Alichondrichlorin for use in treating cancer

Abstract

The present disclosure relates to a compound for use in medicine or veterinary, preferably for use in treating cancer, wherein the compound is alichondrichlorin, which has formula I, or a pharmaceutically acceptable salt, hydrate, solvate, N-oxide, stereoisomer, diastereoisomer, enantiomer or atropisomer, polymorph or ester thereof. Furthermore, the present disclosure relates to a pharmaceutical composition comprising said compound and at least a pharmaceutical acceptable ingredient.

Description

D E S C R I P T I O NALICHONDRICHLORIN FOR USE IN TREATING CANCERTECHNICAL FIELD

[0001] The present disclosure relates to the field of medicinal chemistry and biotechnology, in particular to novel bioactive compounds derived from marine microorganisms. More specifically, it relates to a novel chlorinated compound designated as alichondrichlorin, produced by the marine planctomycetal bacterium Alienimonas chondri strain LzC2, and its use in medicine or veterinary.

[0002] Alienimonas chondri strain LzC2 was received on 17 April 2025 at the University of Coimbra Bacteria Culture Collection (UCCCB) - International Depositary Authority under the Budapest Treaty, with the address Pa$o das Escolas, 3004-531 Coimbra, Portugal, under the accession number UCCCB 264.BACKGROUND

[0003] Humanity continually seeks the discovery of new molecules that could offer beneficial therapeutical or other biotechnological applications. New classes of compounds are especially sought after, as they can potentially generate new effects and have unique properties. Nature has always been a source for chemical inspiration, due to the inherent complexity and biological functions of natural products. However, some habitats and specific taxonomic groups of organisms have been already extensively researched for this purpose, which often leads to rediscovery of already known products or simple variations within the same structural classes. An exciting strategy to find novel chemical diversity would be to explore yet uncharted biomes, such as marine microbial communities (Santos et al., 2020).

[0004] Planctomycetota form a group of Gram-negative bacteria with diverse uncommon and curious features (Wiegand et al., 2020). Ecologically, these bacteria have been found to inhabit most environments, particularly in marine microbiomes, but were also found to be abundant in terrestrial ones, like soils (Vitorino and Lage, 2022). Planctomycetota characteristically have large genomes, high G+C content andextensive unknown coding regions, which can be correlated with flexible metabolite production (Kallscheuer and Jogler, 2021).

[0005] Varied studies have highlighted the diversity and complexity of the biosynthetic gene clusters (BGCs) present in planctomycetal strains (Wiegand et al., 2020; Kallscheuer and Jogler, 2021, Vitorino and Lage, 2022). In-vitro bioactivity screenings have also demonstrated that Planctomycetota are indeed capable of producing bioactive metabolites, however, the compounds responsible for these effects remain unidentified (Wiegand et al., 2020; Kallscheuer and Jogler, 2021, Vitorino and Lage, 2022).

[0006] Based on published studies on Planctomycetota chemistry, the existing collection of natural products derived from these bacteria is still rather limited. It encompasses only four chemically distinct structural types of molecules, amounting to a total of eleven individual compounds, all recently reported. These consist of: (1) three carotenoids, including a rare one, of the saproxanthin family identified in two different Planctomycetia strains (Kallscheuer et al., 2019), (2) 3,5-dibromo-p-anisic acid, a small halogenated molecule that was isolated from a novel yet undescribed planctomycete, likely belonging to the order Pirellulales (Panter et al., 2019), which was considered to have herbicidal activity, (3), stieleriacines A-E, novel / V-acylated tyrosines with mild antimicrobial effects on Gram positive bacteria (Kallscheuer et al., 2020; Sandargo et al., 2020) and (4), two fatty acids obtained from a marine Rhodopirellula baltica strain, including a novel chlorinated one and the known malyngic acid (Lee et al., 2011). Out of these, only stieleriacines and the chlorinated fatty acid were classified as novel compounds, while the other molecules were already previously reported as naturally occurring products in other organisms.

[0007] Cancer remains one of the leading causes of morbidity and mortality worldwide, representing a significant global health burden. Despite continuous advances in cancer diagnosis and therapy, millions of new cases are diagnosed annually, and many cancers still lack effective, targeted, and well-tolerated treatments. The complex and heterogeneous nature of cancer, characterized by uncontrolled cell proliferation, resistance to apoptosis, and frequent relapse, creates an ongoing need for novel therapeutic agents. However, discovering new anticancer compounds thatare both effective and safe remains a substantial scientific and clinical challenge. Many cytotoxic agents lack tumor specificity and are associated with severe side effects due to damage to healthy cells. As a result, there is a pressing demand for new compounds that can selectively target cancer cells while minimizing toxicity to normal tissues.

[0008] These facts are disclosed in order to illustrate the technical problem addressed by the present disclosure.GENERAL DESCRIPTION

[0009] The preset disclosure relates to a compound for use in medicine or veterinary, wherein the compound has a formula I or a pharmaceutically acceptable salt, hydrate, solvate, N-oxide, stereoisomer, diastereoisomer, enantiomer or atropisomer, polymorph or ester thereof.Formula I

[0010] Compound of formula I, also known as alichondrichlorin, is a novel secondary metabolite isolated from Alienimonas chondri strain LzC2. It was surprisingly found that this compound exhibits selective anti-proliferative activity against human cancer cell lines, in particular human breast adenocarcinoma MCF-7, without significant cytotoxicity against non-tumoral human cells.

[0011] The compound was tested against a panel of five human tumor cell lines— MCF- 7 (human breast adenocarcinoma), Hep G2 (hepatocyte carcinoma), A2058 (human skin melanoma), A549 (human lung carcinoma), and MIA PaCa-2 (pancreas carcinoma)— as well as one non-tumoral cell line, THLE-2, derived from human liver cells. The compound of formula I exhibited a potent and selective anti-proliferative effect on tumor cell lines. The most pronounced activity was observed against the MCF-7 breast adenocarcinoma cell line, with an ECso value of 4.06 pM, indicating strong inhibition of cellular proliferation at low micromolar concentrations. Hep G2cells showed also sensitivity to this compound, with an ECso value of 11.5 pM, while A2058 melanoma cells were inhibited at an ECso of 20.8 pM.

[0012] Importantly, no substantial cytotoxicity was observed in the non-tumoral THLE- 2 cell line under the same experimental conditions, with ECso values exceeding 50 pM.

[0013] These results demonstrate that the compound of formula I possesses a targeted cytotoxic profile, with pronounced activity against specific cancer cell lines— particularly MCF-7— while sparing non-cancerous human cells.

[0014] An aspect of the present disclosure relates to a compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, N-oxide, stereoisomer, diastereoisomer, enantiomer or atropisomer, polymorph or ester thereof.Formula I

[0015] In an embodiment, the compound may be used in medicine or veterinary.

[0016] In an embodiment, the compound may be used in the prevention or treatment of hyperproliferative tissue or a neoplasia.

[0017] In an embodiment, the compound may be used in the in the prevention or treatment of cancer.

[0018] In an embodiment, the compound may be used in the in the prevention or treatment of breast cancer.

[0019] In an embodiment, the compound may be used in the in the prevention or treatment of triple-negative breast cancer or estrogen-positive breast cancer.

[0020] In an embodiment, the compound may be used in the in the prevention or treatment of liver cancer.

[0021] In an embodiment, the compound may be used in the in the prevention or treatment of hepatocellular carcinoma.

[0022] In an embodiment, the compound may be used in the prevention or treatment of skin cancer; preferably skin melanoma.

[0023] Another aspect of the present disclosure relates to a pharmaceutical composition comprising the compound of formula I and at least a pharmaceutical acceptable excipient.

[0024] Another aspect of the present disclosure relates to a pharmaceutical composition comprising (i) a therapeutically effective amount of a compound of general formula I; and (ii) at least a pharmaceutically acceptable excipient.

[0025] Another aspect of the present disclosure relates to the use of a compound of general formula I for the manufacture of a medicament for the treatment of cancer.

[0026] Another aspect of the present disclosure relates to a method for treating or preventing cancer in a subject, the method comprising administering the compound of general formula I to the subject.BRIEF DESCRIPTION OF THE DRAWINGS

[0027] The following figures provide preferred embodiments for illustrating the disclosure and should not be seen as limiting the scope of invention.

[0028] Figure 1: Planar structure of alichondrichlorin (a), key COSY and HMBC correlations of substructures A and B (b and c, respectively), key NOESY correlations showing the relative stereochemistry of the chlorohydrin moiety (d) and proposed main conformation of the chlorohydrin moiety (e).

[0029] Figure 2: Chromatogram showing the first round of purification of alichondrichlorin (1) by reversed-phase HPLC (mobile phase was constituted by water (A) and acetonitrile (B) both with 0.1 % TFA). UV detection was set at 254 nm (grey trace) and 210 nm (bold trace).

[0030] Figure 3: HPLC trace (210 nm) (a, Figure 3.1), UV (DAD) (b, Figure 3.2) and (+)- ESI-TOF (c, Figure 3.3) spectra of alichondrichlorin (1).

[0031] Figure 4: Expansion of the (+)-ESI-TOF spectrum of alichondrichlorin (1) (a, Figure 4.1) and comparison of the theoretical (b) an experimental (c) (Figure 4.2) isotopic distribution for the [M+H]+ adduct.

[0032] Figure 5:1H NMR spectrum of alichondrichlorin (1) in CD3OD (500 MHz, 24 °C).

[0033] Figure 6:13C NMR spectrum of alichondrichlorin (1) in CD3OD (125 MHz, 24 °C).

[0034] Figure 7: Dose-response curve of alichondrichlorin tested against MCF-7 (a, Figure 7.1), Hep G2 (b, Figure 7.2), A2058 (c, Figure 7.3), MIA PaCa-2 (d, Figure 7.4) and A549 (e, Figure 7.5) human tumoral cell lines plus the non-tumoral THLE-2 cell line (f, Figure 7.6). Highest concentration tested was 50 pM. Activity of -100% corresponds to total inhibition of cellular growth.DETAILED DESCRI PTION

[0035] The preset disclosure relates to a compound for use in medicine or veterinary, wherein the compound has a formula I or a pharmaceutically acceptable salt, hydrate, solvate, N-oxide, stereoisomer, diastereoisomer, enantiomer or atropisomer, polymorph or ester thereof. Furthermore, the present disclosure relates to a pharmaceutical composition comprising said compound and at least a pharmaceutical acceptable ingredient.

[0036] The new molecule obtained in the present disclosure was designated as alichondrichlorin after the taxonomic name of its producer species (Alienimonas chondri). This report expands the currently limited collection of described bioactive planctomycetal metabolites.

[0037] This work contemplates the description of a large-scale cultivation study of strain LzC2, followed by metabolite extraction and compound isolation using chromatographic approaches, which resulted in the isolation of a novel molecule designated as alichondrichlorin. Structural elucidation of this new molecule was accomplished by a combination of high-resolution mass spectrometry and nuclear magnetic resonance. The molecule was additionally screened for anti-proliferative bioactivity against human tumoral and non-tumoral cell lines. These cytotoxicity assays revealed a targeted effect of alichondrichlorin in the growth of tumoral cell lines, especially human breast adenocarcinoma MCF-7 cell line (ECso=4.O6 pM) without effect on the human non-tumoral THLE-2 cell line (ECso>5O pM).Isolation and structural elucidation of alichondrichlorin

[0038] A scaled-up cultivation of the recently isolated and characterized marine planctomycetal strain Alienimonas chondri LzC2 (Vitorino et al., 2020; Vitorino et al., 2021a) was subjected to chemical analyses to search for possible novel bioactive secondary metabolites. The isolation procedure is described below in the "Experimental procedure" section.

[0039] The HPLC-HRMS analysis of one of the fractions obtained after flash chromatography detected the presence of a putative novel molecule that was purified through semi-preparative reversed phase HPLC (Figure 2).

[0040] The new compound, alichondrichlorin (1) (Figure 1 a), was obtained as a white amorphous solid. (+) Electrospray Ionization Time-of-Flight (ESI-TOF) analysis identified a protonated adduct [M + H]+at m / z 583.3762 (Figure 3), consistent with a molecular formula of C33H55CIO6 and an isotopic distribution confirming the presence of one chlorine atom in the molecule (Figure 4). Inspection of its1H and13C NMR spectra (Figures 5 - 6) and 2D (COSY, HSQC, TOCSY, NOESY and HMBC) NMR spectra revealed the presence in the molecule of a 1,4-disubstituted benzene ring (de 132.8 and 116.3; dH 7.85 and 6.82 ppm, respectively), three signals accounting for oxygenated / chlorinated methines (de 73.3, 72.6, and 64.9; dH 4.03, 5.07, and 4.34, respectively) one doublet methyl group (de 20.6; dH 1.31) and signals for a long aliphatic chain (de 30.6-30.9; dn 1.28). Key COSY and HMBC correlations (Table 1 and Figure 1 b,c) allowed to establish the substructures A and B depicted in Figure 1. Particularly, the attachment of the p-hydroxybenzoic moiety to C-25 was secured by a weak HMBC correlation between H-25 and C-l' and the low field chemical shift of H-25 in substructure A. Substructures A and B were connected by a long aliphatic chain whose length was established based on the molecular formula determined for the compound.

[0001] Table 1. NMR data (CD3OD, 500 MHz) for alichondrichlorin (1)Determined from the indirect dimension of the HMBC spectrum

[0041] Once the planar structure of 1 was established, we investigated the relative configuration of the chlorohydrin moiety. It was proposed to be syn (threo) (Figure 1 a,d,e) based on the comparison of the obtained experimental NMR data with published ones for similar structural moieties (Masuda et al., 1994; Kaluzna et al., 2005; Hirose et al., 2008). For 1, coupling constant JH2-H3 was found to be small (4.3 Hz in CD3OD and 2.8 Hz in CDCI3). A1H-1H coupling constant of 8 Hz was measured in structurally similar bromohydrins (carrying a carbonyl next to the halogenated position) with anti (erythro) configurations (Masuda et al., 1994). These bromohydrin- containing molecules meet the Stiles-House rule due to intramolecular hydrogen bond between the carbonyl and the hydroxy group of the bromohydrin moiety, a behaviour that can also be extended to chlorohydrins next to carbonyl groups (Hirose et al., 2008). Coupling constants reported for a-chloro, |3-hydroxy-ethyl esters with both syn and anti relative configurations for the chlorohydrin moiety can likewise be safely employed for comparison purposes (Kaluzna et al., 2005). Based on these studies, an anti (erythro) relative configuration in the chlorohydrin moiety of 1 is not compatible with the small observed JH2-H3 and therefore, the relative configuration of the chlorohydrin moiety was established as syn (threo). Key NOESY correlations observed in CDCI3 further support this proposal (Figure Id). The configuration of C-25 remainedundetermined. Paucity of sample impeded to perform hydrolysis and Mosher analysis to confirm the absolute configuration of the molecule.Tumoral cytotoxic activity of alichondrichlorin

[0042] In-vitro biological evaluation of alichondrichlorin was performed against a panel of diverse human tumoral cell lines and one non-tumoral cell line, to evaluate if the effect is specific on tumour cells. Respective dose-response curves obtained are represented in Figure 7. This molecule demonstrated a strong growth inhibitory effect in human breast adenocarcinoma MCF-7, with a calculated EC50 value of 4.06 pM (Cl 95% 1.82-9.06 pM) (Figure 7.1). EC50 values of 11.5 pM (Cl 95% 9.8-13.5 pM) and 20.8 pM (Cl 95% 18.1-23.7 pM) were observed in hepatocyte carcinoma Hep G2 and human skin melanoma A2058 (Figure 7.2 and 77.3, respectively. At the highest concentration tested (50 pM), no substantial effects were observed against human lung carcinoma A549 or pancreas carcinoma MIA PaCa-2, as well as against the non-tumoral cell line THLE-2 from a human liver (Figure 7.4-7.6), highlighting the targeted cytotoxicity possessed by this molecule.Experimental procedures

[0043] Cultivation of Alienimonas chondri strain LzC2 and organic extraction of metabolites

[0044] Alienimonas chondri strain LzC2 (Accession number UCCCB 264) is a pink pigmented strain that was previously isolated from the biofilm of the macroalgae Chondrus crispus, collected in a rocky beach near Porto, in Portugal (Vitorino et al., 2020; Vitorino et al., 2021b). The 16S rRNA gene phylogenetic analysis of this strain classified it as a novel species in the bacterial phylum Planctomycetota (class Planctomycetia, order Planctomycetales and family Planctomycetaceae) (Vitorino et al., 2020; Vitorino et al., 2021a; Vitorino et al., 2021b).

[0045] Alienimonas chondri strain LzC2 is also deposited at the Spanish Type Culture Collection (CECT), with the address C / Catedratico Agustin Escardino, 9. 46980 Paterna (Valencia), Spain, received on 17.12.2019 under the accession number CECT 30038, and deposited at the BCCM / LMG Bacteria Collection with the address Laboratory ofMicrobiology Ghent University, K.L. Ledeganckstraat 35, 9000 (Ghent), Belgium, received on 07.09.2020, under the accession number LMG 31701.For the purpose of chemical analysis and molecule isolation, strain LzC2 was cultivated on a large scale (57 L) in glass flasks of 1 L each containing 750 mL of the culture medium M600, prepared as previously described (Lage and Bondoso, 2011; Vitorino et al., 2021b). Cultures were incubated for 7 days at 25°C under constant shaking (120 rotations per minute-rpm). The biomass was separated from the broth through centrifugation [3600 rpm for 10 min in a 5810R Centrifuge (Eppendorf, Hamburg, DE)] and the collected cell pellet was freeze-dried to yield 103 g of cellular material. Cells were extracted with an acetone / methanol mixture (1:1) for several consecutive periods of 1 h while under agitation (120 rpm). Organic solvents were then collected by filtration through cheese cloth and Whatman No 1 filter paper in a Buchner funnel and dried in a rotatory vacuum evaporator (Rotavapor’ R-100, BUCHI, Flawil, CH) to obtain a crude extract (1.5 g).Isolation of alichondrichlorin

[0046] The organic extract previously obtained was mixed with generic silica gel 80 g in a SiliaSep™80g cartridge (FLH-R10030B-IS080, SILICYCLE) and fractioned by flash chromatography in a Pure C- 850 FlashPrep equipment (BUTCHI Flawil, CH). The mobile phase (80-minute run, 12 mL / min flow rate) was constituted by mixture of hexane (A), ethyl acetate (B) and methanol (C), following diverse linear gradients: 30 min ascend from 90 % A + 10 % B to 0 % A + 100 % B, 10 min 100 % B, 30 min ascend to 0 % B + 100 % C and 10 min 100 % C.

[0047] The composition of each fraction obtained was then evaluated by high- performance liquid chromatography coupled to high-resolution mass spectrometry (HPLC-HRMS) conducted as described previously (Martin et al., 2014), and the obtained analytical data searched against MEDINA'S proprietary database (Perez- Victoria et al., 2016) and the Dictionary of Natural Products (DNP) to dereplicate possible known compounds (Taylor and Francis, 2023).

[0048] Purification of the fraction containing the compound of interest (1) was achieved through high performance liquid chromatography in a Gilson GX-281 HPLC(Gilson Technologies, Middleton, Wl, USA) with a reversed-phase C8 column (Zorbax RX-C8, 9.4 x2.5 nm, 5 pm particle diameter). The mobile phase was composed of HPLC grade water (A) and acetonitrile (B), both supplemented with 0.1% trifluoracetic acid (TFA), eluted in a linear gradient of 75-87 %B in 31 min (3.6 mL / min), with UV detection set at 210 nm and 254 nm. Fractions containing the molecule of interest (1) were combined and repurified using the same stationary phase with a linear gradient of 80-85 % B (+0.1 % TFA) in 38 minutes (3.6 mL / min) to yield 0.5 mg of alichondrichlorin with a retention time of 23.7 min.Fain

[0049] Alichondrichlorin (1). -13.0 (c 0.25, MeOH); UV (DAD) Xmax210, 254 nm; forXH and13C NMR data see Table 1; (+)-ESI-TOFMS m / z 583.3762 [M+H]+(calcd for C33H5635CIO6+, 583.3760, D +0.3 ppm); 600.4025 [M+NH4]+(calcd for C33H5935CINO6+, 600.4025, D 0 ppm).General experimental procedures

[0050] Optical rotations were measured in a Jasco P-2000 polarimeter (JASCO Corporation, Tokyo, Japan) in methanol. ID- and 2D-NMR spectra were recorded on a Bruker Avance III spectrometer (500 and 125 MHz for1H and13C NMR, respectively) equipped with a 1.7 mm TCI MicroCryoProbe™ (Bruker Biospin, Fallanden, Switzerland). Chemical shifts were reported in ppm using the signals of the residual solvents as internal reference (6H 3.31 and 6c 49.1 for CD3OD). LC-UV- ESI-TOF analysis was performed using a Bruker maXis QTOF (Bruker Daltonik GmbH, Bremen, Germany) mass spectrometer coupled to an Agilent 1200 LC (Agilent Technologies, Waldbronn, Germany) under conditions already described (Martin et al., 2014).In vitro evaluation of tumoral anti-proliferative activity

[0051] Biological effects of the isolated molecule (1) were evaluated using the MTT assay (Mosmann, 1983), performed in a high-throughput 96-well-plate format according to MEDINA'S workflow (Subko et al., 2021). Pure compound (1) was tested in triplicate starting at a concentration of 50 pM and following serial % dilutions, for 72h, against a panel of 5 tumour cell lines including: human skin melanoma A2058 (ATCC CRL-11147), human lung carcinoma A549 (ATCC CCL-185), breast adenocarcinomaMCF-7 (ATCC HTB-22), pancreas carcinoma MIA PaCa-2 (ATCC CRL-1420) and hepatocyte carcinoma Hep G2 (ATCC HB-8065). As a cytotoxicity control, the compound was additionally tested against the non-tumoral human cell line THLE-2 (ATCC CRL-2706). Data resulting from the assays was interpreted and analysed using the Genedata Screener Software and the EC50 values (half maximal effective concentration) determined accordingly (Cautain et al., 2015).

[0052] Ines Vitorino was supported by a "Funda^ao para a Ciencia e Tecnologia (FCT)" doctoral grant (SFRH / BD / 145577 / 2019). This work was financially co-supported by the project ATLANTIDA (ref. NORTE-01-0145-FEDER-000040), supported by the Norte Portugal Regional Operational Program (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement and through the European Regional Development Fund (ERDF).

[0053] This work was also possible thanks to WP9- Portuguese Blue Biobank under the Blue Economy Pact - Project N^. C644915664-00000026 co-funded by PRR, The Portuguese Republic and the European Union.

[0054] As used herein, the terms "treatment" or "treating" are used in reference to a pharmaceutical or other intervention regimen for obtaining beneficial or desired results in the recipient. Beneficial or desired results include but are not limited to a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit may refer to eradication or amelioration of symptoms or of an underlying disorder being treated. Also, a therapeutic benefit can be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. A prophylactic effect includes delaying, preventing, or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. For prophylactic benefit, a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease may undergo treatment, even though a diagnosis of this disease may not have been made.

[0055] The term "comprising" whenever used in this document is intended to indicate the presence of stated features, integers, steps, components, but not to preclude thepresence or addition of one or more other features, integers, steps, components or groups thereof.

[0056] The disclosure should not be seen in any way restricted to the embodiments described and a person with ordinary skill in the art will foresee many possibilities to modifications thereof. The above-described embodiments are combinable.

[0057] The following dependent claims further set out particular embodiments of the disclosure.ReferencesCautain B., de Pedro N., Schulz C. et al. (2015) Identification of the Lipodepsipeptide MDN- 0066, a Novel Inhibitor of VHL / HIF Pathway Produced by a New Pseudomonas Species. PLoS One 10:e0125221 doi: 10.1371 / journal.pone.0125221Hirose T., Sunazuka T., Tsuchiya S., Tanaka T., Kojima Y., Mori R., Iwatsuki M., Omura S. (2008) Total Synthesis and Determination of the Absolute Configuration of Guadinomines B and C2. Chemistry - A European Journal 14:8220-8238 doi:Kallscheuer N., Jeske O., Sandargo B. et al. (2020) The planctomycete Stieleria maiorica Mall5(T) employs stieleriacines to alter the species composition in marine biofilms. Commun Biol 3:303 doi: 10.1038 / s42003-020-0993-2Kallscheuer N., Jogler C. (2021) The bacterial phylum Planctomycetes as novel source for bioactive small molecules. 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(2016) Combined LC / UV / MS and NMR Strategies for the Dereplication of Marine Natural Products. Planta Med 82:857-871 doi: 10.1055 / s-0042-101763 4Sandargo B., Jeske O., Boedeker C. et al. (2020) Stieleriacines, N-Acyl Dehydrotyrosines From the Marine Planctomycete Stieleria neptunia sp. nov. Front Microbiol 11:1408 doi: 10.3389 / fmicb.2020.01408Santos J.D., Vitorino I., Reyes F., Vicente F., Lage O.M. (2020) From Ocean to Medicine: Pharmaceutical Applications of Metabolites from Marine Bacteria. Antibiotics (Basel) 9 doi: 10.3390 / antibiotics9080455Subko K., Wang X., Nielsen F.H. et al. (2021) Mass Spectrometry Guided Discovery and Design of Novel Asperphenamate Analogs From Penicillium astrolabium Reveals an Extraordinary NRPS Flexibility. 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Claims

C L A I M S1. Compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, N- oxide, stereoisomer, diastereoisomer, enantiomer or atropisomer, polymorph or ester thereof:Formula I for use in medicine or veterinary.

2. Compound for use according to the previous claim for use in the prevention or treatment of hyperproliferative tissue or a neoplasia.

3. Compound according claim 1 for use in the prevention or treatment of cancer.

4. Compound according to claim 1 for use in the prevention or treatment of breast cancer.

5. Compound for use according to the previous claim for use in the prevention or treatment of triple-negative breast cancer or estrogen-positive breast cancer.

6. Compound for use according to claim 3 for use in the prevention or treatment of liver cancer.

7. Compound for use according to the previous claim for use in the prevention or treatment of hepatocellular carcinoma.

8. Compound for use according to claim 3 for use in the prevention or treatment of skin cancer; preferably skin melanoma.

9. Pharmaceutical composition comprising the compound according to claim 1 and at least a pharmaceutical acceptable excipient.

10. Pharmaceutical composition according to the previous claim comprising (i) a therapeutically effective amount of a compound according to claim 1; and (ii) at least a pharmaceutically acceptable excipient.

11. The use of a compound according to claim 1 for the manufacture of a medicament for the treatment of cancer.

12. A method for treating or preventing cancer in a subject, the method comprising administering the compound of claim 1 to the subject.

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