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WO2012038694A1 - Composés anticancéreux - Google Patents

Composés anticancéreux Download PDF

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Publication number
WO2012038694A1
WO2012038694A1 PCT/GB2011/001365 GB2011001365W WO2012038694A1 WO 2012038694 A1 WO2012038694 A1 WO 2012038694A1 GB 2011001365 W GB2011001365 W GB 2011001365W WO 2012038694 A1 WO2012038694 A1 WO 2012038694A1
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Prior art keywords
compound
cancer
group
formula
preventing
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PCT/GB2011/001365
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English (en)
Inventor
Elias Castanas
Marilena Kampa
Vassiliki Pelekanou
Joseph Vercauteren
Katerina Theodoropoulou
Fani Mavromati
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Bionature EA Ltd
TOWLER PHILIP DEAN
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Bionature EA Ltd
TOWLER PHILIP DEAN
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention pertains to lipoylated proanthocyanidin compounds and their use in treating, preventing or ameliorating a disorder or disease influenced by the action of a membrane androgen receptor, including cancer.
  • steroid receptors intracellular receptor proteins, termed steroid receptors, which belong to the nuclear receptor superfamily. Upon binding of steroids the receptors dimerize, translocate to the nucleus and act as ligand-activated transcription factors, thereby modulating the transcriptional activity of target genes.
  • mARs membrane androgen receptors
  • signalling via mARs has been shown to involve ion movements, secretion of intracellular proteins, initiation of rapid signalling cascades leading to actin cytoskeleton modifications and transcription of specific genes independent from those triggered by the action of androgen nuclear receptors.
  • mARs have been reported in a number of normal or malignant tissues and lesions. They have been detected in breast and prostate cancer but notably not in the adjacent non-malignant areas. They have also been detected in T-lymphocytes, spermocytes and sperm, and in colon cancer. They have attracted interest as therapeutic targets for disorders influenced by the action of membrane androgen receptors, particularly cancer.
  • mAR agonists which are large, macromolecular-conjugated androgens, such as testosterone BSA.
  • WO 2004/006966 discloses the use of testosterone-protein conjugates as agonists of membrane testosterone receptors in the treatment of solid cancers and hematologic malignancies.
  • the possibility of combining steroid-protein conjugates with other cytoskeleton acting agents in order to enhance their anti-cancer activity is also disclosed.
  • the use of such androgen molecules in therapy is far from ideal due to their potential androgenic actions (in cases in which free androgen is released) and subsequent induced liver toxicity.
  • steroid-protein conjugates are difficult to manage as medicines, necessitating i.v. administration.
  • a constant delivery of a macromolecule may be harmful, inducing a liver implication, colloidosmotic changes' and interference in renal detoxification and excretion mechanisms.
  • Oligomeric proanthocyanidins also known as procyanidins, are naturally occurring plant compounds. They are almost ubiquitous, but most abundant in parts of our diet such as fruits, vegetables, nuts, seeds, flowers and bark. Other plant sources of proanthocyanidins include wine, cranberries, and the leaves of bilberry, birch, gingko and hawthorn. Procyanidins are the main precursors of blue- violet and red pigments in plants.
  • oligomeric epicatechin and catechin-derived procyanidins can be used as treatments for breast cancer growth through cell cycle arrest.
  • WO 2003/057201 discloses that epigallocatechin gallate, epicatechin gallate, epigallocatechin, epicatechin, and catechin, in association with ascorbic compounds, L-lysine and L-proline can be used for blocking melanoma, breast, colon, lung or brain cancer cell proliferation and metastasis, through interaction with the activity of matrix metaloproteases and plasmin.
  • US 2004/142048 and WO 2002/067965 disclose that administering to a mammal a composition comprising tea catechins adjunctively with a composition comprising proanthocyanidins may treat rectal carcinoma, colon carcinoma, breast carcinoma, ovarian carcinoma, small cell lung carcinoma, chronic lymphocytic carcinoma, hairy cell leukaemia, oesophageal carcinoma, prostate carcinoma, breast cancer, myeloma, and lymphoma, or their metastases, without or as an adjuvant therapy with other anticancer agents.
  • the mode of action proposed is the interaction of catechins or procyanidins with a specific cancer related isoform of the membrane NADH
  • catechin multimers and particularly substituted catechin multimers, as carrier moieties for the delivery of nucleophilic and cationic bioactive therapeutic agents to target sites in vivo.
  • CN 1376464 discloses that catechin and curcumin may together decrease cancer cell (LoVo) growth in vitro.
  • US 2008/0227853 discloses a method of treating or preventing a disorder influenced by the action of a membrane androgen receptor, wherein a patient suffering or expected of suffering of such disorder is administered in pharmaceutically effective amounts an agonist of the membrane androgen receptor, said agonist being selected from the group consisting of natural, unnatural, oligomerised or rearranged catechin, epicatechin, and derivatives thereof.
  • B2 and B5 which are depicted in US
  • R independently is selected among the group consisting of H, Cl-C12-alkyl, C2-C12-alken, C2-C12- alkyn, or gallic acid.
  • Cancer is a leading cause of death worldwide. There is a sustained need for the development of new compounds for use in the treatment of disorders and diseases influenced by the action of membrane androgen receptors, particularly cancer. It is therefore desirable to provide further agonists of membrane androgen receptors.
  • Prostate cancer is the most common diagnosed disease amongst Western males and the second leading cause of cancer-related deaths. Prostate cancer usually starts as an androgen-dependent tumor and evolves to androgen insensitivity. At present, no specific therapy of prostate cancer has been proposed: surgical ablation of the tumor is usually performed, followed by anti-androgen and/or chemotherapy, with poor results. In order to have a realistic chance of tackling the poor outcome of the advanced disease, the identification of alternative therapeutic approaches is necessary.
  • the present inventors have, for the first time, prepared lipoylated dimeric
  • proanthocyanidin compounds and shown them to have particularly desirable properties in relation to membrane androgen receptor binding and regressive activity on tumours.
  • Further advantages of the molecules of the present invention, when compared to the testosterone BSA adduct, are that they have a low molecular weight and that they can be administered by other ways in addition to a parentaral
  • treatment with the molecules of the present invention is not associated with liver toxicity or androgenic effects.
  • the present invention provides a composition comprising at least one compound of Formula I or Formula II, or a pharmaceutically acceptable salt or acid addition salt thereof, as an active ingredient together with a pharmaceutically acceptable carrier, diluent or adjuvant.
  • this invention relates to a compound of Formula I or Formula II, or a pharmaceutically acceptable salt or acid addition salt thereof, for use in therapy.
  • this invention relates to a method of preventing or treating a disorder or disease influenced by the action of a membrane androgen receptor, said method comprising administering to a patient an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt or acid addition salt thereof.
  • said disease is cancer, and still more preferably said cancer is selected from the group consisting of breast cancer, prostate cancer, colon cancer, adrenal cancer, lung cancer, cancer of the kidney, cancer of the ileum, brain tumour, liver cancer and myelohyperplastic disorders such as cancer of the bone marrow.
  • said disease is breast cancer or prostate cancer.
  • said cancer is a hormone resistant cancer, also called a hormone insensitive or hormone non-sensitive cancer.
  • said cancer is hormone sensitive.
  • this invention relates to a compound of Formula I or Formula II, or a pharmaceutically acceptable salt or acid addition salt thereof, for use in preventing or treating a disorder or disease influenced by the action of a membrane androgen receptor.
  • Said disorder or disease may, for example, be any of those listed above.
  • this invention relates to the use of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt or acid addition salt thereof, for the manufacture of a medicament for preventing or treating a disorder or disease influenced by the action of a membrane androgen receptor.
  • Said disorder or disease may, for example, be any of those listed above.
  • this invention relates to the use of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt or acid addition salt thereof, to control the proliferation of cancer cells.
  • this invention relates to a method of controlling the proliferation of cancer cells, said method comprising contacting said cells with a compound of Formula I or Formula II, or a pharmaceutically acceptable salt or acid addition salt thereof.
  • said method is an in vitro method.
  • this invention relates to the use of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt or acid addition salt thereof, for binding, activating or inhibiting a membrane androgen receptor.
  • this invention relates to a method of binding, activating or inhibiting a membrane androgen receptor, said method comprising contacting said receptor with a compound of Formula I or Formula II, or a pharmaceutically acceptable salt or acid addition salt thereof.
  • said method is an in vitro method.
  • said receptors will be contacted by the administration of said compound to cells comprising said receptor.
  • said method is a method of binding or activating said receptor.
  • the compounds of the present invention can be administered as sole active agents or sequentially, concomitantly or in combination with other active agents.
  • said other active agent is a cytoskeletal-acting drug, especially drugs of the Taxane family (e.g. Taxol®, Taxotere ®).
  • Figure 1 shows the chemical structures of a selection of the compounds used or referred to in the Examples of the present application.
  • Figure 2 shows the effect of the dimeric proanthocyanidins Bl -B4 (A), oleylated and non-oleylated B2 (B) and oleylated and non-oleylated B3 (C) on the growth of androgen-sensitive (LnCaP) and resistant (DU145) human prostate cancer cells.
  • the Figure presents normalized results as compared to control (non-treated) cells. The effect was measured after two cell cycles. The data points represent the mean of three different experiments, performed in triplicate.
  • Figure 4 shows (A) the displacement of [ 3 H]-testosterone from membrane binding sites of DU145 cell membranes by B2, B3 and their oleylated derivatives.
  • the Figure presents means ⁇ SEM of three different experiments performed in triplicate.
  • FIG. 1 shows the modification of the actin cytoskeleton cellular distribution in DU145 cells treated with testosterone-BSA, B2 and oleylated B2. Typical sections are presented.
  • Figure 5 shows the in vivo effects of oleylated B2 in the reduction of BALBc " ' " DU 145 tumors.
  • Ten-week male BALBc-/ animals were injected with 5xl 0 6 DU145 cells in Matrigel®. After the development of tumors, animals were injected with PBS (control), testosterone-BSA (8 mg/kg), B2 (0.08 mg/kg) or oleylated-B2 (0.16 mg kg), providing a concentration of 10 "7 M of the substance in body fluids.
  • the tumor volume (A) and inhibitory rate (B) are displayed.
  • C histological sections of the tumors are shown in different magnifications stained with hematoxylin & eosin.
  • the lower panel presents the MIB- 1 staining of tumors.
  • Figure 6 shows the absence of a pro-androgenic effect for B2. Histological sections are presented of testes (A) and liver (B).
  • Figure 7 shows the normalized cell growth inhibition, measured by the MTT assay, of hormone sensitive (LnCaP, T47D) or resistant (DU145, MDA-MB-231) prostate (LnCaP, DU145) and breast cancer cells (T47D, MDA-MB-231) cell lines, after incubation for one or two cell cycles (usually 4-6 days) with a standard concentration of oleylatyed B2 (CMS 1 , 10 "6 M).
  • CMS 1 oleylatyed B2
  • R 3 , R 4 , R 5 , R 8 , R 9 and R 10 are each independently selected from the group consisting of H, C
  • X and Z are each independently selected from the group consisting of H or OH; and pharmaceutically acceptable salts and acid addition salts thereof.
  • the letters A, B, C, D, E and F in the formulae above are trivial name labels applied to the six rings present in the molecules.
  • Proanthocyanidins are known in the art as dimers comprised of monomelic catechin or epicatechin.
  • B-type proanthocyanidins contain a single intermolecular bond between carbons 4 and 8 of adjacent monomers (as in Formula I) or between carbons 4 and 6 of adjacent monomers (as in
  • only one position of each of ring B and ring E in the dimers of the present invention is
  • the R a groups may be the same or different.
  • R 3 , R 4 , R 5 , R 8 , R 9 and R 10 are H, i.e. the compounds of the invention are preferably not substituted at these positions.
  • X and Z are H.
  • Catechin possesses two aromatic rings, known in the art as the A- and B-rings, and a dihydropyran heterocycle known as the C-ring. There are two chiral centres on the molecule, on carbons 2 and 3. Catechin therefore has four diastereoisomers. Two of the isomers are in trans configuration and are called catechin and the other two are in cis configuration and are called epicatechin. The most common trans isomer is
  • (+)-catechin The other stereoisomer is (-)-catechin, also termed erc/-catechin.
  • the most common cis isomer is (-)-epicatechin (also known as L-epicatechin, epicatechol, (-)-epicatechol, /-acacatechin, /-epicatechol, epi-catechin, 2,3-cis-epicatechin or (2 ⁇ ,3/?)-(-)-epicatechin).
  • the other stereoisomer is known as (+)-epicatechin.
  • the dimers of the present invention may comprise any combination of catechin/ epicatechin stereoisomers as monomelic units, provided that the essential features of the invention are provided.
  • the proanthocyanidin dimers known in the art as B 1 to B8 are differentiated by their stereochemical structures, i.e. they consist of different pairs of catechin/epicatechin stereoisomers.
  • the proanthocyanidin dimers B1-B4 are characterized by a C4-C8 linkage, i.e. between the C4 of the heterocyclic C-ring of one monomer and the C8 (A-ring) of the attached monomer.
  • the proanthocyanidin dimers B5 to B8 are also known in the art and are characterised by a C4-C6 linkage, i.e. between the C4 of the heterocyclic C-ring of one monomer and the C6 (A-ring) of the attached monomer.
  • the compounds of Formula I of the present invention are characterised by a C4-C8 linkage between the heterocycle (C-ring) and the attached A ring, i.e. the compounds of the present invention are B1-, B2-, B3- or B4- procyanidins.
  • the compounds of Formula II of the present invention are characterised by a C4-C6 linkage between the heterocycle (C-ring) and the attached A ring, i.e. the compounds of the present invention are B5-, B6-, B7- or B8- procyanidins.
  • the compounds of the present invention may be homodimers or heterodimers.
  • homodimers are made of only one type of catechin or epicatechin stereoisomer, whereas heterodimers comprise two different catechin or epicatechin stereoisomers.
  • heterodimers comprise two different catechin or epicatechin stereoisomers.
  • the compounds of the present invention are homodimers.
  • the present invention provides compounds selected from the group consisting of Formulae I-Bl , I-B2, 1-B3 and I-B4
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , X and 2 are as defined anywhere herein;
  • the fatty acid chains of these lipid groups may be saturated or unsaturated.
  • the unsaturated fatty acid groups may comprise double bonds in the cis or trans configuration, preferably cis.
  • R a is a linear or branched, saturated or unsaturated C 5 -C 2 3 hydrocarbyl group having up to six double or triple carbon-carbon bonds.
  • R a is a linear C 7 -C 23 alkyl or C 7 -C 23 alkenyl having 1 to 6 double bonds. More preferably, R a is a C13-C21 alkyl or Ci 3 -C 2 i alkenyl having 1 to 6 double bonds, still more preferably a C) 3 -C 2 i alkyl or C )3 -C 2 i alkenyl having 1 to 3 double bonds.
  • caprylic acid capric acid
  • lauric acid myristic acid
  • palmitic acid palmitoleic acid
  • palmitoleic acid Z-9-pentadecen- 1 -oic acid
  • stearic acid isostearic acid (17-methyloctadecan-l -oic acid
  • elaidic acid tran.s-9-octadecenoic acid
  • oleic acid cw-9-octadecenoic acid
  • linoleic acid cis, m-9, 12-octadecadienoic acid
  • elaidolinoleic acid (9E, 12E, 15E-octadecatrien-l -oic acid, a-linolenic acid
  • ⁇ -linolenic acid (9Z, 12Z, 15Z-octadecatrien-l-oic acid) and arachidic acid.
  • R a may be a mixture of long chain alkyl/alkenyl compounds such as coco, soya, or tallow.
  • Particularly preferred compounds of the present invention are (3',3')-, (3',4')-, (4',3')- and (4',4') bi-lipoylated B2 and B3 compounds, in particular the compounds selected from the group consisting of:
  • the naturally occurring procyanidin molecules can B2011/001365
  • R 13 , R 14 , R 15 , R 18 R 19 and R 20 are each independently selected from the group consisting of H, Ci-Ce-alkyl, C 2 -C6-alkenyl, and C 2 -C6-alkynyl;
  • Suitable leaving groups in the above processes include any groups conventional in the art for such purpose, including: halides, e.g. chloride, bromide, iodide; and sulfonate esters, e.g. p-toluenesulfonates (tosylates), trifluoromethyl sulfonates (inflates) and fluorosulfonates.
  • halides e.g. chloride, bromide, iodide
  • sulfonate esters e.g. p-toluenesulfonates (tosylates), trifluoromethyl sulfonates (inflates) and fluorosulfonates.
  • the OH groups that are most susceptible to acylation in the compounds of Formulae V and VI are those on the B and E rings. Furthermore, once acylation of one ring has occurred, steric and electronic effects reduce the tendency to further acylation of the same ring.
  • alkyl herein denotes a straight chain or branched chain or cyclic saturated hydrocarbon group. Unless otherwise specifically limited, an alkyl group may be unsubstituted, singly substituted or, if possible, multiply substituted, with substituent groups in any possible position. Unless otherwise specifically limited, a cyclic alkyl group includes monocyclic, bicyclic, tricyclic and polycyclic rings, for example adamantyl, norbornyl and related terpenes.
  • alkenyl alone or in combination, herein denotes a straight chain or branched chain or cyclic unsaturated hydrocarbon group which contains at least one carbon-carbon double bond. Unless otherwise specifically limited, an alkenyl group may be unsubstituted, singly substituted or, if possible, multiply substituted, with substituent groups in any possible position. Alkenyl is meant to include the allenyl group, which possesses two consecutive double bonds.
  • alkynyl alone or in combination, herein denotes a straight chain or branched chain or cyclic unsaturated group which contains at least one carbon-carbon triple bond. Unless otherwise specifically limited, an alkynyl group may be unsubstituted, singly substituted or, if possible, multiply substituted, with substituent groups in any possible position.
  • Substituted refers to groups substituted by a below described substituent group in any possible position.
  • Substituent groups for the above moieties useful in the invention are those groups that do not significantly diminish the biological activity of the inventive compound.
  • Substituent groups that do not significantly diminish the biological activity of the inventive compound may include, for example, ' lower alkyl (acyclic and cyclic), aryl (carbocyclic aryl and heteroaryl), alkenyl, alkynyl, alkoxy, halo, haloalkyl, amino, alkylamino, dialkylamino, mercapto, alkylthio, alkylsulfinyl, alkylsulfonyl, nitro, alkanoyl, alkanoyloxy, alkanoyloxyalkanoyl, alkoxycarboxy, carbalkoxy, carboxamido, formyl, carboxy, hydroxy, cyano, azido, isocyan
  • the present invention also includes pharmaceutically acceptable salts of the compounds of Formula I and Formula II, including acid addition salts.
  • stereocentres exist in compounds of Formula I and Formula II.
  • the present invention includes all possible stereoisomers and geometric isomers of Formula I and Formula II as mixtures or as pure diastereomers.
  • a compound of Formula I or Formula II is desired as a single diastereomer, it maybe obtained either by resolution of the final product or by stereospecific hemisynthesis from either isomerically pure starting material or any convenient intermediate.
  • treat refers to any treatment of a disorder or disease influenced by the action of a membrane androgen receptor in a subject and includes, but is not limited to, preventing the disorder or disease from occurring in a subject who has not yet been diagnosed as having the disorder or disease, inhibiting the disorder or disease, for example arresting the development of the disorder or disease, relieving the disorder or disease, for example, causing regression of the disorder or disease, or relieving the condition caused by the disease or disorder, for example, stopping the symptoms of the disorder or disease.
  • Formulations of the present invention may be administered in standard manner for the treatment of the indicated diseases, including but not limited to oral, parenteral, sublingual, transdermal, rectal, or administration via inhalation or via buccal administration. Additionally, compositions of the present invention may be formulated for parenteral administration by injection or continuous infusion.
  • compositions according to the invention may be formulated as a slow release form or as a depot preparation.
  • the route of administration may be any route that effectively transports the active compound to the desired site for it to exert its effects. Any person trained in the art may extend the former description to any other method of administration, not harming the recipient person.
  • the pharmaceutical compositions of this invention are prepared in conventional dosage unit forms by incorporating an active compound of the invention or a mixture of such compounds, with nontoxic pharmaceutical carrier according to accepted procedures in a nontoxic amount sufficient to produce the desired pharmacodynamic activity in a subject, animal or human.
  • the composition contains the active ingredient in an active, but nontoxic amount which depends on the specific biological activity desired and the condition of the patient.
  • the pharmaceutical carrier employed may be, for example, either a solid or a liquid.
  • Representative solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, microcrystalline cellulose, polymer hydrogels and the like.
  • Typical liquid carriers are propylene glycol, aqueous solutions of ⁇ -cyclodextrins, syrup, peanut oil and olive oil and the like emulsions.
  • the carrier or diluent may include any time-delay material well known to the art, such as glycerol monostearate or glycerol distearate alone or with wax, microcapsules, microspheres, liposomes, and/or hydrogels.
  • the preparation in the case of a solid carrier, can be plain milled, micronized or nanosized, in oil, tableted, placed in a hard gelatin or enteric-coated capsule in micronized powder or pellet form, or in the form of a troche, lozenge, or suppository.
  • a liquid carrier the preparation can be in the form of a liquid, such as an ampoule, or as an aqueous or nonaqueous liquid suspension mixed with
  • nasal spray, sublingual administration and timed release skin patches are also suitable pharmaceutical forms for topical administration.
  • compositions described herein may comprise, consist essentially of, or consist of any . of the elements as described herein.
  • Proanthocyanidins were all obtained from EtOAc grape seeds extracts (Vitis vinifera, Vitaceae) on which Centrifugal Partition Chromatography (CPC) in hexane-ethyl acetate-ethanol-water (1 :8:2:7; v/v/v/v) was applied, as described previously
  • HPLC conditions for analysis of proanthocyanidins (method 1): Column Synergi 4 ⁇ hydro-RP 80A (250x2.0 mm) from Phenomenex ; water- 0.0025 % TFA (v/v, solvent A), methanol-0.0025% TFA (v/v, solvent B) ; gradient : initial 85% A, from 15 to 50% B in 30 min, from 50 to 00 % B in 3 min ; detection at 280 nm, flow rate 0.2 ml/min.
  • HPLC conditions for phloroglucinolysis analysis (method 2) : Column Atlantis dCl 8 (4.6x250mm) from Water, 2% aqueous formic acid (v/v, solvent A),
  • acetonitrile/water/formic acid 80 : 18 :2 v/v/v, solvent B) ; initial 100% A and during 8 min, from 0 to 20% B in 32 min, from 20 to 95% B in 5 min; detection at 280 mm, flow rate : 1 ml/min ; oven temperature 30°C.
  • the ESI-MS apparatus was a LCQ Advantage from ThermoFinnigan, monitored by Xcalibur 2.1 package software.
  • proanthocyanidins have previously been isolated and identified from grapes [see Ricardo da Silva J.M.,
  • dimer B2 (2 g; 3.5 mmol) in 300 ml CHC1 3 .
  • 766 ⁇ of triethylamine (556 mg, 5.49 mmol, 1.57 eq) and the resulting mixture was stirred at room temperature.
  • Oleyl chloride (1.653 g; 5.49 mmol, 1.57 eq.), dissolved in 200 ml CHCI3 was added drop by drop over a 2 hour period.
  • the CHCI3 used was verified to be free of any trace of EtOH (stabilized by amylene).
  • the mixture was stirred at room temperature under nitrogen for 6 additional hours.
  • Sodium bicarbonate aqueous solution was then added until the pH was made alkaline.
  • Oleylated B3 was prepared using the same methodology.
  • the dimer B3 (20 mg; 0.035 mmol) was added to 6 ⁇ of triethylamine (0.041 mmol) dissolved in 3 ml
  • Oleylated B3 was obtained pure after HPLC on a normal phase (52% yield). The major product gave the pseudomolecular [M+H] + ion peak at m/z 1 107. It was further confirmed that 8 hydroxyl groups remained free on the molecule, by measuring a new MS in the same way, after dissolution in deuterated methanol. The 8 free hydroxyl groups were easily exchanged by deuterium and the MS showed a new
  • Prostate cancer cells LNCaP (hormone sensitive) and DU-145 (hormone resistant) were cultured in RPMI 1640 medium (Gibco- Invitrogen, Paisley, UK), 10% foetal bovine serum (FBS) at 37°C in a humidified atmosphere of 5% C0 2 in air.
  • RPMI 1640 medium Gibco- Invitrogen, Paisley, UK
  • FBS foetal bovine serum
  • T47D T47D
  • MDA- MB-231 cell lines were cultured in RPMI 1640 or, L-15 medium respectively
  • Testosterone-3- (O- carboxymethyl) oxime-BSA (10 molecules testosterone per molecule of BS A) was purchased from Sigma Hellas (Athens, Greece) and used dissolved in PBS buffer. Before each experiment, a new solution of BSA- conjugate was prepared and subjected to DCC treatment (dextran 0.05mg/ml and charcoal 50mg/ml) for 30min, in order to remove any potential
  • DU145 cells were washed with phosphate-buffered saline (PBS), removed by scrapping and centrifuged at 1500 rpm. Pelleted cells were homogenized by sonication in 50mM Tris-HCl pH 7.4, containing freshly added protease inhibitors ( ⁇ g/ml PMSF and ⁇ g/ml aprotinin). Unbroken cells were removed by PBS phosphate-buffered saline (PBS), removed by scrapping and centrifuged at 1500 rpm. Pelleted cells were homogenized by sonication in 50mM Tris-HCl pH 7.4, containing freshly added protease inhibitors ( ⁇ g/ml PMSF and ⁇ g/ml aprotinin). Unbroken cells were removed by
  • Binding experiments were performed in a final volume of 0.1 ml, containing DU145 cell membranes (2mg/ml) and 5nM of [ 3 H] -testosterone (specific activity 95
  • PKI polyethylenimine
  • mice Male BalbC "A nude mice (10 week old) were from Harlan (Italy). Animals were injected subcutaneously in the back with 5xl0 6 DU-1 5 cells diluted in Matrigel ® (Sigma) in a total volume of 0.1 ml. After 2 weeks, macroscopic tumors were developed. Then, vehicle (PBS), testosterone-BSA (8 mg/kg), B2 (0.08 mg kg) or oleylated-B2 (0.1 mg kg), were administered to provide a circulating concentration of 10 "7 M of either substance in body fluids. Substances were diluted in PBS and injected intraperitoneally 3 times per week, in a total volume of 0.5 ml.
  • Tumor size was measured with a vernier weekly and its weight was calculated by the formula l/2a x b 2 where 'a' is the long diameter and V is the short diameter of the tumor (both in cm).
  • the animals were sacrificed at the indication time. Tumors were excised, measured, fixed in formalin and analyzed by a pathologist. Liver and testes were analyzed by the same pathologist blindly for changes indicative of testosterone or OPC action.
  • the inhibitory rate (IR) of tumor growth was calculated according to the following formula:
  • Testosterone-BSA is known to be a membrane-acting testosterone analog which, decreases cell proliferation of prostate cancer cell lines [Hatzoglou et al, J. Clin. Endocrinol. Metab. 90, 893-903 (2005); Kampa et al, Exp. Cell. Res. 307, 41 -51 (2005); Kampa et ⁇ ., ⁇ . Cancer. Ther. 5, 1342-51 (2006)].
  • proanthocyanidins B2 and B5 are agonists of the membrane androgen binding site [Nifli et al., Exp. Cell. Res. 309(2), 329-339 (2005)].
  • the inhibitory effect was more pronounced (-40%).
  • OPCs were equally more potent, decreasing cell growth from 12-31%.
  • hormone sensitive (LnCaP, T47D) or resistant (DU145, MDA-MB-231) prostate (LnCaP, DU145) and breast cancer cells (T47D, MDA-MB-231) were incubated for one or two cell cycles (usually 4-6 days) with a standard concentration of oleylatyed B2 (CMSl, 10 ⁇ 6 M). Normalized cell growth inhibition, measured by the MTT assay, was calculated as the difference of growth of cells in the absence
  • mice were inoculated with DU145 cells. After tumor growth (usually 10- 15 days), they were treated with vehicle (PBS), testosterone-BSA (8 mg/kg), B2 (0.08 mg/kg) or 4'B,4'E-dioleyl-B2 (cmsl) (0.16 mg kg), corresponding to a circulating concentration of 10 "7 M of either substance in body fluids. Substances were administered intraperitoneally, three times per week for one month.
  • Tumor size calculated according to the formula presented in the Materials and Methods section above, was measured every 10 days.
  • Figure 5A shows that testosterone-BSA decreased tumor size by ⁇ 40%, in accordance with previously published data.
  • B2 decreased tumor size by ⁇ 30%, while 4'B,4'E-dioleyl-B2 had the maximal effect, decreasing tumor size by -50%.
  • Oleylated OPC does not exert toxicity or androgenic actions
  • lipoylation of positions 4' of rings B and E confers an increased affinity for the mAR.
  • one reason for this might be that lipoylation confers on the molecule a structure similar to that of conjugated testosterone.
  • Another might be the increased lipophilicity of the resulting molecule, permitting its better incorporation into the plasma membrane and a better interaction with growth factor receptors (an element described for membrane-acting androgen), or with membrane anchored conventional or non-conventional androgen sites.
  • lipoylated B2 is not restricted to prostate cancer cells in vitro, but extended also in vivo, to BALBc '/_ mice, xenografted with DU 145 human prostate cancer cells. Lipoylated B2 was observed to exert a 50% inhibitory effect on tumor growth, in animals which had already developed tumors, a situation resembling prostate cancer in humans. From this perspective, the compounds of the invention have utility, alone or in combination with cytoskeletal acting drugs, for the treatment of cancers, such as prostate cancer. Further advantages of the molecules of the present invention are that they have a small molecular weight and that they can be administered orally. As shown by the data above, advantageously, treatment with the molecules of the present invention is not associated with liver toxicity or androgenic effects.

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Abstract

L'invention porte sur des composés de proanthocyanidine lipoylés et sur leur utilisation dans le traitement, la prévention ou l'amélioration d'un trouble ou d'une maladie sur lequel l'action d'un récepteur membranaire aux androgènes a une incidence, dont les cancers. Les composés actifs sont représentés par la formule (I) ou la formule (II) : (Formules (I) (II)) dans lesquelles R3, R4, R5, R8 , R9 et R10 sont chacun indépendamment choisis dans le groupe constitué par H, alkyle en C1-C6, alcényle en C2-C6 et alcynyle en C2-C6 ; R1, R2, R6 et R7 sont chacun indépendamment choisis dans le groupe constitué par H et -C(=O)-Ra , où Ra réprésente un groupe hydrocarbyle en C5-C23 saturé ou insaturé, linéaire ou ramifié, ayant jusqu'à six doubles ou triples liaisons carbone-carbone ; et au moins l'un de R1, R2, R6 et R7 est -C(=O)-Ra ; X et Z sont chacun indépendamment choisis dans le groupe constitué par H et OH ; et des sels ou sels d'addition d'acide pharmaceutiquement acceptables de ceux-ci.
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