, such as caspofungin, anidulafungin, or micafungin.

[0079] In preferred embodiments, when the drug is coupled and / or attached to the compound, the drug is present in an inactive form. Upon release of the drug from the compound, preferably in or due to the presence of ROS, the drug becomes active upon release.

[0080] The term “anti-inflammatory drugs”, as used herein, refers to any pharmaceutical agent, chemical substance, or biologic compound that is intended to reduce, suppress, or modulate inflammation in the body. Anti-inflammatory drugs act by interfering with one or more pathways of the inflammatory response, such as the inhibition of pro-inflammatory pathways, mediators, or immune cell activity, thereby alleviating symptoms such as pain, swelling, redness, and loss of function associated with inflammatory conditions. The term includes, but is not limited to, nonsteroidal anti-inflammatory drugs (NSAIDs), such as naproxen and diclofenac; corticosteroids, such as prednisone and dexamethasone; colchicine; antihistamines; disease-modifying antirheumatic drugs, such as Methotrexate, Sulfasalazine, Hydroxychloroquine, JAK inhibitors such as Tofacitinib or Baricitinib, Immunospressants such as azathioprine, Cylcosporine, Tacrolomus; Antifibrotic agents with anti-inflammatory activity, such as Nintedanib, Pirfenidone; and any other agents that exert anti-inflammatory effects through pharmacological, immunological, or metabolic mechanisms. Antiinflammatory drugs may be administered by any suitable route, including oral, topical, intravenous, or other methods, and may be used alone or in combination with other therapeutic agents.

[0081] The term “inflammatory disease”, as used herein, refers to any medical condition, disorder, or disease state that is characterized by inflammation, which is a biological response of body tissues to harmful stimuli such as pathogens, damaged cells, or irritants. Inflammatory diseases typically involve symptoms such as pain, swelling, redness, heat, and impaired function, and may affect joints, organs, skin, or other tissues. The term encompasses both acute and chronic conditions, and includes, but is not limited to, diseases such as rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, juvenile idiopathic arthritis, gout, psoriatic arthritis, systemic lupus erythematosus, bursitis, tendinitis, acute musculoskeletal injuries, dysmenorrhea, and inflammatory headache conditions. Inflammatory diseases may result from autoimmune, infectious, metabolic, or idiopathic causes and may require treatment with anti-inflammatory drugs or other therapeutic interventions.

[0082] The term “functionalized compound”, as used herein, refers to a compound having a general formula of any one of formulas (I) to (VII) wherein the choice of any of R1to R19enables and / or influences the targeted control of ROS-sensitivity and / the finetuning thereof; and / or enables coupling of the boron-nitrogen heterocycles to various biological macromolecules, such as polyethylene glycol (PEG), peptides, proteins, such as antibodies, or enzymes, such as Aplysia punctata ink toxin (APIT).

[0083] For example, functionalization maybe performed via coupling and / or attaching a drug or a reporter to at least one boron atom at position R1of a compound having a general formula of any one of formulas (I) to (VII), wherein R1either is or comprises said drug or said reporter, optionally wherein the drug or the reporter is coupled and / or is attached to at least one boron atom of the compound via a linker, wherein the linker is preferably a self-immolative linker. Additionally or alternatively, functionalization may also be performed by exchanging R1or choosing a different R1during synthesis of the compound. Functionalization at R1also comprises the (further) functionalization of the linker, preferably the self-immolative linker, wherein the sensitivity of the compound to ROS, such as to H202, is dependent on steric and / or electronic characteristics of the linker, wherein the linker is preferably a self-immolative linker. Functionalization of the compound may also be performed by choice of R2, wherein the sensitivity of the compound to ROS, such as to H202, is dependent on R2, such as is dependent on steric and / or electronic characteristics of R2. Functionalization of the compound may also be performed by choice of any or R2to R9, and / or their subsequent modifications, which enables, for example, the coupling of the boron-nitrogen heterocycles to various biological macromolecules, such as polyethylene glycol (PEG), peptides, proteins, such as antibodies, or enzymes, such as Aplysia punctata ink toxin (APIT). In preferred embodiments of the present invention, functionalization of the compound at any of positions R1to R19enables the targeted control of ROS-sensitivity, even more preferably, enables the finetuning of targeted control of ROS-sensitivity and also the degree of deactivation of the drug or the reporter. In preferred embodiments, the compound according to the present invention is pharmacologically and / or physiologically inactive, after the drug or reporter is released from the compound, wherein, preferably, pharmacologically and / or physiologically inactive refers to that the BNN heterocycle backbone itself, having a general formula of any one of formulas (I) to (VII) and not comprising a drug and / or a reporter, does not produce a physiological or pharmacodynamic effect that is significant or relevant to the intended therapeutic action. Any residual activity of the backbone is substantially less than, and does not contribute meaningfully to, the therapeutic effect provided by the drug and / or reporter.

[0084] In preferred embodiment, the drug is inactive when coupled to a boron-nitrogen heterocycle backbone of a compound having a general formula of any one of formulas (I) to (VII), preferably via a linker; wherein, when the drug is released from the compound, preferably in the presence of ROS, the drug becomes active upon release. This means that when the compound according to the present invention comprises a drug, it is pharmacologically and / or physiologically inactive.

[0085] The term “pharmacologically and / or physiologically inactive”, as used herein, refers to any substance, compound, or molecular entity that does not produce a detectable or significant effect on biological systems, either at the molecular, cellular, tissue, or organism level, when administered or present under normal conditions. Such substances do not exert therapeutic, toxic, immunological, or metabolic effects in the body, and do not interact with biological targets in a manner that alters physiological, pharmacological, immunological, or metabolic processes. The term encompasses compounds that lack activity in relevant pharmacological assays or physiological tests, and may include excipients, carriers, linkers, or other components that serve structural or functional roles without contributing to the biological, therapeutic, immunological, or metabolic action of the formulation. Also, “pharmacologically and / or physiologically inactive” is used to describe a compound that, after release of the drug or reporter, does not elicit a physiological or pharmacodynamic response that is comparable to or that would interfere with the intended therapeutic action of the released drug or reporter. The BNN heterocycle backbone, according to any of formulas (I) to (VII), is considered inactive in this context, even if it may exhibit minor antibiotic or other effects that are negligible relative to the primary action of the drug or reporter.

[0086] In preferred embodiments, the compound according to the present invention is a drug delivery system and / or can be used as a drug delivery system. In one embodiment, the compound according to the present invention is no angiogenesis inhibitor and / or does not comprise an angiogenesis inhibitor.

[0087] In one embodiment, if the compound of the present invention is having a general formula of any one of formulas (II), (III), (V), the two instances of R1within said compound are either be identical or the two instances of R1are different from each other.

[0088] In one embodiment, both instances of R1are or comprise the same drug or reporter.

[0089] In one embodiment, one R1is or comprises a drug, wherein the other R1is or comprises a reporter.

[0090] In one embodiment, one R1is or comprises a first drug, wherein the other R1is or comprises a second drug.

[0091] In one embodiment, one R1is or comprises a first reporter, wherein the other R1is or comprises a second reporter.

[0092] In one embodiment, when the drug or the reporter is coupled and / or is attached to at least one boron atom of the compound via a linker, the linker may be identical for both R1or the linker is different for both instances of R1.

[0093] In one embodiment, one R1is a drug or reporter, wherein the other R1comprises a drug or reporter.

[0094] In one embodiment, one R1is or comprises a drug or reporter, wherein the other R1is selected from a group comprising NfR1^, C1-C5 alkyl, Ci-C20alkoxycarbonyl, alkyne, aryl, alkene, and heteroaryl.

[0095] In one embodiment one R1is or comprises a drug, wherein the other R1is selected from a group comprising NfR^ C1-C5 alkyl, Ci-C20alkoxycarbonyl, alkyne, aryl, alkene, and heteroaryl.

[0096] In one embodiment one R1is or comprises a reporter, wherein the other R1is selected from a group comprising NfR1^, C1-C5 alkyl, Ci-C20alkoxycarbonyl, alkyne, aryl, alkene, and heteroaryl. In one embodiment, the efficacy and / or tolerability of the compound according to the present invention has been confirmed by studies, such as clinical studies, e.g. animal studies.

[0097] The term “anti-cancer drugs”, as used herein, refers to chemical substances or biological agents that are used to prevent, inhibit, or treat cancer. These drugs work through various mechanisms, such as killing cancer cells, inhibiting their growth and proliferation, or preventing metastasis.

[0098] The terms “cancer” and “cancer cells”, as used herein, refer to any cells that exhibit uncontrolled growth in a tissue or organ of a multicellular organism. Particularly preferred cancers in context of the present invention are cancer with solid tumor(s), such as, however not limited to, breast cancer, lung cancer, prostate cancer, colorectal cancer, pancreatic cancer, liver cancer, kidney cancer, bladder cancer, ovarian cancer, melanoma, or sarcomas.

[0099] The term “antibiotics”, as used herein, refers to chemical substances that are used to kill or inhibit the growth of bacteria. Antibiotics are used to treat bacterial infections and can be classified based on their mechanism of action, such as cell wall synthesis inhibitors, protein synthesis inhibitors, and nucleic acid synthesis inhibitors.

[0100] The term “virustatics”, as used herein, refers to agents that inhibit the replication and spread of viruses within a host organism. These compounds do not necessarily kill the virus but rather prevent its proliferation, thereby helping to control viral infections and reduce disease severity.

[0101] The term “active drug”, as used herein, refers to a pharmaceutical compound that is in a form capable of exerting its intended therapeutic effect. Active drugs interact with biological targets to produce a desired pharmacological response, such as alleviating symptoms, curing disease, or preventing illness. The term “inactive drug”, as used herein, refers to a pharmaceutical compound that is in a form (partially) incapable of exerting its intended therapeutic effect. Inactive drugs may require activation through metabolic processes or maybe rendered inactive due to chemical or physical modifications.

[0102] The term “aryl”, as used herein, refers to an aromatic hydrocarbon group derived from an aromatic ring, such as phenyl or naphthyl. In the context of the present disclosure, the term “aryl” is to be understood that the hydrocarbon group may either be unsubstituted or substituted at one or more positions. Possible substitutions include, but are not limited to, halogen, C1-C5 alkyl, C1-C20 alkoxycarbonyl, alkyne, aryl, alkene, and heteroaryl. The term “heteroaryl”, as used herein, refers to an aromatic ring system in which one or more of the ring atoms is a heteroatom (such as nitrogen, oxygen, or sulfur) in place of a carbon atom. In the context of the present disclosure, the term “heteroaryl” is to be understood that the hydrocarbon group may either be unsubstituted or substituted at one or more positions. Possible substitutions include, but are not limited to, halogen, C1-C5 alkyl, C1-C20 alkoxycarbonyl, alkyne, aryl, alkene, and heteroaryl.

[0103] The term “alkene”, as used herein, refers to a hydrocarbon containing at least one carboncarbon double bond. In the context of the present disclosure, the term “alkene” is to be understood that the hydrocarbon group may either be unsubstituted or substituted at one or more positions. Possible substitutions include, but are not limited to, halogen, C1-C5 alkyl, Ci- C20 alkoxycarbonyl, alkyne, aryl, alkene, and heteroaryl.

[0104] The term “alkyne”, as used herein, refers to a hydrocarbon containing at least one carboncarbon triple bond. In the context of the present disclosure, the term “alkyne” is to be understood that the hydrocarbon group may either be unsubstituted or substituted at one or more positions. Possible substitutions include, but are not limited to, halogen, C1-C5 alkyl, Ci- C20 alkoxycarbonyl, alkyne, aryl, alkene, and heteroaryl.

[0105] The term “alkoxycarbonyl”, as used herein, refers to a functional group with the structure - COOR, where R is an alkyl group. In the context of the present disclosure, the term “alkoxycarbonyl” is to be understood that the group may either be unsubstituted or substituted at one or more positions. Possible substitutions include, but are not limited to, halogen, C1-C5 alkyl, C1-C20 alkoxycarbonyl, alkyne, aryl, alkene, and heteroaryl.

[0106] The term “reporter”, as used herein, refers to any molecule, compound, or substance that is capable of generating a detectable signal, either directly or indirectly, in response to a specific chemical, biological, or physical event or condition. The reporter serves as an indicator, marker, or proxy that enables the qualitative or quantitative assessment of the presence, amount, localization, or activity of another substance, analyte, or biological process. The term “reporter” is intended to encompass any molecule or substance that fulfills the above criteria, regardless of its chemical structure, mode of detection, or application context. The reporter may be covalently or non-covalently attached to another molecule, may be used alone or in combination with other reporters, and may be detected by any suitable analytical, optical, or electronic method. Unless otherwise specified, the term “reporter” is not limited to the examples provided herein and includes any functional equivalent that is capable of providing a detectable signal in accordance with the principles of the present invention. In the context of this invention, the reporter is preferably selected from a group comprising fluorescence dyes, such as near infrared (NIR) dyes, e.g. resorufin or 2-[2-(2,3-

[0107] Dihydro-6-hydroxy-iH-xanthen-3-yl)ethenyl]-i-ethyl-3,3-dimethyl-3H-indolium, diagnostic macromolecules, mass reporters, and chemoluminescence dyes.

[0108] Preferably, when the reporter is coupled and / or attached to the compound, it is present in an inactive form. Upon release of the reporter from the compound, preferably in or due to the presence of ROS, the reporter becomes active upon release.

[0109] The term “fluorescence dye(s)”, as used herein, refers to chemical compounds that can absorb light at a specific wavelength and subsequently emit light at a longer wavelength. These dyes are used extensively in biological and chemical assays to label and visualize molecules, cells, or tissues, and are valuable tools in techniques such as fluorescence microscopy, flow cytometry, and fluorescence in situ hybridization (FISH). Examples for suitable fluorescence dyes are near infrared (NIR) dyes.

[0110] The term “near infrared (NIR) dyes”, as used herein, refers to a specific category of fluorescence dyes that emit light in the near-infrared region of the electromagnetic spectrum, typically between 700 nm and 900 nm. These dyes are particularly useful in biological imaging and diagnostic applications because NIR light penetrates tissues more deeply and with less scattering than visible light, resulting in clearer images. Examples for NIR dyes are resorufin or 2-[2-(2,3-Dihydro-6-hydroxy-if / -xanthen-3-yl)ethenyl]-i-ethyl-3,3-dimethyl-3H- indolium.

[0111] The term “diagnostic macromolecules”, as used herein, refers to large molecules, such as proteins, nucleic acids, or polysaccharides, that are used in diagnostic applications to detect, quantify, or monitor specific biological markers or disease states. These macromolecules can include antibodies, aptamers, enzymes, and other biologically active molecules that interact with target analytes to provide diagnostic information.

[0112] The term “mass reporters”, as used herein, refers to molecules or entities that are used to provide a detectable mass signal in mass spectrometry-based assays. Mass reporters are designed to produce a unique and identifiable mass signature that can be easily distinguished from other components in the sample, thereby enabling precise and accurate measurement of the target compound. They are particularly useful in applications such as quantitative proteomics, drug metabolism studies, and biomarker discovery, where high sensitivity and specificity are essential for detecting and analyzing specific molecules within a complex mixture.

[0113] The term “chemoluminescence dyes”, as used herein, refers to chemical compounds that emit light as a result of a chemical reaction. These dyes are used in various analytical and diagnostic applications, including immunoassays, nucleic acid detection, and reporter gene assays, where the emitted light serves as a measurable signal to indicate the presence or activity of a target analyte or biological process.

[0114] The term “active reporter”, as used herein, refers to a reporter molecule that is in a form capable of producing a detectable signal or response. Active reporters are used in various assays and imaging techniques to monitor biological processes, track molecules, or quantify analytes. The term “inactive reporter”, as used herein, refers to a reporter molecule that is in a form (partially) incapable of producing a detectable signal or response. Inactive reporters may require activation through specific triggers or may be rendered inactive due to chemical or physical modifications.

[0115] The term “steric characteristics”, as used herein, refers to the spatial properties and physical dimensions of a molecule that influence its ability to interact with other molecules. These characteristics include the size, shape, and / or bulkiness of the molecule. In the case of “steric characteristics of a linker” these properties can affect the accessibility and binding of the linked molecules to their respective targets. Steric characteristics play a crucial role in determining the overall conformation and flexibility of the linker, as well as its potential to cause steric hindrance or facilitate favorable molecular interactions. Steric characteristics can be determined or assessed using a variety of methods, for example a method selected from one or more of the group comprising: computational modeling and molecular dynamics simulations; analysis of molecular structures obtained by X-ray crystallography, NMR spectroscopy, or cryo-electron microscopy; calculation of parameters such as van der Waals volume, solvent- accessible surface area, or molecular dimensions; and empirical evaluation of the effects of molecular size and shape on binding affinity, reactivity, and biological activity in experimental assays.

[0116] The term “electronic characteristics”, as used herein, refers to the distribution of electrons within a molecule and the resulting chemical reactivity and interaction potential of the molecule. These characteristics include the presence of electron-donating or electron- withdrawing groups, the overall polarity of the molecule, and its ability to participate in electronic interactions such as hydrogen bonding, dipole-dipole interactions, and TT-TT stacking. Electronic characteristics influence the stability, reactivity, and binding affinity of the molecule. In the case of “electronic characteristics of a linker” these characteristics may also influence its ability to modulate the electronic environment of the linked molecules. Electronic characteristics can be determined or assessed using a variety of methods for example a method selected from one or more of the group comprising: computational chemistry approaches such as quantum chemical calculations and molecular orbital analysis; spectroscopic techniques such as UV-Vis, IR, NMR, or X-ray photoelectron spectroscopy; measurement of physical properties such as dipole moment, redox potential, or pKa; and empirical evaluation of the effects of electronic substituents on chemical reactivity, stability, or binding in experimental assays.

[0117] The term “sterically demanding”, as used herein, refers to a chemical entity or moiety that occupies significant spatial volume and exerts considerable steric hindrance on its surroundings. Such entities can interfere with the binding or interaction of other molecules due to their larger size and increased bulk.

[0118] The term “sterically less demanding”, as used herein, refers to a chemical entity or moiety that occupies less spatial volume and exerts minimal steric hindrance on its surroundings. Such entities are less likely to interfere with the binding or interaction of other molecules due to their smaller size and reduced bulk.

[0119] The term “reactive oxygen species (ROS)”, as used herein, refers to highly reactive chemicals formed from oxygen. These species include, but are not limited to, peroxides, superoxide, hydroxyl radical, and singlet oxygen. ROS are known to play a dual role as both toxic byproducts of cellular metabolism and as signaling molecules that modulate various physiological processes. ROS in the context of the present invention preferably refers to H202.

[0120] The term “increases the level of reactive oxygen species (ROS)”, as used herein, such as in “a peptide / a protein / an enzyme which increases the level of reactive oxygen species (ROS)” refers to any peptide, protein, or enzyme that facilitates the production or accumulation of reactive oxygen species within a biological system. This may occur through various mechanisms, such as the activation of specific metabolic pathways, the catalysis of redox reactions, or the disruption of cellular antioxidant defenses. The terms “release of an (active) drug”, “release of an (active) reporter” and the like, as used herein, refers to the process by which a pharmaceutical ingredient or a reporter molecule is liberated from a formulation or a conjugate, preferably in a biologically active form.

[0121] The term “is coupled to”, as used herein, refers to a chemical or physical linkage between two entities, which may involve covalent bonds, ionic bonds, hydrogen bonds, or other forms of association or which may involve the connection of two entities via a linker, preferably a selfimmolating linker. This coupling can be designed to be stable or cleavable or self-immolating under specific conditions, depending on the intended application.

[0122] The term “is attached to”, as used herein, refers to the state in which one entity is connected to another, either through direct bonding or via a linker, preferably a self-immolating linker. This attachment can influence the properties and functions of the entities involved, and can be reversible or irreversible based on the nature of the bond or linkage.

[0123] The term “linker”, as used herein, refers to a chemical moiety, molecular structure, or group that serves to covalently or non-covalently connect two or more entities within a molecular construct. These entities may include, but are not limited to, drugs, reporters and / or further moieties and the BNN heterocycles having a general formula of any of formulas (I) to (VII). The linker provides a bridge or connection between the attached entities, thereby enabling the formation of conjugates, prodrugs, delivery systems, or other multifunctional molecules.

[0124] A linker may be selected based on its chemical composition, length, flexibility, stability, and responsiveness to various stimuli, depending on the intended application. In one embodiment, the linker is be selected from one or more of a group comprising covalent linkers, non-covalent linkers, cleavable linkers, self-immolative linkers, non-cleavable linkers, spacer linkers, affinity linkers and biorthogonal linkers. In the context of this invention, the linker also refers to the following types:

[0125] Alkyl-based linkers, which comprise one or more alkyl chains (linear, branched, or cyclic hydrocarbons) that provide flexibility and spacing between the connected entities.

[0126] Aryl-based linkers, which comprise aromatic rings (such as phenyl, benzyl, or other aromatic systems) that may impart rigidity, electronic properties, or specific reactivity to the linker.

[0127] Linkers comprising ether groups, which contain one or more ether (-O-) linkages, providing increased flexibility, solubility, or stability to the molecular construct.

[0128] Linkers comprising ester groups, which contain one or more ester (-COO-) functionalities, allowing for potential hydrolytic or enzymatic cleavage under physiological conditions, and which may be used to facilitate controlled release of the attached entity. The term “self-immolative linker”, as used herein, refers to a chemical moiety or molecular structure that is designed to connect two or more entities and that is capable of undergoing spontaneous cleavage or fragmentation upon activation by a specific triggering event or stimulus. Self-immolative linkers may be used to attach a drug or a reporter to the BNN heterocycles having a general formula of any of formulas (I) to (VII) . Upon activation, the self- immolative linker initiates a cascade of chemical reactions that result in the rapid and complete disassembly of the linker structure. This process leads to the release of the attached molecule (such as a drug or reporter) in its active or unmodified form, thereby restoring its original chemical and biological properties. The triggering can be initiated by various stimuli, such as the presence of ROS, enzymatic action, light, or changes in pH, preferably the presence of ROS, and the self-immolative nature ensures that the linker disassembles to a large extent, preferable the linker disassembles completely, releasing the active agent in its original form. Preferably, the triggering event is the presence of ROS. The self-immolative nature of the linker ensures that, upon activation, the linker undergoes disassembly, such that the attached active agent (drug or reporter) is released substantially in its original, unmodified form, preferably, without residual linker fragments remaining attached to the released molecule. Preferably, the self-immolative linker has a general formula of any of formulas (A) to (F).

[0129] The term “further moiety”, as used herein, refers to any additional chemical group, molecular entity, or substituent that is covalently or non-covalently attached to a compound, in particular to a compound having a general formula of any one of formulas (I) to (VII), at one or more positions, such as any of R2to R9. The further moiety may serve to modify, enhance, or impart specific physicochemical, biological, or functional properties to the compound. The further moiety may be attached directly to the compound or indirectly via a linker. In embodiments where more than one further moiety is present, the further moieties may be identical or different, and may be attached to different positions (e.g., any of R2to R9) or to the same position, either directly or via one or more linkers. In certain embodiments, a first further moiety is attached to the BNN heterocycle (optionally via a linker), and a second further moiety is attached to the first further moiety, either directly or indirectly. Combinations of further moieties, such as a polymer or polymer conjugate (preferably PEG or DBCO-PEG) and a peptide or protein (such as one that increases ROS levels), may also be attached to the compound, optionally via a linker.

[0130] The term “alkyl-based linker”, as used herein, refers to a linker composed predominantly of alkyl groups. These linkers are characterized by their flexibility and hydrophobic nature, and are often used to connect molecules in a way that allows for rotational freedom and minimal steric hindrance. The term “aryl -based linker”, as used herein, refers to a linker composed predominantly of aryl groups, which are aromatic hydrocarbons. These linkers are characterized by their rigidity and planarity, and can impart specific electronic and steric properties to the conjugated molecules, influencing their behavior and interactions.

[0131] The term “pharmaceutically acceptable salt thereof’, as used herein, refers to a salt form of a compound that is suitable for use in pharmaceutical applications, ensuring safety and efficacy. These salts may be formed by the reaction of the compound with pharmaceutically acceptable acids or bases, and are used to enhance the solubility, stability, and bioavailability of the compound.

[0132] The term “chemically modified” such as in “the compound is chemically modified”, as used herein, refers to any intentional alteration made to the chemical structure of a compound, which may involve the addition, deletion, or substitution of atoms or functional groups. Chemical modification may be achieved through a variety of chemical reactions or processes, including but not limited to alkylation, acylation, esterification, amidation, oxidation, reduction, halogenation, sulfonation, phosphorylation, glycosylation, conjugation with other molecules, or the introduction of isotopic labels. Chemical modification may be carried out using organic, inorganic, or enzymatic methods. Such modifications can be made to improve the compound's pharmacokinetic properties, alter the stability, reduce toxicity, enhance efficacy, or introduce new functionalities. In one embodiment, chemical modification refers to, but is not limited to, the attachment of a drug or a reporter, either directly or via a linker, preferably a self-immolative linker, or the attachment with one of the group selected from OH, OR1, NfR^ja, N02, SO2, P(R16)3-5, halogen, C1-C5 alkyl, C1-C20 alkoxycarbonyl, alkyne, aryl, alkene, and heteroaiyl, wherein said aryl or said heteroaryl is optionally substituted with one or more of R18, wherein R15, R16and R18are as defined herein.

[0133] The term “Aplysia punctata ink toxin (APIT)”, as used herein, refers to a specific toxin derived from the ink of the sea hare Aplysia punctata, known for its biological activity. This toxin has been studied for its potential therapeutic applications, including its ability to modulate immune responses, inhibit microbial growth, or induce cell death in certain cancer cells. Preferably, said APIT comprises or consists of an amino acid sequence which is at least 90% identical, preferably at least 95% identical, more preferably at least 98% identical, even more preferably at least 99% identical, optionally identical, to the amino acid sequence of SEQ ID NO. 1. The term “drug delivery system (DDS)”, as used herein, refers to a formulation designed to transport a pharmaceutical compound to its target site within the body in a controlled manner. Drug delivery systems aim to improve the efficacy, safety, and bioavailability of drugs by optimizing their release profile, targeting specific tissues or cells, and minimizing side effects.

[0134] The term “antibody”, as used herein, is used interchangeably with the term “immunoglobulin”, and refers to a glycoprotein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds. The term also includes all recombinant forms of antibodies, e.g. antibodies expressed in prokaryotes, unglycosylated antibodies and derivatives as described below. There are five different types of heavy chains, which define antibody isotypes of different functional activity: IgM, IgD, IgG, IgA and IgE. Each heavy chain comprises a heavy chain variable region (abbreviated herein as VH region) and a heavy chain constant region. Each light chain comprises a light chain variable region (abbreviated herein as VL region) and a light chain constant region. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.

[0135] The terms “diagnosis” or “diagnostic”, or similar expressions, as used herein, refer to identifying the presence or absence, or identifying the nature of a condition, preferably a pathologic condition, in a subject. Diagnostic methods differ in their sensitivity and specificity. While a particular diagnostic method may not provide a definitive diagnosis of a condition, it suffices if the method provides a positive indication that aids in diagnosis.

[0136] The term “prevention of a disease”, as used herein, refers to measures or interventions such as a process of providing a subject with a pharmaceutical treatment, e.g., the administration of a drug, such that at least one symptom of the disease prevented from occurring.

[0137] The term “treatment of a disease”, as used herein, refers to therapeutic interventions such as the process of providing a subject with a pharmaceutical treatment, e.g., the administration of a drug, such that at least one symptom of the disease is decreased. Treatment of a disease is aimed at improving, curing, mitigating, or managing the symptoms or progression of a disease in a subject. In the context of the present invention, the BNN heterocycles are depicted using standard conventions established in the field of boron-nitrogen (BN) heterocyclic chemistry. Specifically, the structures are shown with a B=N double bond, and without explicit depiction of formal charges on the boron and nitrogen atoms.

[0138] This approach is based on the following considerations:

[0139] Due to the Lewis acidity of the boron atom in these BNN heterocycles, the electron density of the nitrogen atom’s free eletron pair is delocalized towards the boron atom, resulting in a B=N double bond. From a formal Lewis structure perspective, this delocalization would be represented by assigning a formal negative charge to the boron atom (“-1”) and a formal positive charge to the nitrogen atom (“+i”). However, such a depiction with formal charges does not accurately reflect the actual electronic structure or chemical reactivity of the compounds. In particular, the boron atom remains substantially Lewis acidic, which is a key feature enabling, for example, its reaction with reactive oxygen species (ROS).

[0140] Therefore, it is well-established and widely accepted in the chemistry of BN-heterocycles to depict the B=N bond without indicating the formal charges on boron and nitrogen. This convention provides a more accurate representation of the electronic character and reactivity of these compounds. The omission of formal charges in structural formulae is a standard practice in the field and does not introduce ambiguity regarding the nature or properties of the BNN heterocycles described herein.

[0141] Accordingly, the depiction of the BNN heterocycles in formulae (I) to (V) without formal charges is intentional and consistent with established chemical conventions. This representation should be understood as reflecting the delocalized electronic structure and the persistent Lewis acidity of the boron atom, rather than a strict assignment of formal charges.

[0142] BRIEF DESCRIPTION OF THE FIGURES

[0143] The present invention is now further described by reference to the following figures.

[0144] All methods mentioned in the figure descriptions below were carried out as described in detail in the examples.

[0145] Figure 1. Reaction of the BNN heterocycles to phenols (R = aromatic). Figure 2. Release of the drug (represented by grey circles) in the presence of H202illustrated using a example structure.

[0146] Figure 3. HPLC stability measurements of selected BNN heterocycles upon reaction with 1000 equivalents of ROS.

[0147] Figure 4. HPLC stability measurement of selected BNN heterocycles when reacted by APIT and lysine.

[0148] Figure 5. HPLC stability measurements of selected BNN heterocycles upon reaction with too equivalents of ROS.

[0149] Figure 6. HPLC stability measurements of a BNN-diazaborole and a NBN-diazaborole upon reaction with 1000 equivalents of ROS.

[0150] Figure 7. HPLC stability measurements of BNN heterocycles demonstrate the influence of the ring size of the heterocycles on the ROS-sensitivity.

[0151] Figure 8. Example molecule for ROS-sensitive drug release systems with Camptothecin.

[0152] Figure 9. Example molecule for ROS-sensitive drug release systems with maleimidohexanoic acid.

[0153] Figure 10. HPLC stability measurement of a chlorambucil-modified BNN, when reacted with 1000 equivalents of ROS.

[0154] A) Exemplified reaction mechanism. B) The chlorambucil-modified BNN (compound A) and chlorambucil (compound B) exhibit distinct retention times. C) Stability of compound A and compound B over time.

[0155] Figure 11. Synthesis of compounds of type Fl or Gi without further functionalization at the N atom (PG = protecting group, LG = leaving group, Hal = halogen, Tf = triflate, Ts = tosylate) illustrated using an example structure.

[0156] Figure 12. Synthesis of compounds of type SS post-synthetic functionalization at the N atom (PG = protecting group, LG = leaving group, Hal = halogen, Tf = triflate, Ts = tosylate, M = metal) illustrated using example structures. Figure 13. Stability of exemplary BNN heterocycles according to the present invention in acetonitrile incubated with 1000 eq. of H202.

[0157] Figure 14. Coupling of drugs to BNN heterocycles increases the stability of the compounds. A) Schematic representation of the coupling of Naproxen, Diclofenac or Chlorambucil to an exemplary compound. B) Stability of compounds coupled to Naproxen, Diclofenac or Chlorambucil in PBS buffer.

[0158] Figure 15. Drug release in the presence of radical oxygen species. A) Schematic illustration of active substance release in the presence of H202or in the presence of an enzymes which increase the level of ROS, such as APIT. B) Intensity of the released active substances in the presence of H202over 4 hours. C) Concentration of released active substances over 4 hours. The dashed line represents the maximum amount of diclofenac and naproxen that can be released by the linker molecules.

[0159] Figure 16. Drug release in the presence of APIT. A) Intensity of the released active substances in the presence of ROS produced by APIT over 4 hours. B) Concentration of released active substances over 4 hours. The dashed line represents the maximum amount of Diclofenac and Naproxen that can be released by the linker molecules.

[0160] Figure 17. Synthesis of compounds with a DBCO-PEG-NHS-APIT moiety. R’ is equivalent to R1as defined herein. R” is selected from R2or NR2, wherein R2is as defined herein. A) Attachment of a linker for connecting the BNN heterocycles with a combination of DBCO-PEG and APIT via different synthetical methods. B) Connection of DBCO-PEG-NHS-APIT via click reaction.

[0161] In the following, reference is made to the examples, which are given to illustrate, not to limit the present invention.

[0162] EXAMPLES

[0163] ROS, such as H202, are physiological transmitters, wherein for the levels of ROS pathophysiological differences exist between healthy and diseased tissues. Therefore, the present application aims on exploiting their potential for targeted and controllable drug or reporter release. To this end, the present invention provides compounds comprising boronnitrogen heterocycles which may be differently functionalized and which can be used both therapeutically and diagnostically. Example 1

[0164] In the compounds for drug delivery systems according to the invention, increased concentrations of ROS, in particular H202, are utilized in diseased tissue. In order to utilize the increased H202concentrations, various BNN heterocycles were prepared. The BNN heterocycles according to the invention react in the presence of H2O2to form phenols (Figure i). This reactivity can be used, for example, to determine the hydrogen peroxide level of mitochondria in living cells or oxidative stress in vivo using fluorescence.

[0165] According to the present invention, the phenolic and boronic acid derivatives formed by the H202-induced reaction in the compounds shown subsequently react further and thus release the desired active ingredient in a cascade reaction or already during the decomposition reaction (Figure 2).

[0166] For the compounds described herein, ROS, such as H202, are used as a trigger to release the active drug or the active reporter. An increased ROS concentration, such as an increased H202concentration compared to healthy tissue is therefore necessary for effective drug release in diseased tissue. The compounds according to the present invention are therefore particularly suitable for use in diseases in which an increased ROS level can be observed, such as proliferative diseases, a neurodegenerative diseases, viral infections, or non-viral infections.

[0167] Example 2

[0168] Molecules were produced which can (partially) inactivate the active substance by coupling (self-immolative prodrug), as well as molecules which can additionally be linked to macromolecules by modifying the naphthalenoid benzene ring. Such a coupling to macromolecules can, among other things, enable a targeted distribution of the construct in the body (self-immolative linker).

[0169] One unique feature of this invention is at least the targeted control of ROS-sensitivity and thus also the degree of deactivation through the functionalization of the boron-nitrogen heterocycle. For example, this may involve the targeted control of ROS-sensitivity and thus also the degree of deactivation through the functionalization of the self-immolative linker on the boron or the adjacent a-nitrogen atom. In a series of experiments, the structure-activity principles (SAR) between electronics and sterics of the boron and nitrogen substituents were determined. Without wishing to be bound by any theory, two parameters are proposed for fine tuning, depending on the magnitude of the ROS concentrations present: (1) for increased ROS gradients: manipulating the steric demand on the boron atom, e.g. via ortho-substitution with a suitable residue (alkyl group, aryl group, halogen) / by anellation of the aryl substituent in the form of a naphthalinoid or anthranoid system or

[0170] (2) for lower ROS gradients: modifying the steric demand on the neighboring o-nitrogen atom via analogous manipulations.

[0171] Figure 3 shows an example of the stability of three selected BNN heterocycles with variable steric demand at the boron atom towards 1000 equivalents of ROS. A stabilization of the heterocycles is achieved by successively increasing the steric demand by introducing orthomethyl groups.

[0172] The same effect can be observed when the heterocycles are incubated with the protein APIT and the amino acid lysine (see Figure 4). The enzyme APIT is able to deaminate lysine and generate ROS in the process. These ultimately attack the heterocycles as described above.

[0173] Similarly, Figure 5 shows the stability with variable steric demand on the a-nitrogen atom compared to too equivalents of ROS. Increasing the steric demand by introducing two orthomethyl groups also stabilizes the heterocycles.

[0174] Summary of the underlying experimental procedure:

[0175] For the reaction of the compounds with hydrogen peroxide in Figure 3 a solution (1000 equivalents) was prepared with too pL 3% hydrogen peroxide and 780 pL millipore water. For Figure 5 a too equivalents hydrogen peroxide solution was prepared from 10 pL 3% hydrogen peroxide and 870 pL millipore water.

[0176] A 10 mM stock solution was prepared in acetonitrile. 10 pL of the stock solution was diluted with 990 pL ix phosphate buffered saline to get a concentration of 100 pM. For the reaction with H2O2, 250 pL of the 100 pM solution was mixed with 250 pL of the respective hydrogen peroxide solution so that the final sample concentration was 50 pM.

[0177] For the reaction of the compounds with lysine and Aplysia punctata ink toxin (APIT) (Figure 4), a 100 mM lysine solution was prepared by mixing 0.365 g lysine hydrochloride with 20 mL ix phosphate buffered saline. Then a 10 mM stock solution was prepared in acetonitrile. 10 pL of the stock solution was diluted with 990 pL ix phosphate buffered saline to get a concentration of 100 pM. For the reaction, 250 pL of the 100 pM solution was mixed with 250 pL lysine solution and 1.7 pL APIT, so that the final sample concentration was 50 pM. The analytical HPLC study was performed with an Agilent 1260 infinity II HPLC (Agilent Technologies Inc., Waldbronn, Germany), using a Zorbax XDC-18 analytical 4.6 x 150 mm LC column (Agilent Technologies Inc., Waldbronn, Germany). The instrument was equipped with a variable wavelength detector (G7114A, Agilent 1260 DAD WR), an automatic vial sampler (G7129C, Agilent), a flexible pump (G7104C, Agilent pump (G7104C, Agilent) and 3 multi- column ovens (G7116A, Agilent). For the high-performance liquid chromatography procedure, the mobile phase C was 0.1% formic acid in millipore water. Mobile phase D was acetonitrile with 0.1% formic acid, the flow rate was set to 1 mL / min, the injection volume was 20 pL, and the wavelength of the detector was set to X [nm] = 254, 278, 300, 310 and 350. The gradient was held at 5% D and 95% C for 2 minutes, increased to 100% D and 0% C within 7 minutes, held for 2 minutes, then reduced back to 5% D and 95% C within 2 minutes and held for 2 minutes.

[0178] Example 3

[0179] Besides the substituents, the ROS-sensitivity can also be further adjusted by the ring size and / or the placement of the heteroatoms in the BNN heterocycle. Figure 6 shows the stability of two diazaborole isomers, whereby the NBN isomer is clearly stabilized in comparison to the BNN isomer.

[0180] Moreover, the compounds of the present invention can be used together with various macromolecules that produce ROS, e.g. H202, such as Aplysia punctata ink toxin (APIT). Various strategies are encompassed by the present invention. On the one hand, the compounds can be administered in combination with APIT, on the other hand, it is possible to directly or indirectly attach APIT to a compound having a general formula of any of the formulas (I) to (VII) at any of R2to Ry, preferably at any of R3 to Ry.

[0181] The influence of the ring size of the BNN heterocycle has also been tested. Figure 7 demonstrates that compounds comprising a 5-membered BNN heterocycle exhibit a higher stability compared to compounds comprising a 6-membered BNN heterocycle. These data demonstrate that ROS-sensitivity can be adjusted by the choice of the ring size of the BNN heterocycles or the positioning of the heteroatoms within the heterocycle.

[0182] Example 4

[0183] According to the present invention, it is further possible to couple and / or attach an active drug or reporter to a compound having a general formula of any of the formulas (I) to (VII). As exemplified in Figure 8, a drug, such as the commercially available chemotherapeutic agent camptothecin may be coupled to the compound via an ether bond (Figure 8, left and middle) or via an ester bond (Figure 8, right). In the presence of H202the active drug is released from the compound.

[0184] Moreover, the compounds of the present invention having a general formula of any of the formulas (I) to (VII) may further be modified at one or more of position of R2-9, wherein said modification(s) enable the attachment of at least one further moiety. Figure 9 illustrates the coupling of maleimidohexanoic acid to a compound via a NH2group. This functionalization makes it possible to connect the molecule with macromolecules via free thiols.

[0185] Example

[0186] The release of an active agent from a heterocycle is shown in Figure 10. First, a heterocycle is modified by esterification with the chemotherapeutic agent chlorambucil. This molecule is then reacted with 1000 eq. H202and its absorption measured over 4 h on the HPLC. The modified heterocycle elutes after a retention time of 11.7 min, while chlorambucil elutes after 9.2 min (Figure 10B). Initially, only the modified heterocycle is detected in the chromatogram. However, after an incubation time of one hour, a clear chlorambucil signal can be seen, while the signal of the modified heterocycle is reduced (Figure 10C).

[0187] Example 6

[0188] Synthesis of compounds according to the present invention

[0189] The preparation of the compounds described herein is possible via several synthesis routes. Due to the good yield and simple isolation, the compounds described in the present invention are ring-closed to the BNN heterocycle A in the first step starting from a 2-formylphenyl boronic acid derivative by reaction with a hydrazine derivative. The boronic acid derivative used can also be a thiophene, pyrrole or furan derivative. The hydrazine used can have various substituents on the / ^-nitrogen atom (e.g. H, alkyl, aryl, hydroxy, thiol, COOR, amine protecting group; Figures 11 and 12) and optionally be present as a hydrochloride salt.

[0190] In the next step, if no further nitrogen functionalization is required, the boric acid function is replaced by a better leaving group such as a boronic acid ester Bi (R = silyl, alkyl, aryl), a halogen B2 or a triflate / tosylate B3. Subsequently, the boron atom is functionalized by reaction with a trimethyl silyl compound in a TMSC1 (trimethylsilyl chloride) elimination reaction or, alternatively, a suitable nucleophile to Ci or C2 in a metathesis reaction. Suitable carbon nucleophiles for this purpose include alkali metal organyls (R'-Li, R'-Na, R'-K), Grignard reagents (R'MgX), organocuprates or organocer compounds. In the case of a molecule such as Ci, a deprotection (Di) and subsequent leaving group transformation (El) is then carried out. Final reaction with deprotonated camptothecin can yield Fl-type compounds (Figure 11).

[0191] Alternatively, a conjugate of the form Gi can also be obtained by direct reaction of Bi, B2 or B3 with deprotonated camptothecin in a metathesis reaction (Figure 11).

[0192] For an additional functionalization of the Ni atom, either the parent hydrazine N2H4or an N- protected hydrazine with deprotection after ring closure reaction is used to obtain the parent compound A2 (Figure 12). Here, the boric acid function is also replaced by a more suitable leaving group such as a boronic acid ester B4 (R = silyl, alkyl, aryl), a halogen B5 or a triflate / tosylate B6. Subsequently, the boron atom is functionalized by reaction with a suitable nucleophile in a metathesis reaction with simultaneous deprotonation to Hi. Suitable carbon nucleophiles for this purpose include alkali metal organyls (R'-Li, R'-Na, R'-K), Grignard reagents (R'MgX), organocuprates or organocer compounds.

[0193] The metallated diazaborinines of type Hi can be isolated and subsequently further functionalized at the Ni atom. By reaction with suitable organoboron compounds, compounds of type H2 can be obtained which, for example, allow the introduction of a substituent R" (R" = aryl, OR, halogen, C1-C5 alkyl, C1-C4 alkoxy, C1-C20 alkoxycarbonyl) by transition metal- catalyzed cross-coupling reactions (H3). Similarly, an R"-substituted diazaborinine H3 can be obtained by reaction of Hi with an organotriflate, -tosylate, or -iodide. By reaction with a carboxylic acid source such as carbon dioxide, carboxylic acid amides (H4) are obtained. Compounds of type H5 can be obtained by reaction with suitable transition metal precursors. The reaction with phosphorus halides (H6) with subsequent hydrolysis yields phosphoric acid derivatives (H7) which are subsequently functionalized with sugar molecules (H8). Depending on the carbon nucleophile used, the N-functionalization can be followed by camptothecin loading analogous to Figure 11.

[0194] Example 7

[0195] In Example 2 the stability of exemplary BNN heterocycles according to the present invention was assessed in an aqueous solution (PBS-Buffer). However, to exclude the possibility of side effects due to a possibly poor water solubility of the compounds, the stability of exemplary compounds was also tested in acetonitrile incubated with 1000 eq. of H202(Figure 13).

[0196] Compounds LEOO63, LEO165 and LEOO73 are similar to the compounds tested in Example 2, where they have been incubated with 1000 eq. H202(Figure 3) and with APIT (Figure 4). The stability of compounds LEO167, LEOO73 and LEO156 in aqueous solution when incubated with too eq. H202is shown in Example 2 and Figure 5.

[0197] Figure 13 demonstrates the stability of these and other selected BNN heterocycles with variable steric demand at the boron atom and the nitrogen atom towards 1000 equivalents of ROS in an acetonitrile environment (H202in acetonitrile). A stabilization of the heterocycles is achieved by successively increasing the steric demand. However, the electron pushing group of compound LEO162 (methyl ether) and the electron withdrawing group of compound LEO163 (triflour methyl) destabilize the compounds towards ROS. This shows that the stability of the BNN heterocycle can be influenced by the substituents at the boron and nitrogen atoms.

[0198] Summary of the underlying experimental procedure:

[0199] For the reaction of the compounds with hydrogen peroxide in (Figure 13) a solution (1000 equivalents) was prepared with 20.4 pL 30% hydrogen peroxide and 979.6 pL acetonitrile. A 10 mM stock solution was prepared in acetonitrile. 20 pL of the stock solution was diluted with 980 pL acetonitrile to get a concentration of 200 pM. For the reaction with H202, 250 pL of the 200 pM solution was mixed with 250 pL of the respective hydrogen peroxide solution so that the final sample concentration was too pM. The analytical HPLC study was performed as described in Example 2.

[0200] Example 8

[0201] In the next step, it should be analyzed whether the stability of the compounds in an aqueous solution can be altered by coupling drugs to the BNN heterocycles. As can be seen in Figure 14, the example compound LEA04 exhibits poor stability in PBS buffer. However, when coupled to various drugs, such as naproxen, diclofenac and chlorambucil, the stability of the compound in a PBS solution is increased significantly (Figure 14 A-B). This indicates that the compounds can be influenced by modifying the chemical environment around the BNN heterocycle.

[0202] Summary of the underlying experimental procedure:

[0203] For the reaction of the compounds Linker-Nap roxen, Linker-Diclofenac and Linker- Chlorambucil with PBS-Buffer a 10 mM stock solution of all three compounds were prepared in acetonitrile. 2 pL of the stock solution was diluted with 68 pL PBS-Buffer and 30 pl DMSO to get a concentration of 200 pM. For the mixing with PBS, too pL of the 200 pM stock solution was mixed with too j_iL PBS-Buffer so that the final sample concentration was too pM. The analytical HPLC study was performed as described in Example 2.

[0204] Next, it was analyzed whether the compounds are capable of releasing the drugs that are coupled and / or attached to the BNN heterocycles in dependence of the presence of radical oxygen species. To this end, the drug release of the example compounds of Example 8, i.e. compounds Linker-Naproxen, Linker-Diclofenac and Linker-Chlorambucil, was assessed (Figure 15A). Figure 15B demonstrates that the exemplary compounds are capable of releasing not only tumor therapeutics such as Chlorambucil, but also other drugs such as Naproxen and Diclofenac in the presence of radical oxygen species (H202). The bar chart shows the intensity of the released active substances when incubated with H202over a time course of 4 hours. The longer the compounds are incubated with H202the more drug (Naproxen and Diclofenac) gets released. The intensity of Chlorambucil decreases slightly over time (Figure 15B). However, a decrease in the measured intensity of Chlorambucil released over a period of 4 hours can be seen. This is presumably not due to less active substance being released, but rather to the fact that Chlorambucil is not stable in an aqueous environment.

[0205] Moreover, the released amounts of Diclofenac and Naproxen were determined using a calibration curve (Figure 15C). The experiments show that around 50-60% of Naproxen and around 30-40% of Diclofenac is released after 4 hours, wherein the compound coupled to Naproxen appears to be more sensitive to reactive oxygen species than the compound coupled to Diclofenac.

[0206] Due to the fact that Chlorambucil is decaying over time in PBS-Buffer, the exact released amount of Chlorambucil could not be determined. Nevertheless, these results convincingly demonstrate that the compound of the present invention can be used as a drug delivery system that is capable of releasing different drugs in the presence of radical oxygen species.

[0207] Summary of the underlying experimental procedure:

[0208] For the reaction of the compounds Linker-Naproxen, Linker-Diclofenac and Linker- Chlorambucil with hydrogen peroxide in a solution (too equivalents) was prepared with 2 pl 30% hydrogen peroxide and 998 pL PBS-Buffer. A 10 mM stock solution of all three compounds was prepared in acetonitrile. 2 pL of the stock solution was diluted with 68 pL PBS- Buffer and 30 pl DMSO to get a concentration of 200 pM. For the reaction with hydrogen peroxide 100 pL of the 200 pM solution was mixed with toopL of the respective hydrogen peroxide solution so that the final sample concentration was too pM. The analytical HPLC study was performed as described in Example 2.

[0209] Example 10

[0210] In the next step, it was assessed whether the compound according to the present invention is capable of releasing not only tumor therapeutics such as chlorambucil, but also other drugs such as naproxen and diclofenac in the presence of the protein APIT which is able to produce radical oxygen species. Thus, this experiment aimed on determining the sensibility of exemplary compounds in presence of radical oxygen species generated through the protein APIT, instead of pure H202. Figure 16A shows the intensity of the released active substances over 4 hours while incubated with APIT. The longer the compounds are incubated with the protein the more drug gets released.

[0211] The released amounts of Diclofenac and Naproxen were determined using a calibration curve (Figure 16B). It can be seen that around 5-6% of Naproxen and around 1-2% of Diclofenac gets released after 4 hours, wherein the compound coupled to Naproxen appears to be more sensitive to reactive oxygen species than the compound coupled to Diclofenac.

[0212] Even though, the intensity of Chlorambucil, Diclofenac and Naproxen is about 10 times lower compared to the experiment with pure H202in Example 9 (Figure 15B-C), the results demonstrate that the exemplary compounds can release different drugs not only in the presence of pure H202but also in presence of peptides or proteins which increases the level of reactive oxygen species (ROS), for example an antibody or an enzyme which increases the level of ROS, such as APIT.

[0213] Summary of the underlying experimental procedure:

[0214] For the reaction of the compounds Linker-Nap roxen, Linker-Diclofenac and Linker- Chlorambucil with lysine and Aplysia punctata ink toxin (APIT), a too mM lysine solution was prepared by mixing 0.365 g lysine hydrochloride with 20 mL lx phosphate buffered saline (PBS-Buffer). A 10 mM stock solution of all three Linker-drug-compounds was prepared in acetonitrile. 2 pL of the stock solution was diluted with 68 pL PBS-Buffer and 30 pl DMSO to get a concentration of 200 pM. For the reaction, too pL of the 200 pM solution was mixed with 96.6 pL lysine solution and 3.4 pL APIT (1 mg / mL), so that the final sample concentration was too pM. The analytical HPLC study was performed as described in Example 2. Example 11

[0215] The compounds according to the present invention may comprise one or more further moieties or a combination of two or more further moieties that are attached to each other, such as a combination of a polymer or polymer conjugate, e.g. polyethylene glycol (PEG) or DBCO-PEG, and a peptide or a protein, such as a peptide or a protein which increases the level of reactive oxygen species (ROS). These further moieties may be attached to the BNN heterocycle via a linker.

[0216] The attachment of a linker for connecting the BNN heterocycles with a combination of DBCO- PEG and APIT can be performed via different synthetical methods (Figure 17A). The first being Buchwald Hartwig coupling to connect bifunctional aryl linkers with the BN-nitrogen atom (II’). Second being the metalation of the N-H unit which gives a suitable platform for a wide range of functionalization reactions (III’) (see also Figure 12), thereby allowing for the introduction of bifunctional linkers. The metalation procedure has previously been established (Wiist et al., 2025).

[0217] After metalation, for example by deprotonation of the N-H-functionality with strong, non- nucleophilic bases such as Na[HMDS] or K[HMDS], the resulting compounds can be reacted in situ with substrates such as alkyl iodides (e.g., TBDMS-protected 3-iodopropanol) (IV’). Following deprotection of the hydroxy group, the obtained N-alkylated diazaborinine can be either directly coupled to APIT by esterification or be further converted into an organo azide via Mitsunobu reaction (IX’). The latter allows for connecting APIT to the DAB via a click reaction (Figure 17B).

[0218] The azide group (-N3) is highly reactive, especially in click chemistry (IX’). In this example, a DBCO-PEG-NHS (Dibenzocyclooctine-polyethylene glycol -N-hydroxy succinimide) is highly suitable to prepare the APIT for a copper-free free click reaction with the azide-modified DAB- linker. In a subsequent step, the DBCO-modified APIT is reacted with the azide-modified DAB- linker. ROS formation by APIT results in the discharge of a drug or reporter coupled to R’, wherein R’ equals R1as defined herein.

[0219] Besides alkyl iodides possible substrates to form alcohols are also epoxides which can be opened up by nucleophilic attack from a metalated Diazaborinine (V’) (Figure 17A). In addition to reactions with alkyl iodides, the metalated diazaborinines may also be reacted with carbon dioxide (VT) and subsequently treated with trimethylsilyl chloride to yield carboxylsubstituted diazaborinines. These DABs with carboxyl function can then be used for coupling of the DAB to the APIT by esterification. Furthermore, metalated diazaborinines may be reacted with trimethylsilyl chloride or trimethyltin chloride to form jV-tri methyl silyl (VII’) or N-trimethylstannyl (VIII’) diazaborinines. These groups can subsequently be exchanged, for example by elimination of TMSC1, and thereby also provide a tool for late-stage functionalization.

[0220] Conclusion

[0221] The above examples convincingly and surprisingly show that the boron-nitrogen heterocycles of the present invention are highly suitable for the targeted and controllable release of an active drug or an active reporter in diseased tissues with increased ROS concentrations. In particular, in a series of experiments, the structure-activity principles (SAR) between electronics and sterics of the boron and nitrogen substituents were determined. By functionalizing at the boron atom, using different ring sizes and BNN positions in the ring, as well as independent functionalization at the nitrogen atom, fine adjustment of the ROS-sensitivity of the compounds is made possible by steric and electronic factors. This fine adjustment enables a targeted and controllable release of the active substance / dye / fluorophore in tissues in which the ROS concentration is upregulated due to various diseases. First, a ROS-induced reaction enables the conversion of the BNN heterocycles to phenylboronic acid derivatives and phenol derivatives. By prior attachment of cascade linkers to the boron or nitrogen atom or direct attachment of the active substance / dye / fluorophore to the boron or nitrogen atom, the active substance is then released unchanged (self-immolative prodrug). The above-examples further demonstrate that different types of drugs can be attached to the BNN heterocycles and that these drugs can be released in the presence of ROS or peptides or a proteins which increase the level of reactive oxygen species (ROS), such as APIT. Moreover, possible functionalization on the aromatic compound enables coupling of the boron-nitrogen heterocycles to various biological macromolecules, such as polyethylene glycol (PEG), DBCO-PEG, peptides, proteins, such as antibodies, or enzymes, such as Aplysia punctata ink toxin (APIT). The examples show that by this functionalization, the BNN heterocycles of the present invention can comprise a drug and / or reporter in combination with peptides or a proteins which increase the level of reactive oxygen species (ROS). This enables, among other things, an extension of the half-life or a targeted distribution of the construct in the body. In this case, the boron-nitrogen heterocycles may act as linkers between the macromolecule and the active substance (self- immolative linkers). In particular, substances that are used for the treatment of diseases in which the concentration of ROS is upregulated are to be used as drugs or active substances.

[0222] REFERENCES

[0223] 1Wiist, L., Scheming, L., Welinitz, T., Radacki, K., & Braunschweig, H. (2025). Alkali metal salts of 1, 2, 3-benzodiazaborines: platforms for late-stage N-functionalization and metal complexation. Chemical Science, 16(22), 9934-9942.

Claims

Julius-Maximilians-Universitat WurzburgCLAIMS1. A compound having a general formula of any one of formulas (I) to (VII)whereinR1is or comprises, at each occurrence, independently a drug or a reporter, or is, at each occurrence, independently selected from a group comprising N(RX5)2, C1-C5 alkyl, Ci- C20alkoxycarbonyl, alkyne, aryl, alkene, and heteroaryl, wherein at least one R1is or comprises a drug or a reporter, optionally wherein the drug or the reporter is coupled and / or is attached to at least one boron atom of the compound via a linker, wherein the linker is preferably a self- immolative linker, such as an alkyl -based linker or an aryl -based linker, and / or a linker comprising an ether and / or an ester group,R2to R9 are, at each occurrence, independently selected from a group comprising H, OH, OR15, N(RX5)2, NO2, SO2, P(R16)3-5, halogen, C1-C5 alkyl, C1-C20 alkoxycarbonyl, alkyne, aryl, alkene, and heteroaryl, wherein said aryl or said heteroaryl is optionally substituted with one or more of R18, preferably one or two of R18,X is O, NR>5, S, SO, or S02,R' is, at each occurrence, independently selected from a group comprising H, OH, halogen, C1-C10 alkyl, aryl, heteroaryl, and (C=0)R19,R16is, at each occurrence, independently O or OR17,R17is, at each occurrence, independently selected from a group comprising P, C1-C10 alkyl, C1-C10 aryl, Ci-C 10 heteroaryl, and ribose,R18is, at each occurrence, independently H or C1-C5 alkyl, andR19is, at each occurrence, independently C3-C10 alkyl, optionally substituted with a maleimide group, or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein at least one boron atom or nitrogen atom of the compound is chemically modified.

3. The compound according to claim 1 or 2, wherein the linker, preferably the self- immolative linker, has a general formula of any one of formulas (A) to (F):wherein R10, R11, R12, and R13are each independently selected from a group comprising H, OH, OR15, halogen, C1-C10 alkyl, aryl, and heteroaryl, and wherein R14is or comprises a drug or a reporter.

4. The compound according to any one of claims 1 to 3, wherein the compound comprises one or more further moieties, wherein the one or more further moiety is preferably a polymer or a polymer conjugate, more preferably polyethylene glycol (PEG) or DBCO-PEG, wherein said polymer or polymer conjugate is preferably attached to the compound having a general formula of any one of formulas (I) to (VII) at any of R2to R9, more preferably at any of Rs to R9, and / or wherein the one or more further moiety is preferably a peptide or a protein, such as a peptide or a protein which increases the level of reactive oxygen species (ROS), for example an antibody or an enzyme which increases the level of ROS, preferably an L- amino acid oxidase, such as Aplysia punctata ink toxin (APIT), which comprises or consists of an amino acid sequence which is at least 90% identical, preferably at least 95% identical, more preferably at least 98% identical, even more preferably at least 99% identical, optionally identical, to the amino acid sequence of SEQ ID NO. 1, wherein said peptide or protein is preferably covalently attached to the compound having a general formula of any one of formulas (I) to (VII) at any of R2to R9, more preferably at any of R3to R9; wherein, optionally, one or more of the further moieties, are attached to the compound having a general formula of any one of formulas (I) to (VII) via a linker.

5. The compound according to any one of claims 1 to 4, wherein R1or R14is or comprises a drug which is selected from a group comprising anti-cancer drugs, such as antimetabolites (e.g., methotrexate), alkylating drugs, such as chlorambucil or cylcophosphamid, topoisomerase blockers, such as etoposide, enzymes, such as asparaginase, hormonal antagonists, such as tamoxifen, mitose blockers, such as vinca alkaloids, camptothecin, anthracyclines, such as doxorubicin, kinase inhibitors, such as erlotinib, gefitinib, imatinib, or lapatinib, hormones, such as estrogens or antiestrogens (e.g., estramustin), fulvestrant, gemcitabine, cytarabine, or proteasome inhibitors, such as bortezomib, anti-inflammatory drugs, such as nonsteroidal anti-inflammatory drugs (e.g. naproxen and diclofenac), corticosteroids, colchicine, and antihistamines, virustatics, such as nucleosides (e.g., emitricitabin), nucleotides, such as tenofovir, or non-nucleosides, such as nevirapine, ribavirin, ganciclovir, vidarabine, acyclovir, pencici ovir, zalcitabine, protease inhibitors, such as lopinavir, blockers of the integrase, such as raltegravid, entry inhibitors, such as enfuvirtide, or amantadine, andantibiotics, such as betalactam antibiotics, penicillins, aminopenicillins, acylaminopenicillins, cephalosporins, cabapenems, monobactams, aminoglycosides, streptomycin, kanamycins, tetracyclines, macrolides and their analoga, streptogramines, oxazolidones, such as linezolid, benzochinon ansamycins, such as geldanamycin, chloramphenicol, fusidic acid, mupirocin or retapamulin, gyrase inhibitors, such as fluorochinolones, folic acid antagonists, such as sulfonamides, fidaxomicin, cyclic lipopeptids, such as daptomycin, polypeptides, such as polymyxin or colistin, and antitubercular medications, such as isoniazid, pyrazinamide, or ethambutol, RNA polymerase inhibitors, such as rifampicin, or clofazimin drugs, and antimycotic drugs, such as azol-antimycotics (e.g. voriconazole or posaconazole), polyen-antimycotics, such as amphotericin B, nystatin, or natamycin, echinocandines, such as caspofungin, anidulafungin, or micafungin.

6. The compound according to any one of claims 1 to 5, wherein R1or R14is or comprises a reporter which is selected from a group comprising fluorescence dyes, such as near infrared (NIR) dyes, e.g. resorufin or 2-[2-(2,3- Dihydro-6-hydroxy-iH-xanthen-3-yl)ethenyl]-i-ethyl-3,3-dimethyl-3H-indolium, diagnostic macromolecules, mass reporters, and chemoluminescence dyes.

7. The compound according to any one of claims 1 to 6, wherein the coupling and / or attaching of the drug or the reporter to a boron-nitrogen heterocycle backbone of a compound having a general formula of any one of formulas (I) to (VII) inactivates the drug or the reporter, such as partially and / or temporarily inactivates the drug or the reporter, optionally wherein an active drug and / or an active reporter is released in presence of a reactive oxygen species (ROS), such as hydrogen peroxide (H202).

8. The compound according to any one of claims 1 to 7, wherein the sensitivity of the compound to ROS, such as to H202, is dependent on steric and / or electronic characteristics of the linker, wherein the linker is preferably a self-immolative linker, and wherein the release of an active drug and / or an active reporter in presence of ROS, such as H202, is faster when the linker is (a) small and / or sterically less demanding compared to the release of an active drug and / or an active reporter in presence of ROS, such as H202, when the linker is (b) large and / or sterically demanding, and / or wherein the release of an active drug and / or an active reporter in presence of ROS, such as H202, is slower when the linker is (a) large and / or sterically demandingcompared to the release of an active drug and / or an active reporter in presence of ROS, such as H202, when the linker is (b) small and / or sterically less demanding.

9. The compound according to any one of claims 1 to 8, wherein the sensitivity of the compound to ROS, such as to H202, is dependent on R2, such as is dependent on steric and / or electronic characteristics of R2, and wherein the release of an active drug and / or an active reporter in presence of ROS, such as H2O2, is faster when R2is (i) small and / or sterically less demanding compared to the release of an active drug and / or an active reporter in presence of ROS, such as H2O2, when R2is (ii) large and / or sterically demanding, and / or wherein the release of an active drug and / or an active reporter in presence of ROS, such as H202, is slower when R2is (ii) large and / or sterically demanding compared to the release of an active drug and / or an active reporter in presence of ROS, such as H2O2, when R2is (i) small and / or sterically less demanding, optionally wherein R2is (i) small and / or sterically less demanding if R2is H, OH, OR15, N(RX5)2, NO2, SO2, P(R16)3-5, halogen, C1-C5 alkyl, C1-C5 alkoxycarbonyl, alkyne, or alkene,R15is H, OH, halogen, andR16is O, further optionally wherein R2is (ii) large and / or sterically demanding if R2is OR15, N(RX5)2, P(R16)3-5, C6-C20 alkoxycarbonyl, aryl, or heteroaryl, wherein said aryl or said heteroaryl is optionally substituted with one or more of R18, preferably one or two of R18,R' is C1-C10 alkyl, aryl, or heteroaryl,R16is OR1',R'7is P, C1-C10 alkyl, C1-C10 aryl, C1-C10 heteroaryl, or ribose, andR18is, at each occurrence, independently selected from H or C1-C5 alkyl, such as wherein R2is (ii) large and / or sterically demanding if R2is phenyl, 2- methylphenyl, 2,6-dimethylphenyl, or 2,6-diisopropylphenyl.

10. The compound according to any one of claims 1 to 9, wherein R5is 6-Maleimidohexanamide moiety.

11. A kit of pharmaceutical ingredients comprising(1) a peptide or a protein which increases the level of reactive oxygen species (ROS), for example an antibody or an enzyme, preferably an L-amino acid oxidase, such as Aplysia punctata ink toxin (APIT), which comprises or consists of an amino acid sequence which is at least 90% identical, preferably at least 95% identical,more preferably at least 98% identical, even more preferably at least 99% identical, optionally identical, to the amino acid sequence of SEQ ID NO. 1, and (2) a compound according to any one of claims 1 to 10.

12. Use of a compound according to any one of claims 1 to 10, or a kit according to claim 11, as a drug delivery system (DDS), in particular a DDS that releases an (active) drug and / or an (active) reporter in presence of reactive oxygen species (ROS), such as hydrogen peroxide (H202).

13. The compound according to any one of claims 1 to 10, or the kit according to claim 11, for use in medicine.

14. The compound according to any one of claims 1 to 10, or the kit according to claim 11, for use in a method of diagnosis, prevention and / or treatment of a disease, such as a proliferative disease, an inflammatory disease, a neurodegenerative disease, a viral infection, and / or a non-viral infection in a subject in need thereof; wherein, preferably, the proliferative disease is cancer, more preferably a cancer with solid tumor(s); and / or wherein, preferably, the viral infection is an infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) and / or hepatitis C virus (HCV); and / or wherein, preferably, the non-viral infection is a microbial infection.

15. A method for the diagnosis, prevention and / or treatment of a disease, such as a proliferative disease, an inflammatory disease, a neurodegenerative disease, a viral infection, and / or a non-viral infection, comprising the administration of a therapeutically effective amount of the compound according to any one of claims 1 to 10, or the kit according to claim 11, to a subject in need thereof; wherein, preferably, the proliferative disease is cancer, more preferably a cancer with solid tumor(s); and / or wherein, preferably, the viral infection is an infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) and / or hepatitis C virus (HCV); and / or wherein, preferably, the non-viral infection is a microbial infection; wherein, optionally, the compound or the kit is administered via oral, intravenous and / or intratumoral administration.

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