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WO2024028519A1 - Composés et leur utilisation en tant qu'agents photodynamiques - Google Patents

Composés et leur utilisation en tant qu'agents photodynamiques Download PDF

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WO2024028519A1
WO2024028519A1 PCT/EP2023/071852 EP2023071852W WO2024028519A1 WO 2024028519 A1 WO2024028519 A1 WO 2024028519A1 EP 2023071852 W EP2023071852 W EP 2023071852W WO 2024028519 A1 WO2024028519 A1 WO 2024028519A1
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alkyl
cancer
sulphonate
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Nasim SABOURI
Marco DEIANA
Clement Cabanetos
Cyrille MONNEREAU
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/06—Peri-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/12—Keratolytics, e.g. wart or anti-corn preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/06—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered

Definitions

  • the invention relates to compounds of formula (I) and derivatives thereof. These compounds act as photosensitizing agents, that upon photon absorption generates cytotoxic reactive oxygen species.
  • the invention also relates to pharmaceutical compositions comprising these compounds and to the use of these compounds as a DNA damaging agent and in the treatment of various forms of cancer, skin conditions, and ophthalmology conditions.
  • BACKGROUND Exosomes are nanometre scale vesicles involved in inter-cellular signalling. When present inside the cell, the exosomes are localised inside multivesicular bodies (MVBs). At that time, they are commonly referred to as intraluminal vesicles (ILVs).
  • the intraluminal vesicles Upon fusion of the MVB with the cell membrane, the intraluminal vesicles are released into the extracellular space, at which point they are referred to as exosomes (Grant, B.D. et al. Nat Rev Mol Cell Biol 10, 597-608 (2009) and Zhang, Y. et al. Cell Biosci 9, 19 (2019)).
  • Bioactive molecules such as DNA, RNA, and proteins, carried inside the exosome, are then transported from the inside of the cell to the outside of the cell. They are also involved in key biological processes including cell to cell communication (Balaj, L. et al. Nat Commun 2, 180 (2011); Thakur, B.K. et al. Cell Res 24, 766-9 (2014); Mateescu, B. et al.
  • G4 structures The position of G4 structures is predicted not to be randomly spread in the nuclear genome, but enriched at certain areas i.e., at promoters, at ribosomal DNA, and at telomeres (Varshney, D et al. Nat Rev Mol Cell Biol 21, 459-474 (2020)).
  • BG4 specific antibody Biffi, G. et al. Nat Chem 5, 182-6 (2013) and Biffi, G. et al. PLoS One 9, e102711 (2014)
  • live-cell fluorescent probes Liu, L.Y. et al. Angew Chem Int Ed Engl 59, 9719-9726 (2020); Deiana, M. et al.
  • G-rich sequences are sensitive to reactive oxygen species (ROS) (Fleming, A.M. & Burrows, C.J. et al. J Am Chem Soc 142, 1115-1136 (2020)).
  • ROS reactive oxygen species
  • This sensitivity to oxidative stress can be applied in cancer therapeutics to induce cancer cell death, especially as many cancer cells have impaired DNA damage response (DDR) machinery.
  • Light-activated anticancer strategies including photodynamic therapy (PDT), have been established as safe, non-surgical methods for treating numerous cancer types.
  • PDT involves the administration of a photosensitizing (PS) agent that upon photon absorption promotes the generation of cytotoxic reactive oxygen species (ROS).
  • PS photosensitizing
  • ROS cytotoxic reactive oxygen species
  • the primary selectivity of PDT is due to the control of the illumination of particular regions with high spatiotemporal precision.
  • organelle-selective PS agents targeting the nuclei, mitochondria and lysosomes have been reported and their phototherapeutic properties deeply investigated, for example by Wang et. al. (ACS Appl Mater Interfaces 13, 19543-19571 (2021)).
  • the majority of these PS agents show relatively low triplet quantum yields and phototoxicity index (the ratio of the IC 50 values in the dark to those obtained upon light irradiation).
  • Fig.2 shows the cytotoxic effects of 2-(pentan-3-yl)-1H-benzo[7,8]thioxantheno[2,1,9- def]isoquinoline-1,3(2H)-dione (DBI) on a) HeLa cells and b) MCF-7 cells.
  • Fig.3 shows the cytotoxic effects of 2-(pentan-3-yl)benzo[lmn]naphtho[2,1- c][2,8]phenanthroline-1,3(2H,6H)-dione on HeLa cells a) without light, and b) with light.
  • Fig 4 shows the cytotoxic effects of 2-(pentan-3-yl)-1H-benzo[7,8]xantheno[2,1,9- def]isoquinoline-1,3(2H)-dione on HeLa cells a) without light, and b) with light.
  • Fig.5 shows the cytotoxic effects of DBI on tumor organoids.
  • Fig.6 shows growth of yeast cells in liquid media containing a reference or DBI after light treatment.
  • DETAILED DESCRIPTION OF THE INVENTION The present invention discloses heavy-metal free photosensitizers that feature a twisted ⁇ - conjugated system providing enhanced intersystem crossing capabilities and consequential singlet oxygen ( 1 O2) generation efficiency, designed to overcome the limitations outlined in the background.
  • the disclosed compounds show high phototherapeutic efficacy at low nanomolar concentrations against monolayer cancer cells and 3D tumour organoids.
  • the high cytotoxicity is demonstrated by in vivo experiments on zebrafish embryos.
  • the compounds of the invention are shown to be accumulated in ILVs/exosomes as well as its subcellular G4 structures.
  • the photoinduced generation of 1 O 2 reveals a close connection between DNA damage, G4 structures, and replicative stress that ultimately lead to cell death.
  • the dual targeting of cancer mediators/markers ILVs/exosomes and G4s renders the present compounds very suitable for broad biomedical applications, for example treatment of cancer, various skin conditions, bacterial infections, and ophthalmology conditions.
  • the present compounds show a high phototherapeutic efficacy even in systems with reduced oxygen supply.
  • the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from a group consisting of C 1-20 alkyl, C 3-6 cycloalkyl, COOH, C 1-20 COOH, COOC 1-20 alkyl, COC 1-20 alkyl, CONHC 1-20 alkyl, C 1-20 alkyl sulphonate, C 1-20 alkyl phosphonate, C 6-20 aryl, C 4-20 heteroaryl, C 1-4 alkyloxy C 1-4 alkyl sulphonate, methyl (C 1-4 alkyloxy C 1-4 alkyl sulphonate) 2 , C 1-4 alkyl terminally substituted with a C 5-6 heterocyclyl with one or two heteroatoms being O, S or N, C 1-4 alkyl terminally substituted with N(C 1-4 alkyl)(C 1-4 al
  • C 1-20 alkyl refers to a straight or branched alkyl group having from 1 to 20 carbon atoms.
  • Examples of C1-20 alkyl include methyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, octyl, dodecyl, heptadecyl and icosyl.
  • C3-6 cycloalkyl refers to a monocyclic saturated hydrocarbon ring having from 3 to 6 carbon atoms. Examples of C3-6 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • COOC1-20 alkyl As used herein, the terms “COOC1-20 alkyl”, “COC1-20 alkyl”, and “CONHC1-20” refers to a straight or branched alkyl group being attached to the nitrogen atom of formula (I) via an ester, a ketone, or an amide, where the nitrogen atom of formula (I) is bound the carbonyl carbon in the respective moieties.
  • C1-20 alkyl sulphonate” and “C1-20 alkyl phosphonate” refers to a straight or branched alkyl group being attached to the nitrogen atom of formula (I) via a sulphonate or a phosphonate group.
  • C 6-20 aryl refers to an aryl group having 6-20 carbon atoms, having one or more aromatic rings.
  • C6-20 aryl include phenyl, naphthyl, terpenyl, phenantryl, and antracyl.
  • C 4-20 heteroaryl refers to an aryl group having 4-20 carbon atoms, and wherein one or more atom is N, O or S, and having one or more aromatic rings.
  • Examples of C 4-20 heteroaryl include pyridyl, triazyl, and azanaphthyl.
  • the invention relates to a compound of formula (I), wherein R 1 is selected from a group consisting of C1-20 alkyl, C3-6 cycloalkyl, COOH, COOC1-20 alkyl, COC1-20 alkyl, CONHC 1-20 alkyl, C 1-20 alkyl sulphonate, C 1-20 alkyl phosphonate, C 6-20 aryl, C 4-20 heteroaryl, C 1-4 alkyloxy C 1-4 alkyl sulphonate, methyl (C 1-4 alkyloxy C 1-4 alkyl sulphonate) 2 , C 1-4 alkyl terminally substituted with a C 5-6 heterocyclyl with one or two heteroatoms being O, S or N, C 1-4 alkyl terminally substituted with N(C 1-4 alkyl)(C 1-4 alkyl), polyethylene glycol, an amino acid, zwitterionic (C 1-4 alkyl)N + (C 1-4 alkyl) 2 (C 1-4 alkyl), poly
  • R 1 is an amino acid selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, hydroxyproline, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, and an amino acid according to formula (II), wherein R 6 is selected from a group consisting of C1-20 alkyl, COOC1-20 alkyl, COC1-20 alkyl, CONHC1-20 alkyl, C1-20 alkyl sulphonate, C1-20 alkyl phosphonate, C6-20 aryl, C4-20 heteroaryl, C1-4 alkyl terminally substituted with a C5-6 heterocyclyl with one or two heteroatoms being O, S or N, C1-4 alkyl terminally substituted with N(C
  • R 1 is C 1-20 alkyl, or any one of .
  • R 2 and R 3 are independently selected from H, halogen, CF3, CN, and NO2.
  • R 2 and R 3 are H.
  • R 4 is selected from H, halogen, CF 3 , CN, and NO 2 , preferably H.
  • R 5 is selected from the group consisting of C 1-20 alkyl, COOH, COOC 1-10 alkyl, COC 1-20 alkyl, CONHC 1-20 alkyl, C 1-20 alkyl sulphonate, C 1-20 alkyl phosphonate, C 6-20 aryl, C 4-20 heteroaryl.
  • A is S or NR 5 , wherein R 5 is defined as above. In some embodiments, A is S. In some embodiments, the compound is a 1H-benzo[7,8]thioxantheno[2,1,9-def]isoquinoline- 1,3(2H)-dione according to formula (I), substituted with R 1 , R 2 , R 3 , and R 4 as defined above.
  • the compound according to the present invention is selected from the group consisting of: 2-(pentan-3-yl)-1H-benzo[7,8]thioxantheno[2,1,9-def]isoquinoline-1,3(2H)-dione, 2-(pentan-3-yl)benzo[lmn]naphtho[2,1-c][2,8]phenanthroline-1,3(2H,6H)-dione, 2-(pentan-3-yl)-1H-benzo[7,8]xantheno[2,1,9-def]isoquinoline-1,3(2H)-dione, 3-(1,3-dioxo-1H-benzo[7,8]thioxantheno[2,1,9-def]isoquinolin-2(3H)-yl)-N,N,N-trimethylpropan- 1-aminium, 3-(1,3-dioxo-1H-benzo[7,
  • the compound of formula (I) is 2-(pentan-3-yl)-1H- benzo[7,8]thioxantheno[2,1,9-def]isoquinoline-1,3(2H)-dione (DBI) .
  • the designed photosensitiser (PS) of the present invention is capable of enhanced intersystem crossing (ISC) from the excited singlet state to a long-lived triplet state and provides a close-to- unit singlet oxygen quantum yield, while remaining luminescent enough for in-situ detection and monitoring.
  • the compounds of the present invention target two cancer-specific mediators/markers in cells: - the DNA-rich tumor-derived ILVs/exosomes that are well-known cancer biomarkers; and - non-canonical DNA G4 structures which are promising targets for cancer therapy.
  • Different functional groups can be used to target different areas in the cell. For example, ammonium and pyridinium are quite efficient in targeting the nucleus, while phosphonium are associated to mitochondrial targeting.
  • the high phototoxic damage of the compounds of the present invention towards cancer cells is likely attributed to the accumulation in the ILVs and the binding to G4 structures. Additionally, phototoxicity toward 2D cancer cell models is high while remaining non-toxic under dark conditions. This is demonstrated by the biological studies presented below.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound according to formula (I), or a pharmaceutically acceptable salt thereof wherein R 1 is selected from a group consisting of C1-20 alkyl, C3-6 cycloalkyl, COOH, C1-20 COOH, COOC1-20 alkyl, COC1-20 alkyl, CONHC1-20 alkyl, C1-20 alkyl sulphonate, C1-20 alkyl phosphonate, C6-20 aryl, C4-20 heteroaryl, C 1-4 alkyloxy C 1-4 alkyl sulphonate, methyl (C 1-4 alkyloxy C 1-4 alkyl sulphonate) 2 , C 1-4 alkyl terminally substituted with a C 5-6 heterocyclyl with one or two heteroatoms being O, S
  • such pharmaceutical compositions may be prepared in a conventional manner using conventional excipients, carriers, and diluents.
  • R 1 , R 2 , R 3 , R 4 , R 5 , X, Y and A are as defined in any of the embodiments above.
  • the invention also relates to the use of the pharmaceutical composition according to the invention as a medicament.
  • the pharmaceutical composition may be in a form that is suitable for oral administration, for parenteral injection (including intravenous, subcutaneous, intramuscular, and intravascular injection), for topical administration or for rectal administration.
  • the pharmaceutical composition is in a form that is suitable for intravenous or topical administration.
  • the dosage required for the therapeutic or prophylactic treatment will depend on the route of administration, the severity of the disease, the age and weight of the patient and other factors normally considered by the attending physician, when determining the appropriate regimen and dosage level for a particular patient.
  • the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from a group consisting of C 1-20 alkyl, C 3-6 cycloalkyl, COOH, C 1-20 COOH, COOC 1-20 alkyl, COC 1-20 alkyl, CONHC 1-20 alkyl, C 1-20 alkyl sulphonate, C 1-20 alkyl phosphonate, C 6-20 aryl, C 4-20 heteroaryl, C 1-4 alkyloxy C 1-4 alkyl sulphonate, methyl (C 1-4 alkyloxy C 1-4 alkyl sulphonate) 2 , C 1-4 alkyl terminally substituted with a C 5-6 heterocyclyl with one or two heteroatoms being O, S or N, C1-4 alkyl terminally substituted with N(C1-4 alkyl)(C1-4 alkyl), polyethylene glycol, an amino acid, zwitterionic (C1-4 alkyl)N + (C1-4 alkyl)2(C1-4 alkyl SO3-), (C1-4 alkyl)N + (C1-4
  • R 1 , R 2 , R 3 , R 4 , R 5 , X, Y and A are as defined in any of the embodiments above.
  • the invention relates to a compound of formula (I) for use as a DNA damaging agent.
  • the DNA damage can be in the form of oxidative base lesions such as 7,8-dihydro-8- oxoguanine or DNA strand breaks.
  • the invention relates to a compound of formula (I) for use as G-quadruplex inducing agent.
  • the invention relates to a compound of formula (I) for use as a marker for intraluminal vesicles or exosomes.
  • Exosomes can be purified from biofluids, and using compounds of formula (I) as markers enables DNA damage assessment in a blood sample with fluorescence microscopy. Thereby the use of antibodies in immunofluorescence becomes redundant.
  • Compounds of formula (I) can be used as a biomarker to monitor the treatment efficiency of PDT.
  • the invention relates to a compound of formula (I) used for producing singlet oxygen.
  • the invention relates to a compound of formula (I), wherein R 1 is selected from a group consisting of C1-20 alkyl, C3-6 cycloalkyl, COOH, C1-20 COOH, COOC1-20 alkyl, COC1-20 alkyl, CONHC1-20 alkyl, C1-20 alkyl sulphonate, C1-20 alkyl phosphonate, C6-20 aryl, C4-20 heteroaryl, C1-4 alkyloxy C1-4 alkyl sulphonate, methyl (C1-4 alkyloxy C1-4 alkyl sulphonate)2, C1-4 alkyl terminally substituted with a C5-6 heterocyclyl with one or two heteroatoms being O, S or N, C 1-4 alkyl terminally substituted with N(C 1-4 alkyl)(C 1-4 alkyl), polyethylene glycol, an amino acid, zwitterionic (C1-4 alkyl)N + (C1-4 alkyl)2(C1-4 alkyl SO3-
  • R 1 , R 2 , R 3 , R 4 , R 5 , X, Y and A are as defined in any of the embodiments above.
  • the invention relates to a compound of formula (I), for use in cancer diagnostics.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from a group consisting of C1-20 alkyl, C3-6 cycloalkyl, COOH, C1-20 COOH, COOC1-20 alkyl, COC 1-20 alkyl, CONHC 1-20 alkyl, C 1-20 alkyl sulphonate, C 1-20 alkyl phosphonate, C 6-20 aryl, C 4-20 heteroaryl, C1-4 alkyloxy C1-4 alkyl sulphonate, methyl (C1-4 alkyloxy C1-4 alkyl sulphonate)2, C1-4 alkyl terminally substituted with a C5-6 heterocyclyl with one or two heteroatoms being O, S or N, C1-4 alkyl terminally substituted with N(C1-4 alkyl)(C1-4 alkyl), polyethylene glycol, an amino acid, zwitterionic (C1-4 alkyl)N + (C1-4 alkyl)2(C1-4 alkyl
  • R 1 , R 2 , R 3 , R 4 , R 5 , X, Y and A are as defined in any of the embodiments above.
  • the treatment is photodynamic treatment of cancer.
  • the cancer is selected from the group consisting of skin cancer, basal cell skin cancer, squamous skin cancer, head and neck cancer, prostate cancer, lung cancer, gastrointestinal cancer, liver cancer, bile duct cancer, small intestine cancer, colon cancer, rectal cancer, prostate cancer, brain cancer, bladder cancer, and breast cancer.
  • the cancer is due to mutations in genes encoding specialized G4 helicases, such as FANCJ, PIF1 helicases, or DNA repair genes, such as BRCA1, BRCA2, TREX1, EXO1, CHEK2, ATM, Fanconi’s anemia genes, mismatch repair genes, PolB, APEX1, PALB2, TP53, and MRE11.
  • G4 helicases such as FANCJ, PIF1 helicases
  • DNA repair genes such as BRCA1, BRCA2, TREX1, EXO1, CHEK2, ATM, Fanconi’s anemia genes, mismatch repair genes, PolB, APEX1, PALB2, TP53, and MRE11.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from a group consisting of C 1-20 alkyl, C 3-6 cycloalkyl, COOH, C 1-20 COOH, COOC 1-20 alkyl, COC 1-20 alkyl, CONHC 1-20 alkyl, C 1-20 alkyl sulphonate, C 1-20 alkyl phosphonate, C 6-20 aryl, C 4-20 heteroaryl, C1-4 alkyloxy C1-4 alkyl sulphonate, methyl (C1-4 alkyloxy C1-4 alkyl sulphonate)2, C1-4 alkyl terminally substituted with a C 5-6 heterocyclyl with one or two heteroatoms being O, S or N, C1-4 alkyl terminally substituted with N(C1-4 alkyl)(C1-4 alkyl), polyethylene glycol, an amino acid, zwitterionic (C1-4 alkyl)N + (C1-4 alkyl)2(C
  • the ophthalmology condition is selected from the group consisting of age-related macular degeneration (AMD) (such as by stopping abnormal blood vessel growth below the macula), choroidal hemangioma, central serous chorioretinopathy (CSC), and polypoidal choroidal vasculopathy (PCV).
  • AMD age-related macular degeneration
  • CSC central serous chorioretinopathy
  • PCV polypoidal choroidal vasculopathy
  • R 1 , R 2 , R 3 , R 4 , R 5 , X, Y and A are as defined in any of the embodiments above.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from a group consisting of C1-20 alkyl, C3-6 cycloalkyl, COOH, C1-20 COOH, COOC1-20 alkyl, COC1-20 alkyl, CONHC1-20 alkyl, C1-20 alkyl sulphonate, C1-20 alkyl phosphonate, C6-20 aryl, C4-20 heteroaryl, C1-4 alkyloxy C1-4 alkyl sulphonate, methyl (C1-4 alkyloxy C1-4 alkyl sulphonate)2, C1-4 alkyl terminally substituted with a C5-6 heterocyclyl with one or two heteroatoms being O, S or N, C 1-4 alkyl terminally substituted with N(C 1-4 alkyl)(C 1-4 alkyl), polyethylene glycol, an amino acid, zwitterionic (C 1-4 alkyl)N + (C 1-4 alkyl)
  • the invention relates to a method for preparing a 1H- benzo[7,8]thioxantheno[2,1,9-def]isoquinoline-1,3(2H)-dione according to present invention comprising the steps of: a. subjecting an aromatic thiazole to basic reflux conditions; b.
  • Solvents were dried and purified using standard techniques, readily understood by one skilled in the art. Silica gel chromatographies were performed on technical grade silica gel, with a pore size of 60 ⁇ and a 230-400 mesh particle size, packed with analytical-grade solvents. NMR spectra were recorded with a Bruker AVANCE III 300 ( 1 H, 300 MHz and 13 C, 75MHz) spectrometer unless stated otherwise. Chemical shifts are given in ppm relative to TMS and coupling constants J in Hz. UV-vis spectra were recorded on a Shimadzu UV-1800 spectrometer. High-resolution mass spectrometry (HRMS) was performed with a JEOL JMS-700 B/E.
  • HRMS high-resolution mass spectrometry
  • the mixture was cooled to room temperature and extracted with CH2Cl2 / water. After drying over MgSO4, the solvent was removed by rotary evaporation and the crude material was subjected to silica gel column chromatography using petroleum ether/CH2Cl2 as eluent. A red powder was obtained (300 mg, 89%).
  • the resulting crude 1-aminonaphthalene-2-thiol was directly engaged in the next step without further purification.
  • the crude mixture was blended with 4-bromo-1,8-naphthalic anhydride (11.0 g, 39.7 mmol) and potassium carbonate (5.49 g, 39.7 mmol).
  • DMF 270 mL
  • Isopentyl nitrite (15.7 mL, 119.1 mmol) was then added.
  • reaction mixture was stirred at reflux temperature for 24 h before being extracted with EtOAc, water and brine. After drying over MgSO4, the solvent was removed by rotary evaporation and the crude material was subjected to silica gel column chromatography using CHCl3 as eluent. The title compound was obtained as an orange powder (195 mg, 81%).
  • BIOLOGICAL ASSAYS Cellular oxidative stress (figure 1) The ability of DBI to generate cellular oxidative stress was evaluated.
  • CellROXTM green reagent was used as a fluorogenic probe for detecting oxidative stress in the nucleus of live cells. This dye is weakly fluorescent in a reduced state while displaying bright green fluorescence upon oxidation by ROS.
  • Human cervical epithelioid carcinoma (HeLa) cells treated with DBI (1 ⁇ M) and irradiated with blue light showed a bright green fluorescent signal mainly localized in the cell nucleus supporting the ability of DBI to generate ROS.
  • Phototherapeutic efficacy toward HeLa and breast cancer cell lines (figures 2 - 4)
  • the phototherapeutic efficacy of the compounds prepared in Examples 1, 2 and 3 here above toward HeLa and breast (MCF-7) cancer cell lines was determined using the PrestoBlueTM cell viability assay (Invitrogen). Briefly, 5000 HeLa cells/well and 4000 MCF-7 cells/well were seeded in complete culture medium (Dulbecco ⁇ s modified eagle medium (DMEM) supplemented with penicillin-streptomycin (1 ⁇ ), and 10% fetal bovine serum) on 96-well plates the day before the treatment. Compounds were dissolved in the culture medium at the indicated concentrations and added to the cells.
  • DMEM Dulbecco ⁇ s modified eagle medium
  • PrestoBlue was added to each well and the cells were incubated at 37 °C for three additional hours.
  • HeLa and MCF-7 cells were then treated with various concentrations the compounds prepared in Example 1, 2 and 3 (ranging from 0 to 0.3 ⁇ M) for 24 h, followed by irradiation for 8 minutes with blue light (18 mW cm -2 ) using a LED light cube (470/22 nm), and further incubated for 24 h.
  • These experimental conditions were optimized in order to avoid cell death caused by overexposure to light and to match the incubation time and general experimental conditions used in the dark cytotoxicity studies.
  • Figure 3a shows the effect of the compound of Example 2 with no light and figure 3b shows the effect of the compound of Example 2 with light.
  • Figure 4a shows the effect the compound of Example 3 with no light and figure 4b shows the effect the compound of Example 3 with light.
  • Table 1. IC50 values and high dark IC50/light IC50 phototoxic index (PI) ratios LIVE/DEADTM assay used to determine the viability of HeLa cells.
  • the compound of Example 1 (DBI) photo-triggered cancer cell death was also confirmed by using a LIVE/DEADTM viability/cytotoxicity stain assay.
  • HeLa cells were treated with DBI (1 ⁇ M) or with an equivalent amount of DMSO (0.02 % v/v) and incubated at 37 °C for 24 h.
  • the anti- ⁇ H2AX antibody an established marker of DSBs, was used to assess the induction of DNA damage.
  • Zebrafish are relevant models for human drug discovery not only because of the conserved physiology between humans and zebrafish, but also because about 70% of human protein coding genes have a zebrafish gene orthologue, and that the drug metabolism pathways are conserved. Zebrafish embryos are also translucent and allow real-time monitoring of drug uptake. Because DBI is emissive, its accumulation in zebrafish was monitored. Wildtype zebrafish embryos were dechorionated at the 6-somite stage, twelve hours post fertilization (hpf), and treated with DBI in the embryo medium for twelve hours in dark, until they reached the prim-5 stage (24 hpf).
  • the DBI-treated 24 hpf embryos showed a widespread fluorescence signal along the whole embryonic body confirming effective uptake of the drug.
  • the photocytotoxic effect of DBI on the embryos treated with different concentrations of DBI after light irradiation was investigated.
  • morphological changes were detected in the embryos, particularly in the tails, with an increasing severity correlated to increased DBI concentration.
  • these morphological changes were not detected in the no light-treated embryos even at the highest DBI concentration treatment.
  • DBI DBI signal that overlap with Hoechst are not within the nucleus.
  • Immunofluorescence experiments To determine the exact sub-localization of DBI, immunofluorescence experiments were performed using a set of organelle-specific antibodies. Anti-LAMP1, anti-EEA1 and anti-CD63 antibodies were used as lysosome, early endosome, and ILV markers, respectively. HeLa cells were treated with DBI (1 ⁇ M) for 24 h and either non- irradiated or irradiated with a blue LED light cube (20 mW cm -2 ) for 20 min and incubated for additional 30 min at 37 °C before paraformaldehyde (PFA) fixation.
  • PFA paraformaldehyde
  • ⁇ exc / ⁇ em 405/440-460 nm for Hoechst (blue signal); and 528/540-590 nm for DBI (green signal); and ⁇ exc / ⁇ em : 598/620-750 nm for anti-LAMP1, anti-EEA1 and anti-CD63 (red signal).
  • Anti-LAMP1, anti-EEA1 and anti-CD63 antibodies were used as lysosome, early endosome, and ILV markers, respectively. Without light irradiation, no apparent co-localization between DBI and anti-LAMP1 or anti-EEA1 antibodies could be detected, excluding its accumulation in lysosomes and early endosomes.
  • DBI signal perfectly matched the anti-CD63 signal, suggesting that DBI localizes in the ILVs.
  • Intracellular distribution of DBI after light exposure Under light-activated conditions, the signals of anti-CD63 and DBI remained overlapped.
  • Hoechst is a nuclear dye that preferentially binds double-stranded DNA (dsDNA).
  • DNase deoxyribonuclease
  • the cytoplasmic signal from Hoechst and the DBI signal were unaffected, demonstrating that both DBI and Hoechst localized inside the ILVs.
  • the fluorescent signal of Hoechst was enhanced compared to non- irradiated conditions, suggesting an increased level of DNA in the ILVs supporting the theory that the use of genotoxic drugs increases DNA abundance in exosomes.
  • the data provide solid evidence of the uptake of DBI inside the ILVs, and show that DBI causes DSBs and genomic instability through a light-induced oxidative stress which results in increased amounts of DNA inside the ILVs or exosomes when released outside the cells.

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Abstract

L'invention concerne des composés de formule (I) dans laquelle R1, R2, R3, R4, X, Y et A sont tels que définis dans la description. Ces composés sont des agents photodynamiques qui génèrent des espèces réactives de l'oxygène lorsqu'ils sont soumis à un rayonnement UV. L'invention concerne également des compositions pharmaceutiques comprenant ces composés et l'utilisation de ces composés dans le traitement du cancer et d'autres maladies.
PCT/EP2023/071852 2022-08-05 2023-08-07 Composés et leur utilisation en tant qu'agents photodynamiques Ceased WO2024028519A1 (fr)

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Citations (2)

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Patent Citations (2)

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JPS5473987A (en) * 1977-11-21 1979-06-13 Mitsubishi Chem Ind Coloring of organic high molecular weight material
CN106674262B (zh) * 2016-12-07 2018-10-16 合肥学院 一种富勒烯-苝-氟硼荧三重态光敏分子及其制备方法

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