Copper n-heterocyclic carbene compounds, copper n-heterocyclic carbene compounds for use in the treatment of cancer

Abstract

The present invention relates to compound of formula (I) representing : (II)or (III)or (IV) with R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15 and R16 representing independently H, (C1-C8)-alkyl, F, Br, Cl, I, formyl, -COOH, -COO-(C1-C6)-alkyl, -NO2, -NH2, - NHCOO-(C1-C6)-alkyl, -OH, mono or polycyclic C5-C12-aryl, mono or polycyclic C3-C12-heteroaryl, -benzyl, -N3, (C2-C6)- alkenyl, (C2-C6)-alkynyl, (C1-C6)-alkoxy, -SH, (C1-C6)- thioalkyl, -CnF3+2(n-1) n being an integer between 1 and 6, - SO3H, -S-CpF3+2(p-1) p being an integer between 1 and 6, –O- CqF3+2(q-1) q being an integer between 1 and 6, or –O-(CH2CH2O)m- H with m being an integer between 1 and 1000.

Description

[0001] Description

[0002] Title of the invention: COPPER N-HETEROCYCLIC CARBENE COMPOUNDS, COPPER N-HETEROCYCLIC CARBENE COMPOUNDS FOR USE IN THE TREATMENT OF CANCER

[0003] The present invention relates to the compound of Formula (I), and the compound of Formula (I) for its use in the treatment of cancer, in particular of cisplatinresistant cancer.

[0004] Cancer is the second most common cause of death worldwide. For the past century, it has been the focus of many organisations and institutions, aiming at defining the causes and developing treatments. Despite major breakthroughs achieved in diagnostic techniques, more than half of new cancer patients still undergo the same treatment, namely platinum-based chemotherapy. However, these treatments, based on the three FDA-approved drugs cisplatin, oxaliplatin and carboplatin, are finite, induce numerous side-effects, and are eventually hindered by resistance development. These drawbacks have initiated research of novel chemotherapeutic drugs, based on different metals and / or new specificity-focused approaches.

[0005] Therefore, the present invention relates to a compound of formula (I)

[0006]

[0007] representing a single or double bond;

[0008] R representing:

[0009]

[0010] with R1, R2, R3, R4representing independently H, (Ci-Cs) -alkyl, F, Br, Cl, I, formyl, -COOH, -COO- (Ci-Ce) -alkyl, -NO2, -NH2, -NHCOO- (Ci-Ce) -alkyl, -OH, mono or polycyclic C5-C12- aryl, mono or polycyclic C3-Ci2-heteroaryl, -benzyl, -N3, (C2- Ce) -alkenyl, (C2-C6) -alkynyl, (Ci-Ce) -alkoxy, -SH, (Ci-Ce) - thioalkyl, -CnF3+2(n-1) n being an integer between 1 and 6, -SO3H, -S-CpF3+2(p-1) p being an integer between 1 and 6, -O-CqF3+2(q-1) q being an integer between 1 and 6, or -0- (CH2CH2O)m-H with m being an integer between 1 and 1000, and with the proviso that R1, R2, R3and R4are not H simultaneously; or

[0011]

[0012] with R5, R6, R7, R8, R9representing independently H, (Ci-Cs) -alkyl, F, Br, Cl, I, formyl, -COOH, -COO- (Ci-Ce) -alkyl, -NO2, -NH2, —NHCOO— (Ci— Ce) —alkyl, -OH, mono or polycyclic C5-C12- aryl, mono or polycyclic C3-Ci2-heteroaryl, -benzyl, -N3, (C2- Ce) -alkenyl, (C2-C6) -alkynyl, (Ci-Ce) -alkoxy, -SH, (Ci-Ce) - thioalkyl, -CnF3+2(n-1) n being an integer between 1 and 6, -SO3H, -S-CpF3+2(p-1) p being an integer between 1 and 6, -O-CqF3+2(q-1) q being an integer between 1 and 6, or -0- (CH2CH2O)m-H with m being an integer between 1 and 1000, and with the proviso that R5, R6, R7, R8, R9are not H simultaneously; or

[0013]

[0014] with R10, R11, R12, R13, R14, R15and R16representing independently H, (Ci-Cs) -alkyl, F, Br, Cl, I, formyl, -COOH, -COO- (Ci-C6) -alkyl, -NO2, -NH2, -NHCOO- (Ci-C6) -alkyl, -OH, mono or polycyclic C5~Ci2-aryl, mono or polycyclic C3~Ci2-heteroaryl, -benzyl, -N3, (C2-Ce) -alkenyl, (C2-Ce) -alkynyl, (Ci-Ce) -alkoxy, -SH, (Ci-Ce) -thioalkyl, -CnF3+2(n-1) n being an integer between 1 and 6, -SO3H, -S-CpF3+2(p-1) p being an integer between 1 and 6, -O-CqF3+2(q-1) q being an integer between 1 and 6, or -0- (CH2CH2O)m-H with m being an integer between 1 and 1000.

[0015] In a particular embodiment, R1, R2, R3, R4may represent independently H, (Ci-Cs) -alkyl, in particular tertbutyl, F, Cl, Br, I, -CF3, -COOMe, -OMe, -SMe, -OCF3, -SCF3, -N2O, phenyl or pyridinyl; and

[0016] R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15and R16may represent independently H, F, Cl, Br, I, -CF3, -OCF3, -SCF3 or -OMe.

[0017] In an other particular embodiment, R1, R3, R4may represent H, and R2may represent (Ci-Cs) -alkyl, in particular tert-butyl, F, Cl, Br, I, CF3, -OMe, -OCF3, -SCF3, -N2O, phenyl or pyridinyl;

[0018] R5, R6, R8, R9may represent H, and R7may represent F, Cl, Br, I, -CF3, -OCF3, -SCF3or -OMe; and

[0019] R10, R11, R12, R13, R14, R15and R16may represent H.

[0020] The compound of formula (I) may be chosen from:

[0021]

[0022]

[0023] The present invention also relates to a compound of formula (I) for use in the treatment of cancer,

[0024]

[0025] >..... representing a single or double bond;

[0026] R representing: 4; 4

[0027] R I. R

[0028]

[0029] * R1R^

[0030] with R1, R2, R3, R4representing independently H, (Ci-Cs) -alkyl, F, Br, Cl, I, formyl, -COOH, -COO- (Ci-Ce) -alkyl, -NO2, -NH2, —NHCOO— (Ci— Ce) —alkyl, -OH, mono or polycyclic C5-C12- aryl, mono or polycyclic C3-Ci2-heteroaryl, -benzyl, -N3, (C2- Ce) -alkenyl, (C2-C6) -alkynyl, (Ci-Ce) -alkoxy, -SH, (Ci-Ce) - thioalkyl, -CnF3+2(n-1) n being an integer between 1 and 6, -SO3H, -S-CpF3+2(p-1) p being an integer between 1 and 6, -O-CqF3+2(q-1) q being an integer between 1 and 6, or -O- (CH2CH2O)m-H with m being an integer between 1 and 1000; or

[0031]

[0032] with R5, R6, R7, R8, R9representing independently H, (Ci-Cs) -alkyl, F, Br, Cl, I, formyl, -COOH, -COO- (Ci-Ce) -alkyl, -NO2, -NH2, -NHCOO- (Ci-Ce) -alkyl, -OH, mono or polycyclic C5-C12- aryl, mono or polycyclic C3-Ci2-heteroaryl, -benzyl, -N3, (C2- Ce) -alkenyl, (C2-C6) -alkynyl, (Ci-Ce) -alkoxy, -SH, (Ci-Ce) - thioalkyl, -CnF3+2(n-1) n being an integer between 1 and 6, -SO3H, -S-CpF3+2(p-1) p being an integer between 1 and 6, -O-CqF3+2(q-1) q being an integer between 1 and 6, or -0- (CH2CH2O)m-H with m being an integer between 1 and 1000; or

[0033]

[0034] with R10, R11, R12, R13, R14, R15and R16representing independently H, (Ci-Cs) -alkyl, F, Br, Cl, I, formyl, -COOH, -COO- (Ci-C6) -alkyl, -NO2, -NH2, -NHCOO- (Ci-C6) -alkyl, -OH, mono or polycyclic Cs-Ci2-aryl, mono or polycyclic C3-C12- heteroaryl, -benzyl, -N3, (C2-C6) -alkenyl, (C2-C6) -alkynyl, (Ci-Ce) -alkoxy, -SH, (Ci-Ce) -thioalkyl, -CnF3+2(n-1) n being an integer between 1 and 6, -SO3H, -S-CpF3+2(p-1) p being an integer between 1 and 6, -O-CqF3+2(q-1) q being an integer between 1 and 6, or -0- (CH2CH2O)m-H with m being an integer between 1 and 1000.

[0035] In a particular embodiment, R1, R2, R3, R4may represent independently H, (Ci-Cs) -alkyl, in particular tertbutyl, F, Cl, Br, I, -CF3, -COOMe, -OMe, -SMe, -OCF3, -SCF3, -N2O, phenyl or pyridinyl; and

[0036] R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15and R16may represent independently H, F, Cl, Br, I, -CF3, -OCF3, -SCF3 or -OMe.

[0037] In an other particular embodiment, R1, R3, R4may represent H, and R2may represent H, (Ci-Cs) -alkyl, in particular tert-butyl, F, Cl, Br, I, CF3, -OMe, -OCF3, -SCF3, -N2O, phenyl or pyridinyl; and

[0038] R5, R6, R8, R9, R10, R11, R12, R13, R14, R15and R16may represent H and R7may represent H, F, Cl, Br, I, -CF3, -OCF3, -SCF3 or -OMe. The compound of formula (I) for use in the treatment of cancer according to the invention, may be chosen from:

[0039]

[0040]

[0041] The cancer may be ovarian cancer, colon cancer, colorectal cancer, throat cancer, bladder cancer or stomach cancer.

[0042] The cancer may be a cisplatin-resistant cancer, in particular cisplatin-resistant ovarian cancer.

[0043] The following examples illustrate the present invention without limiting its scope. In these examples, the following abbreviations are used:

[0044] r. t.: room temperature

[0045] TMSCL: trimethylsilyl chloride THF: tetrahydrofuran

[0046] DMF: dimethylformamide

[0047] Chemicals were purchased from Sigma Aldrich, TCI Chemicals, Fluorochem and BLD Pharmatech. Deuterated solvents were purchased from Eurisotop. NMR spectra were recorded in deuterated solvents on a Bruker 400 MHz spectrometer (1H) and 500 MHz (13C) at room temperature. The chemical shifts 5, are reported in ppm (parts per million).

[0048] The residual solvent peaks were used as internal references.

[0049] Peak multiplicities are abbreviated as follows: s (singlet), d (doublet), t (triplet), m (multiplet) and bs (broad singlet). NMR calibration was performed according to Organometallics 2010, 29, 2176-2179. Thin-layer chromatography was performed on silica gel 60 F254 on aluminium plates and visualized under UV for all compounds without copper. All final compounds were not stable on silica or alumina, so reactions were followed by NMR. Elemental analysis measurements were performed on a CHNS ELEMENTAR Vario apparatus. UV measurements were performed on a Cary UV-Vis Multicell Peltier.

[0050] Example 1: Synthesis of the compound of Formula (I) with R=carbazole derivative

[0051] I - Preparation of imidazolium chloride salt 2

[0052] Ethanol r.t., 24 h Ethyl Acetate CH2O, TMSCl 70°C, 2.5 h

[0053]

[0054] 1

[0055] 2 Compounds 1 and 2 were synthetised following the procedure from Hintermann, L. Expedient Syntheses of the N- Heterocyclic Carbene Precursor Imidazolium Salts IPr - HCl, IMes - HCl and IXy - HCl. Beilstein J. Org. Chem. 2007, 3.

[0056] 1: ¹H NMR ( 400 MHz, CDCl3): δ 8. 10 ( s, 2H), 7. 23 - 7. 12 (m, 6H), 2. 94 (hept, J = 6. 9 Hz, 4H), 1. 21 (d, J = 6. 9 Hz, 24H). Yield: 73 %.

[0057] 2: iH NMR ( 400 MHz, CDC13): Z 5 10. 14 (t, J = 1. 6 Hz, 1H), 8. 15 (d, J = 1. 6 Hz, 2H), 7. 57 (t, J = 7. 8 Hz, 2H), 7. 35 (d, J = 7. 9 Hz, 4H), 2. 45 (hept, J = 6. 8 Hz, 4H), 1. 27 (dd, J = 16. 1, 6. 9 Hz, 24H). Yield: 71 %.

[0058] II - Preparation of copper chloride carbene 3

[0059]

[0060] Compound 3 synthesis was adapted from Albright, A.; Eddings, D.; Black, R.; Welch, C. J.; Gerasimchuk, N. N.; Gawley, R. E. Design and Synthesis of C 2 -Symmetric N- Heterocyclic Carbene Precursors and Metal Carbenoids. J. Org. Chem. 2011, 76 ( 18 ), 7341-7351.

[0061] In a two-necked round-bottom flask 380 mg of the imidazolium salt 2 ( 1 eq. ), copper ( I ) chloride ( 1. 2 eq. ) and sodium tert-butoxide ( 1. 2 eq. ) were added and placed under nitrogen atmosphere. 20 mL of dry THF were added and the mixture was stirred at room temperature overnight. The mixture was filtered on celite and the solvent removed under vacuum. 3:1H NMR ( 400 MHz, CDCl3): δ 7. 49 (t, J = 7. 8 Hz, 2H), 7. 30 (d, J = 7. 8 Hz, 4H), 7. 13 ( s, 2H), 2. 56 (hept, J = 6. 9 Hz, 4H), 1. 27 (dd, J = 30. 4, 6. 9 Hz, 24H).13C NMR ( 400 MHz, CDCl3) δ 145. 71, 134. 51, 130. 72, 124. 35, 123. 26, 77. 36, 28. 87, 24. 95, 24. 02, 23. 77. Yield: 72 %.

[0062] II I - Preparation of carbazole derivatives B, C and D

[0063]

[0064] The carbazole derivatives were synthetised by following Wu, S.; Liu, Y.; Yu, G.; Guan, J.; Pan, C.; Du, Y.; Xiong, X.; Wang, Z. Facile Preparation of Dibenzoheterocycle-Functional Nanoporous Polymeric Networks with High Gas Uptake Capacities. Macromolecules 2014, 47 ( 9 ), 2875-2882 for compound B; Fu, B.; Dong, X.; Yu, X.; Zhang, Z.; Sun, L.; Zhu, W.; Liang, X.; Xu, H. Meso -Borneol-and Meso -Carbazole-Substituted Porphyrins: Multifunctional Chromophores with Tunable Electronic Structures and Antitumor Activities. New J. Chem. 2021, 45 ( 4 ), 2141-2146 for compound C; and EL-Mahdy, A. F. M.; Hung, Y. -H.; Mansoure, T. H.; Yu, H. -H.; Hsu, Y. -S.; Wu, K. C. W.; Kuo, S. -W. Synthesis of [3 + 3] p-Ketoenamine-Tethered Covalent Organic Frameworks (COFs) for High-Performance Supercapacitance and C02 Storage. Journal of the Taiwan Institute of Chemical Engineers 2019, 103, 199-208 for compound D.

[0065] B:1H NMR (400 MHz, CDCl3) δ 8.16 - 8.10 (m, 2H), 7.52 (dd, J = 8.6, 1.9 Hz, 2H), 7.31 (dd, J = 8.6, 0.6 Hz, 2H).

[0066] C:1H NMR (400 MHz, CDCl3) δ 8.24 (broad s, 2H), 8.15 (s, 1H), 8.05 - 7.93 (m, 2H), 7.46 - 7.34 (m, 4H).

[0067] D:1H NMR (400 MHz, DMSO) δ 12.70 (broad s, 1H), 9.51 (d, J = 2.3 Hz, 2H), 8.40 (dd, J = 9.0, 2.3 Hz, 2H), 7.77 (d, J = 9. 0 Hz, 2H).

[0068] IV - Preparation of carbene compounds Cui, Cu2, Cu3, Cu4, Cu 5, Cu6 and Cu7

[0069]

[0070] Cu1 R=H, Cu2 R=Br, Cu3 R=Cl, Cu4 R=NO2, Cu5 R=Ph, Cu6 R=OMe, Cu7 R=t-Bu

[0071] Compounds Cu1, Cu2, Cu3, Cu4, Cu 5, Cu6 and Cu7 were synthetised following the procedure from Li, J.; Wang, L.; Zhao, Z.; Li, X.; Yu, X.; Huo, P.; Jin, Q.; Liu, Z.; Bian, Z.; Huang, C. Two-Coordinate Copper ( I ) / NHC Complexes: Dual Emission Properties and Ultralong Room-Temperature Phosphorescence. Angew. Chem. Int. Ed. 2020, 59 (21), 8210- 8217.

[0072] Cu1:1H NMR (400 MHz, CDCl3): δ 7.90 (d, J = 7.6, 1.0 Hz, 2H), 7.65 (t, J = 7.8 Hz, 2H), 7.42 (d, J = 7.8 Hz, 4H), 7.21 (s, 2H), 7.02 - 6.79 (m, 4H), 6.30 (dd, J = 8.1, 0.9 Hz, 2H), 2.69 (hept, J = 6.8 Hz, 4H), 1.26 (dd, 24H).13C NMR (400 MHz, CDCl3) δ 146.3, 134.8, 130.7, 124.5, 124.0, 123.2, 119.4, 115.1, 114.4, 28.9, 25.0, 24.1. Elemental analysis: (Calculated C39H44CuN3 C=75.75 H=7.17 N=6.80) Found: C44H58OCuN3 C=74.95 H=7.71 N=5.95, 0.38 difference with 0.5 C5H12 and 0.5 H2O. Yield: 99 %.

[0073] Cu2:1H NMR (500 MHz, CD2Cl2): δ 7.89 (d, J = 2.0 Hz, 2H), 7.69 (t, J = 7.8 Hz, 2H), 7.55 - 7.44 (m, 4H), 7.34 (s, 2H), 7.02 (dd, J = 8.6, 2.1 Hz, 2H), 6.10 (d, J = 8.7 Hz, 2H), 2.68 (hept, J = 6.9 Hz, 4H), 1.26 (dd, J = 19.1, 6.9 Hz, 24H).13C NMR (500 MHz, CD2Cl2) δ 181.6, 149.1, 146.7, 135.1, 131.0, 129.7, 126.9, 124.8, 123.9, 122.2, 116.3, 112.9, 29.1, 25.0, 24.1. Elemental analysis: (Calculated C39H42Br2CuN3C= 60.35 H=5.45 N=5.41) Found: C45H55Br2Cl3CuN3C=58.35 H=5.03 N=5.40, 0.58 difference with 0.5 CHCl3and 0.5 C5H12. Yield: 95 %.

[0074] Cu3:1H NMR (500 MHz, CD2Cl2): δ 7.74 (d, J = 2.2 Hz, 2H), 7.69 (t, J = 7.8 Hz, 2H), 7.46 (d, J = 7.8 Hz, 4H), 7.34 (d, J = 2.1 Hz, 2H), 6.90 (dd, J = 8.6, 2.2 Hz, 2H), 6.14 (d, J = 8.6 Hz, 2H), 2.69 (hept, J = 7.0 Hz, 4H), 1.26 (dd, J = 17.7, 6.9 Hz, 24H).13C NMR (500 MHz, CD2Cl2): δ 181. 6, 149.1, 146.7, 135.1, 131.0, 124.8, 124.3, 124.3, 123.9, 120.8, 119.1, 115.8, 29.3, 25.0, 24.1. Elemental analysis: (Calculated C39H42Cl2CuN3C=68.16 H=6.16 N=6.11) Found: C39H44OCl2CuN3C=67.56 H=6.32 N=6.07, 0.28 difference with 0.5 H2O. Yield: 71 %.

[0075] Cu4:1H NMR (500 MHz, CD2Cl2): δ 8.86 (d, J = 2.3 Hz, 2H), 7.96 (dd, J = 9.0, 2.4 Hz, 2H), 7.75 (t, J = 7.9 Hz, 2H), 7.49 (d, J = 7.8 Hz, 4H), 7.39 (s, 2H), 6.18 (d, J = 9.1 Hz, 2H), 2.68 (p, J = 6.9 Hz, 4H), 1.29 - 1.24 (m, 24H).13C NMR (500 MHz, CD2Cl2): δ 155.6, 146.7, 139.6, 134.9, 131.3, 124.9, 124.4, 124.1, 121.4, 117.6, 114.8, 29.3, 25.0 24.1. Elemental analysis: (Calculated C39H42CuN5O4 C=66.13 H=5.98 N=9.89=) Found: C39H44CuN5O5 C=64.56 H=5.58 N=9. 9 0.53 difference with 1 H2O. Yield: 91 %.

[0076] Cu5:1H NMR (400 MHz, CD2Cl2): δ 8.17 - 8.15 (m, 2H), 7.72 (t, J = 7.9 Hz, 2H), 7.69 - 7.64 (m, 4H), 7.50 (d, J = 7.8 Hz, 4H), 7.40 (t, J = 7.8 Hz, 4H), 7.36 (s, 2H), 7.29 - 7.20 (m, 4H), 6.33 (dd, J = 8.4, 0.6 Hz, 2H), 2.74 (p, J = 6.9 Hz, 4H), 1.31 (dd, J = 6.9, 3.1 Hz, 24H).13C NMR (101 MHz, CD2Cl2): δ 150.57, 146.70, 143.55, 135.18, 131.02, 128.92, 127.12, 125.75, 124.76, 123.81, 123.41, 118.00, 114.98, 29.33, 25.00, 24.12. Yield: 56 %

[0077] Cu6:1H NMR (400 MHz, CD2Cl2): δ 7.68 (t, 2H), 7.45 (d, J = 7.8 Hz, 4H), 7.32 (s, 2H), 7.28 (d, J = 2.5 Hz, 2H), 6.57 (dd, J = 8.8, 2.6 Hz, 2H), 6.13 (d, J = 8.7 Hz, 2H), 2.70 (p, J = 6. 8 Hz, 4H), 1.27 (dd, J = 6. 9, 4. 9 Hz, 26H).13C NMR (101 MHz, CD2Cl2): δ 151.26, 146.05, 135.19, 152.88 - 110.77 (m), 101.68, 56.32, 31.00, 32.90 - 22.69 (m). Yield: 29 %.

[0078] Cu7:1H NMR (400 MHz, CD2Cl2): δ 7.83 (d, J = 2.0 Hz, 2H), 7.68 (t, J = 7.8 Hz, 2H), 7.46 (d, J = 7.8 Hz, 4H), 7.32 (s, 2H), 6.99 (dd, J = 8.6, 2.1 Hz, 2H), 6.21 (d, J = 8.5 Hz, 2H), 2.71 (h, J = 6.9 Hz, 4H), 1.36 (s, 18H), 1.29 (dd, J = 6.9, 2.7 Hz, 25H). Yield: 9 %.

[0079] Example 2 Synthesis of the compound of Formula (I) with R=aryl-alkyne

[0080] I - Preparation of imidazolium acetate salt 5

[0081]

[0082] Compounds 4 and 5 were synthetised following the procedure from Nolte, C.; Mayer, P.; Straub, B. F. Isolation of a Copper (I) Triazolide: A " Click" Intermediate. Angewandte Chemie International Edition 2007, 46 (12), 2101- 2103.

[0083] 4:1H NMR (400 MHz, CDCl3): δ 7.18 - 7.02 (m, 6H), 3.37 (hept, J = 6.8 Hz, 4H), 3.16 (s, 4H), 1.27 (d, J = 6.8 Hz, 24H). Yield: 97 %.

[0084] 5:1H NMR (400 MHz, CDCl3): δ 7.47 (t, J = 7.8 Hz, 2H), 7.28 (dd, J = 7.8, 1.1 Hz, 4H), 4.74 (s, 4H), 3.08 (hept, 4H), 1.96 - 1.80 (m, 3H), 1.31 (dd, 24H). Yield: 71 %.

[0085] II- Preparation of copper acetate carbene 6

[0086]

[0087] Compound 6 was synthetised following the procedure from Worrell, B. T.; Malik, J. A.; Fokin, V. V. Direct Evidence of a Dinuclear Copper Intermediate in Cu ( I ) - Catalyzed Azide-Alkyne Cycloadditions. Science 2013, 340 ( 6131 ), 457-460.

[0088] 6:1H NMR ( 400 MHz, CDCl3): δ 7. 40 (t, J = 8. 2, 7. 3 Hz, 2H), 7. 25 (d, J = 7. 7 Hz, 4H), 4. 02 ( s, 4H), 3. 07 (hept, J = 6. 8 Hz, 4H), 1. 51 (d, J = 2. 9 Hz, 3H), 1. 36 (dd, J = 9. 5, 6. 9 Hz, 24H). Yield: 60 %.

[0089] III - Preparation of carbene compounds Cu8 and Cu9

[0090]

[0091] In a Schlenk flask under nitrogen atmosphere 970 pmol ( 5 eq. ) of alkyne and 1. 5 mL of dry THF were added. The mixture was cooled to -78 ° C. 970 pmol of n-BuLi ( 2, 5 M in hexanes ) were added and stirred for 30 minutes. In Schlenk flask 2, 100 mg ( 1 eq. ) of the copper acetate carbene 6 were added under a nitrogen atmosphere. Then 1. 5 mL of dry THF were added and the mixture was cooled to -78 ° C. The contents of Schlenk flask 1 were transferred into Schlenk flask 2 with a purged syringe. The cold bath was removed, and the reaction was stirred, protected from light, until it reached room temperature. The mixture was filtered on celite and washed with THF. The solvent was removed under vacuum and the solid was precipitated with pentane.

[0092] Cu8:1H NMR (500 MHz, CD2Cl2): δ 7.52 - 6.99 (m, 11H), 4.00 (s, 4H), 3.10 (p, J = 6.9 Hz, 4H), 1.38 (dd, J = 21.0, 6.9 Hz, 24H).13C NMR (500 MHz, CD2Cl2): δ 204.8, 147.4, 135.0, 131.8, 130.1, 128.1, 127.7, 125.7, 124.9, 121.6, 105.2, 29.3, 25.8, 23.9. Elemental analysis: (Calculated C35H43CuN2C=75.71 H=7.81 N=5.04) Found: C36H46OCuN2Cl3C=62.27 H=6.61 N=3.91, 0.15 difference with 1 CHCl3and 1 H2O. Yield: 58 %.

[0093] Cu9:1H NMR (400 MHz, CDCl3): δ 7.72 - 7.21 (m, 2H), 7.53 (d, J = 8.6 Hz, 2H), 7.41 (t, J = 7.7 Hz, 2H), 7.36 - 7.21 (m, 7H), 3.99 (s, 4H), 3.12 (m, J = 13.7, 6.8 Hz, 4H), 1.40 (dd, J = 35.1, 6.9 Hz, 24H).13C NMR (500 MHz, CD2Cl2): δ 204.7, 147.4, 135.1, 133.7, 131.9, 130.1, 129.1, 127.8, 127.5, 127.4, 126.1, 125.5, 124.9, 105.6, 29.3, 25.8, 23.9. Elemental analysis: (Calculated C39H45CuN2C=77.38 H=7.49 N=4.63) Found: C39H45CuN2C=71 H=7 N=4, 0.34 difference with 0.5 CHCl3. Yield: 93 %.

[0094] Exemple 3 Synthesis of the compound of Formula (I) with R=aryl-alkyne

[0095] Preparation of carbene compounds Cu10 to Cu13

[0096]

[0097] Compounds Cu10 to Cu 13 were synthetised following a modified procedure from Ibni Hashim, I.; Scattolin, T.; Tzouras, N. V.; Bourda, L.; Van Hecke, K.; Ritacco, I.; Caporaso, L.; Cavallo, L.; Nolan, S. P.; Cazin, C. S. J., Straightforward synthesis of [ Cu (NHC) (alkynyl ) ] and [Cu (NHC) (thiolato) ] complexes (NHC = N-heterocyclic carbene ). Dalton Trans 2021, 51 ( 1 ), 231-240.

[0098] Compound 3 ( 200 mg, 0. 42 mmol, 1. 0 equiv), 1-chloro-4-ethynylbenzene ( 62 mg, 0. 46 mmol, 1. 1 equiv), and freshly ground K2CO3( 170 mg, 1.24 mmol, 3. 0 equiv) were added to degassed EtOH ( 20 mL) under an inert atmosphere. The reaction mixture was stirred at room temperature for 16 h. The solvent was then removed under reduced pressure, and the residue was dissolved in diethyl ether. The resulting suspension was filtered, and colorless crystals of CulO formed from the filtrate after 1 h.

[0099] Cu10:1H NMR ( 400 MHz, CD2Cl2): δ 7. 56 (t, J = 7. 8 Hz, 2H), 7. 37 (d, J = 7. 8 Hz, 4H), 7. 16 ( s, 2H), 7. 12 - 7. 04 (m, 4H), 2. 59 (p, J = 6. 9 Hz, 4H), 1. 33 (d, J = 6. 9 Hz, 12H), 1. 24 (d, J = 6. 9 Hz, 12H). Yield: 63 %

[0100] Cu11 was obtained as light yellow precipitate from compound 3 ( 100 mg, 0. 21 mmol, 1. 0 equiv), 1-bromo-4-ethynylbenzene ( 63 mg, 0. 22 mmol, 1. 1 equiv), and K2CO3( 85 mg, 0.62 mmol, 3.0 equiv) in degassed EtOH (15 mL), following the same procedure used for the synthesis of CulO.

[0101] Cu11:1H NMR (400 MHz, CD2Cl2): δ 7.56 (t, J = 7.8 Hz, 2H), 7.37 (d, J = 7.8 Hz, 4H), 7.21 (d, J = 8.5 Hz, 2H), 7.16 (s, 1H), 7.04 (d, J = 8.5 Hz, 2H), 2.59 (p, J = 6.9 Hz, 4H), 1.33 (d, J = 6. 9 Hz, 12H), 1.24 (d, J = 6. 9 Hz, 13H).13C NMR (101 MHz, CD2Cl2): δ 182.37, 146.22, 134.99, 133.45, 131.17, 130.79, 126.78, 124.54, 123.65, 119.20, 29.13, 25.13, 23.89. Yield: 63 %.

[0102] Cu12 was obtained as yellow precipitate from compound 3 (100 mg, 0.21 mmol, 1.0 equiv), 1-ethynyl-4-(trifluoromethyl)benzene (38 mg, 0.22 mmol, 1.1 equiv), and K2CO3(85 mg, 0.62 mmol, 3.0 equiv) in degassed EtOH (15 mL), following the same procedure used for the synthesis of Cu 10.

[0103] Cu12:1H NMR (400 MHz, CD2Cl2): δ 7.57 (t, J = 7.8 Hz, 2H), 7.36 (dd, J = 10.7, 7.9 Hz, 6H), 7.27 (d, J = 8.1 Hz, 2H), 7.16 (s, 2H), 2.65 - 2.54 (m, 4H), 1.33 (d, J = 6.9 Hz, 11H), 1.24 (d, J = 6. 9 Hz, 12H).13C NMR (101 MHz, CD2Cl2): δ 182.27, 146.23, 134.97, 132.01, 131.67, 130.82, 126.43, 124.98 (d, J = 4.0 Hz), 124.56, 123.70, 104.00, 29.14, 25.13, 23.90.19F NMR (376 MHz, CD2Cl2) δ -62.69. Yield: 46 %.

[0104] Cu13 was obtained as white solid from compound 3 (100 mg, 0.21 mmol, 1.0 equiv), 4-Ethynylanisole (30 mg, 0.22 mmol, 1.1 equiv), and K2CO3(85 mg, 0.62 mmol, 3.0 equiv) in degassed EtOH (15 mL), following the same procedure used for the synthesis of Cu10. Cu13:1H NMR (400 MHz, CD2Cl2): 5 7.56 (t, J = 7.8 Hz, 3H), 7.37 (d, J = 7.8 Hz, 4H), 7.15 (s, 2H), 7.10 (d, J = 8.8 Hz, 2H), 6.64 (d, J = 8.8 Hz, 3H), 3.70 (s, 4H), 2.66 - 2.52 (m, 5H), 1.33 (d, J = 6.9 Hz, 12H), 1.24 (d, J = 6.9 Hz, 13H). Yield: 33 %.

[0105] Example 4 - Stability of compounds Cui, Cu2, Cu3, Cu4, Cu8 and Cu9

[0106] The stability of the compounds Cui, Cu2, Cu3, Cu4, Cu8 and Cu9 in Dulbecco' s Modified Eagle Medium (DMEM) was measured at 100 pM by UV-vis over 48 h, at 24 h intervals. All the compounds are stable in DMEM over 48 h. no disappearance of UV absorption bands was observed, as well as no new bands which could correspond to the release of one of the ligands. There is also no blue or red shift observed.

[0107] Example 5 - Cytotoxicity

[0108] The cytotoxicity of the compounds was tested on several cellular types. The cytotoxicity experiments of the synthesised compounds Cui, Cu2, Cu3, Cu4, Cu8 and Cu9 were performed by incubating murine and human, cancerous and non-cancerous cells for 24 h. The compounds Cui, Cu2, Cu3, Cu4, Cu8 and Cu9 were then incubated. Cisplatin was used as positive control. After 48 h incubation, quantification of the compounds' toxicities was measured using a resazurin assay. The cisplatin-resistant cell strain A2780c was acquired already resistant and kept in media treated with 1 pM of cisplatin until needed. These assays were performed in murine and human cells to assess the specificity of the compounds against cancerous or normal cells as well as their activity against cisplatin-resistant cells. For all cell lines a standard protocol was followed:

[0109] Cells were seeded at a varying cells / well density in 96-well plates (100 pL / well) and were incubated at 37 °C, 5% CO2 for 24 h. The medium was replaced by test compound dilutions in fresh medium (100 pL / well) and cells were incubated at 37 °C, 5% CO2 for 48 h. The medium was replaced with 100 µL of fresh medium containing resazurin (0.2 mg / mL). After 4h of incubation at 37 °C, 5% CO2, plates were read using a SpectraMaxM2 Microplate Reader (λexc = 540 nm; λread = 590 nm). Fluorescence data were normalized, then they were fitted using GraphPad Prism Software and IC50was calculated by non-linear regression.

[0110] I - Murine cells

[0111] Two cell lines were tested for murine cells: NIH3T3, healthy fibroblasts, and CT26, colorectal cancer cells. CT26 cells were seeded at 4000 cells / well in DMEM. NIH 3T3 cells were seeded at 5000 cells / well in DMEM.

[0112] The cytotoxicity results are indicated in Table 1.

[0113] Table 1

[0114] IC50(pM)

[0115] Healthy Cancerous

[0116] Compound S

[0117] NIH3T3 CT26

[0118] Cisplatin 4.22 ± 1.31 13.8 ± 2.5 0.3

[0119] Cui 4.08 ± 0.39 0.77 ± 0.06 5

[0120] Cu2 1.68 ± 0.30 0.28 ± 0.01 7

[0121]

[0122] Cu3 2.35 ± 0.41 0.70 ± 0.04 3

[0123] Cu4 11.3 ± 2.8 1.40 ± 0.20 8

[0124] Cu8 6.12 ± 0.77 0.39 ± 0.10 15

[0125] Cu9 2.63 ± 0.70 0.25 ± 0.01 10

[0126]

[0127] Specificity (value S) is the ratio of the IC50values of the compounds in cancer cells and in healthy cells.

[0128] The data suggest that compounds Cui, Cu2, Cu3, Cu4, Cu8 and Cu9 have a high toxicity overall, possessing IC50values in the range of 0.25-1.40 pM in cancer cells and of 1.68-11.3 pM in healthy cells. Although the toxicity of the compounds Cui, Cu2, Cu3, Cu4, Cu8 and Cu9 in healthy cells is like cisplatin, in CT26 cells, each compound is significantly more active, with toxicities between 10 and 50-fold greater than cisplatin. We can highlight compounds Cu2, Cu8 and Cu9, which have IC50values under 0.5 pM, being the most active ones of the series. Moreover, the increased toxicity of the Cu (I) NHCs against the cancer cell line compared to the healthy one is an appealing characteristic. For example, the specificity values calculated for the acetylide series (Cu8-9) are high. These compounds are between 10 to 15-fold more toxic against CT26 cells than healthy NIH3T3 cells, while the carbazole series (Cul-4) are approximately 5 to 8-fold more toxic against cancer cells. Significantly, this is not the case for cisplatin, which is more toxic against the tested healthy cell lines.

[0129] II - Human cells

[0130] Six cell lines were tested for human cells healthy fibroblasts RPE-1, healthy lung cells MRC-5, lung cancer cells A549, colorectal cancer cells HT-29 and ovarian cancer A2780 and the analogue cisplatin-resistant cancer cells A2780c. RPE-1 cells were seeded at 6000 cells / well in DMEM- F12. MRC-5 cells were seeded at 8000 cells / well in DMEM. A549 cells were seeded at 8000 cells / wells in F12-K. HT29 cells were seeded at 8000 cells / wells in McCoy medium. A2780 cells were seeded at 8000 cells / wells in RPMI. A2780c cells were seeded at 8000 cells / wells in RPMI.

[0131] The cytotoxicity results are indicated in Table 2 for RPE-1, MRC-5, A549 and HT-29, and in Table 3 for A2780 and A2780c.

[0132] Table. 2

[0133] IC50 (pM)

[0134] Healthy Cancerous

[0135] Compound

[0136] RPE-1 MRC-5 A549 S1 / S2 HT-29 S1 / S2 Cisplati 48.2 ± 4.96 ± 6.11 ± 7.9 / 0 23.0 ± 2.1 / 0 n 1. 5 0.83 0.32.8 1.8.2 Cui 0.93 ± 1.12 ± 1.27 ± 0.7 / 0 1.36 ± 0.7 / 0

[0137] 0.13 0.02 0.04.9 0.06.8 Cu2 0.72 ± 1.10 ± 1.34 ± 0.5 / 0 1.26 ± 0.6 / 0

[0138] 0.07 0.07 0.05.8 0.06.9 Cu3 0.53 ± 0.85 ± 1.14 ± 0.5 / 0 1.33 ± 0.4 / 0

[0139] 0.06 0.09 0.09.7 0.03.6 Cu4 0.97 ± 2.70 ± 1.40 ± 0.7 / 1 3.27 ± 0.3 / 0

[0140] 0.10 0.31 0.06.9 0.21.8 Cu8 0.46 ± 0.99 ± 1.00 ± 1.06 ± 0.4 / 0

[0141] 0.5 / 1

[0142] 0.01 0.05 0.06 0.08.9 Cu9 0.29 ± 0.81 ± 0. 96 ± 0.3 / 0 0.88 ± 0.3 / 0

[0143] 0.02 0.08 0.06.8 0.07.9

[0144]

[0145] RPE-1 and MRC-5 are healthy cells while A549 (lung) and HT- 29 (colorectal) are cancer cells. Specificity (value S1 and S2) is the ratio of the IC50s of the compounds in cancer cells and in RPE-1 (S1) and MRC-5 (S2) healthy cells. Table. 3

[0146] Compound A2780c A2780 s Cisplatin 16.7 ± 1.8 1.89 ± 0.22 8.8

[0147] Cui 0.41 ± 0.08 0.14 ± 0.01 2.9

[0148] Cu2 0.20 ± 0.01 0.17 ± 0.02 1.2

[0149] Cu3 0.26 ± 0.01 0.12 ± 0.01 2.2

[0150] Cu4 0.63 ± 0.08 0.17 ± 0.01 3.7

[0151] Cu8 0.28 ± 0.01 0.10 ± 0.01 2.8

[0152] Cu9 0.075 ±

[0153] 0.28 ± 0.02 3.7

[0154] 0.002

[0155]

[0156] A2780 is ovarian cancer cell line, A2780 is a cisplatinresistant strain. Specificity (value S) is the ratio of the IC50s of the compounds in cisplatin resistant cells and noncisplatin resistant cells

[0157] From Table 2, it can be noticed that cisplatin was on average, 6-fold and 20-fold less toxic than the compounds Cui, Cu2, Cu3, Cu4, Cu8 and Cu9 versus cancerous cells A549 and HT-29, respectively.

[0158] From Table 3, it can be noticed that there is a noticeable increase of toxicity against A2780 and A2780c cells, with IC50values as low as 0.30 µM on. Very interestingly, in cisplatin-resistant cells A2780c, compounds Cui, Cu2, Cu3, Cu4, Cu8 and Cu9 are up to 80-fold more toxic than cisplatin and are up to 7-fold more toxic towards them than towards non-cancerous cells. Moreover, while the toxicity of cisplatin is 9 times higher in cisplatin resistant cells versus non-resistant cells, the Cui, Cu2, Cu3, Cu4, Cu8 and Cu9 compounds activity is less variable between these two cell lines (on average only 3- fold less active). These results imply that the compounds Cui, Cu2, Cu3, Cu4, Cu8 and Cu9 probably have a different mechanism of action that cisplatin, which enables them to kill cisplatin resistant cells.

[0159] Overall, compounds Cui, Cu2, Cu3, Cu4, Cu8 and Cu9 have low IC50values of around 1 pM or even lower. Compounds Cu8 and Cu9 are consistently the ones with the highest toxicity in human cell lines, with IC50values always lower than 1.2 pM. They are followed by compound Cu3 and Cu4 with IC50values lower than 1.5 pM. Thus compounds Cui, Cu2, Cu3, Cu4, Cu8 and Cu9 have an encouraging toxicity profile, as they can be up to 15-fold more toxic than cisplatin, and up to 80 times more toxic versus cisplatin resistant cell line A2780c.

Claims

Claims

1. - Compound of formula (I)R representing:with R1, R2, R3, R4representing independently H, (Ci-Cs) - alkyl, F, Br, Cl, I, formyl, -COOH, -COO- (Ci-Ce) -alkyl, -NO2, -NH2, -NHCOO- (Ci-Ce) -alkyl, -OH, mono or polycyclic C5-C12- aryl, mono or polycyclic C3-Ci2-heteroaryl, -benzyl, -N3, (C2-Ce) -alkenyl, (C2-C6) -alkynyl, (Ci-Ce) -alkoxy, -SH, (Ci-Ce) - thioalkyl, -CnF3+2(n-1)n being an integer between 1 and 6, -SO3H, -S-CpF3+2(p-1)p being an integer between 1 and 6, -O-CqF3+2(q-1)q being an integer between 1 and 6, or -0- (CH2CH2O)m- H with m being an integer between 1 and 1000, and with the proviso that R1, R2, R3and R4are not H simultaneously; orwith R5, R6, R7, R8, R9representing independently H, (Ci-Cs) -alkyl, F, Br, Cl, I, formyl, -COOH, -COO- (Ci-Ce) -alkyl, -NO2, — NH2, —NHCOO— ( CI— Ce) —alkyl, -OH, mono or polycyclic C5~Ci2-aryl, mono or polycyclic C3-Ci2-heteroaryl, -benzyl, -N3, (C2-Ce) -alkenyl, (C2-Ce) -alkynyl, (Ci-Ce) -alkoxy, -SH, (Ci-Ce) - thioalkyl, -CnF3+2(n-1)n being an integer between 1 and 6, -SO3H, -S-CpF3+2(p-1)p being an integer between 1 and 6, -O-CqF3+2(q-1)q being an integer between 1 and 6, or -0- (CH2CH2O)m-H with m being an integer between 1 and 1000, and with the proviso that R5, R6, R7, R8, R9are not H simultaneously; orwith R10, R11, R12, R13, R14, R15and R16representing independently H, (Ci-Cs) -alkyl, F, Br, Cl, I, formyl, -COOH, -COO- (Ci-C6) -alkyl, -NO2, -NH2, -NHCOO- (Ci-C6) -alkyl, -OH, mono or polycyclic C5~Ci2-aryl, mono or polycyclic C3~Ci2-heteroaryl, -benzyl, -N3, (C2-Ce) -alkenyl, (C2-Ce) -alkynyl, (Ci-Ce) -alkoxy, -SH, (Ci-Ce) -thioalkyl, -CnF3+2(n-1) n being an integer between 1 and 6, -SO3H, -S-CpF3+2(p-1) p being an integer between 1 and 6, -O-CqF3+2(q-1) q being an integer between 1 and 6, or -0- (CH2CH2O)m-H with m being an integer between 1 and 1000.

2. - Compound of formula (I) according to claim 1, wherein:R1, R2, R3, R4represent independently H, (Ci-Cs) -alkyl, F, Cl, Br, I, -CF3, -COOMe, -OMe, -SMe, -OCF3, -SCF3, -N2O, phenyl or pyridinyl; andR5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15and R16represent independently H, F, Cl, Br, I, -CF3, -OCF3, -SCF3or -OMe.

3. - Compound of formula (I) according to claim 2, wherein:R1, R3, R4represent H, and R2represents (Ci-Cs) -alkyl, F, Cl, Br, I, CF3, -OMe, -OCF3, -SCF3, -N2O, phenyl or pyridinyl; R5, R6, R8, R9represent H and R7represents F, Cl, Br, I, -CF3, -OCF3, -SCF3or -OMe; andR10, R11, R12, R13, R14, R15and R16represent H.

4. Compound of formula (I) according to one of claims 1 to 3, wherein the compound of formula (I) is chosen from:

5. - Compound of formula (I) for use in the treatment of cancer,R representing:with R1, R2, R3, R4representing independently H, (Ci-Cs) -alkyl, F, Br, Cl, I, formyl, -COOH, -COO- (Ci-Ce) -alkyl, -NO2, -NH2, —NHCOO— (Ci— Ce) —alkyl, -OH, mono or polycyclic C5-C12- aryl, mono or polycyclic C3-Ci2-heteroaryl, -benzyl, -N3, (C2- Ce) -alkenyl, (C2-C6) -alkynyl, (Ci-Ce) -alkoxy, -SH, (Ci-Ce) - thioalkyl, -CnF3+2(n-1) n being an integer between 1 and 6, -SO3H, -S-CpF3+2(p-1) p being an integer between 1 and 6, -O-CqF3+2(q-1) q being an integer between 1 and 6, or -O- (CH2CH2O)m-H with m being an integer between 1 and 1000; orwith R5, R6, R7, R8, R9representing independently H, (Ci-Cs) -alkyl, F, Br, Cl, I, formyl, -COOH, -COO- (Ci-Ce) -alkyl, -NO2, -NH2, -NHCOO- (Ci-Ce) -alkyl, -OH, mono or polycyclic C5-C12- aryl, mono or polycyclic C3-Ci2-heteroaryl, -benzyl, -N3, (C2- Ce) -alkenyl, (C2-C6) -alkynyl, (Ci-Ce) -alkoxy, -SH, (Ci-Ce) - thioalkyl, -CnF3+2(n-1) n being an integer between 1 and 6, -SO3H, -S-CpF3+2(p-1) p being an integer between 1 and 6, -O-CqF3+2(q-1) q being an integer between 1 and 6, or -0- (CH2CH2O)m-H with m being an integer between 1 and 1000; orwith R10, R11, R12, R13, R14, R15and R16representing independently H, (Ci-Cs) -alkyl, F, Br, Cl, I, formyl, -COOH, -COO- (Ci-C6) -alkyl, -NO2, -NH2, -NHCOO- (Ci-C6) -alkyl, -OH, mono or polycyclic C5~Ci2-aryl, mono or polycyclic C3~Ci2-heteroaryl, -benzyl, -N3, (C2-Ce) -alkenyl, (C2-Ce) -alkynyl, (Ci-Ce) -alkoxy, -SH, (Ci-Ce) -thioalkyl, -CnF3+2(n-1) n being an integer between 1 and 6, -SO3H, -S-CpF3+2(p-1) p being an integer between 1 and 6, -O-CqF3+2(q-1) q being an integer between 1 and 6, or -0- (CH2CH2O)m-H with m being an integer between 1 and 1000.

6. - Compound of formula (I) for use in the treatment of cancer according to claim 5, wherein:R1, R2, R3, R4represent independently H, (Ci-Cs) -alkyl, F, Cl, Br, I, -CF3, -COOMe, -OMe, -SMe, -OCF3, -SCF3, -N2O, phenyl or pyridinyl; andR5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15and R16represent independently H, F, Cl, Br, I, -CF3, -OCF3, -SCF3or -OMe.

7. - Compound of formula (I) for use in the treatment of cancer according to one of claims 5 or 6, wherein:R1, R3, R4represent H, and R2represents H, (Ci-Cs) -alkyl, F, Cl, Br, I, CF3, -OMe, -OCF3, -SCF3, -N2O, phenyl or pyridinyl; andR5, R6, R8, R9, R10, R11, R12, R13, R14, R15and R16represent H and R7represents H, F, Cl, Br, I, -CF3, -OCF3, -SCF3 or -OMe.

8. - Compound of formula (I) for use in the treatment of cancer according to one of claims 5 to 7, wherein the compound of formula (I) is chosen from:

9. - Compound of formula (I) for use in the treatment of cancer according to one of claims 5 to 8, wherein the cancer is ovarian cancer, colon cancer, colorectal cancer, throat cancer, bladder cancer or stomach cancer.

10. - Compound of formula (I) for use in the treatment of cancer according to one of claims 5 to 9, wherein the cancer is a cisplatin-resistant cancer, in particular cisplatin-resistant ovarian cancer.

Images