WO2017198849A1 - Dérivés de limonoïdes pour le traitement et/ou la prévention de la croissance de cellules du cancer du sein - Google Patents

Dérivés de limonoïdes pour le traitement et/ou la prévention de la croissance de cellules du cancer du sein Download PDF

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Publication number
WO2017198849A1
WO2017198849A1 PCT/EP2017/062166 EP2017062166W WO2017198849A1 WO 2017198849 A1 WO2017198849 A1 WO 2017198849A1 EP 2017062166 W EP2017062166 W EP 2017062166W WO 2017198849 A1 WO2017198849 A1 WO 2017198849A1
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WIPO (PCT)
Prior art keywords
breast cancer
compound
compound according
formula
treating
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PCT/EP2017/062166
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English (en)
Inventor
Sophie BARILLE-NION
Illa TEA
Mbaye Diaw DIOUM
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Institut National De La Sante Et De La Recherche Medicale (Inserm)
Centre National De La Recherche Scientifique (Cnrs)
Universite De Nantes
Universite D'angers
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Publication of WO2017198849A1 publication Critical patent/WO2017198849A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to some derivatives of limonoids for treating and/or preventing growth of cancer cells, particularly for treating the breast cancer.
  • Breast cancer is cancer that develops from breast tissue. It is the most common invasive cancer in women.
  • Treatment options include surgery to remove the tumor, drug treatment which includes chemotherapy and hormonal therapy, radiation therapy and immunotherapy.
  • hormone-blocking agents in particular tamoxifen, toremifen or aromatase inhibitor such as letrozole, anastrozol or exemestane
  • chemotherapy medications such as the combination of cyclophosphamide and doxorubicin, docetaxel, or cyclophosphamide, methotrexate and fluorouracil
  • monoclonal antibodies such as trastuzumab.
  • Limonoids are also known in the treatment of cancers, and in particular of breast cancers.
  • tetranortriterpenoids are well known for their cytotoxic effect on different human cancer cells lines.
  • azadiradione showed a good activity on the breast cancer cell line MCF7.
  • epoxyazadiradione the structure equivalent to azadiradione but with an epoxide on the D cycle, a cytotoxic effect was noted in the breast cancer cell line MCF7.
  • gedunin inhibits ovarian cancer cell proliferation.
  • Gedunin induces apoptosis of human prostate, colon, ovarian, cervical and breast cancer cell lines (see also WO 2007/117466 and Gary E. L. Brandt et al, Journal of Medicinal Chemistry, 2008, vol. 51, n° 20, p. 6495-6502).
  • the compounds of the present invention showed high activity against breast cancer cell lines. Furthermore, they are very effective in inducing mitotic arrest, i.e. in inducing mitotic blockade of the tumor cells, and thus to induce cell death of the cancerous cells and to limit the tumor growth, as illustrated in the following examples.
  • the compound of formula (I) is of formula (V):
  • 5,6-dehydro-7-deacetoxy-7-oxogedunin is a limonoid of the ring-D-seco class ⁇ Taylor DAH et al., Progress in the Chemistry of Organic Natural Products, 1984 and Tan Q-G et al, Chem. Rev., 2011, vol. 111, p. 7437-7522).
  • this compound is also very effective in inducing mitotic arrest.
  • the compounds of the invention may contain one or several asymmetric carbon atoms. Accordingly, they may exist in the form of enantiomers or diastereoisomers. These enantiomers and diastereoisomers, and also mixtures thereof, including racemic mixtures, form part of the invention. Further, the alkene functions present in the compound of the invention can either be in the Z or in the E configuration.
  • the present invention also relates to the tautomeric forms of the compounds according to the invention.
  • a tautomeric form is understood to mean a constitutional isomer, the structure of which differs in the position of an atom, for example a hydrogen atom, and of one or more multiple bonds. Two tautomeric forms are capable of easily and reversibly converting into one another.
  • the compounds of the invention may also exist in the form of bases or of acid-addition salts. These salts are pharmaceutically acceptable acids and also form part of the invention.
  • pharmaceutically acceptable means what is useful in preparing a pharmaceutical composition generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes what is acceptable for veterinary as well as human pharmaceutical use.
  • salts are included in the invention. They may serve as intermediates in the purification of the compounds, in the preparation of other salts, or in the identification and characterization of the compounds or intermediates.
  • the compounds of the invention may also exist in the form of hydrates or solvates, i.e. in the form of associations or combinations with one or more molecules of water or with a solvent such as methanol, ethanol, dimethylformamide, ethyl acetate and the like. Mixtures of such solvates can also be prepared.
  • the source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent. Such solvates are within the scope of the present invention.
  • the compound of formula (I) is of formula (II):
  • the compound of formula (I) or (II) is of formula (III):
  • Ri 0 or -O-COCH 3 .
  • the compound of formula (I), (II) or (III) is of formula (IV):
  • the compounds of the invention may be obtained according to methods well-known by the skilled artisan.
  • the compound 5,6-dehydro-7-deacetoxy-7-oxogedunin may also be isolated from members of the Meliaceae.
  • the 5,6-dehydro-7-deacetoxy-7-oxogedunin may be isolated from Carapa procera, and notably from Carapa procera seeds.
  • Carapa procera DC. (Meliaceae), commonly known as “Crabwood” in English and as “Touloucouna” in Senegalese, is native to tropical regions of Africa and South America. In Senegal, it is found in the South, in the area of Casamance, where it is widely exploited for the production of seed oil.
  • C. procera is one of the most popular members of the Meliaceae family plants used in West African traditional medicine.
  • the present invention relates to compounds for use for treating breast cancer, and in particular the human breast cancer.
  • the present invention describes the use of a compound of the present invention to treat the breast cancer, and in particular the human breast cancer.
  • the present invention describes the use of a compound of the present invention for the preparation of a medicament intended to treat the breast cancer, and in particular the human breast cancer.
  • the present invention also describes a method for treating the breast cancer, and in particular the human breast cancer, comprising at least a step of administering to a patient at least an effective amount of at least one compound according to the invention as above defined.
  • a compound according to the invention may be used in a composition comprising a pharmaceutically acceptable excipient.
  • composition is considered as a pharmaceutical composition or as a medicament and may more particularly contain an effective dose of at least one compound according to the invention as above defined.
  • an “effective dose” means an amount sufficient to induce a positive modification in the condition to be treated, but low enough to avoid serious side effects.
  • An effective dose may vary with the pharmaceutical effect to obtain or with the particular condition being treated, the age and physical condition of the end user, the severity of the condition being treated/prevented, the duration of the treatment, the nature of other treatments, the specific compound or composition employed, the route of administration, and like factors.
  • a compound used according to the invention may be administered in an effective dose by any of the accepted modes of administration in the art.
  • this compound may be used in a composition intended to be administrated by oral, rectal or parenteral injection route.
  • parenteral injection refers to an administration via injection under or through one or more layers of skin or mucus membranes of an individual. This injection may be for instance intradermal, subcutaneous, intravenous or intramuscular.
  • the compound of the invention may be administered to a subject once a week, twice a week, four times a week, once a day, twice a day, three times a day or more if necessary, and such administration can be for one day, two days, three days, four days, five days, six days, or a week, two weeks, three weeks, a month, two months, four months, six months, more than six months, one year, two years, or continuously through the life of the patient.
  • a pharmaceutical composition of the invention may be formulated with any known suitable pharmaceutically acceptable excipients according to the dose, the galenic form, the route of administration and the likes.
  • pharmaceutically acceptable excipients include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. Except insofar as any conventional excipient is incompatible with the active compounds, its use in a medicament or pharmaceutical composition of the invention is contemplated.
  • a medicament or pharmaceutical composition of the invention may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, sprays, gels, soft and hard gelatine capsules, suppositories, sterile injectable solutions or sterile packages powders.
  • a pharmaceutical composition of the invention may be intended to be administered separately, sequentially or simultaneously with an agent useful for the prevention and/or the treatment of a disease and/or condition related to the breast cancer, and in particular to the human breast cancer, said agent being different from the compound of formula (I) of the invention.
  • a compound according to the present invention may be administered alone or in combination with one or more compound(s) which has (have) an anti-angiogenic activity or with one or more cytotoxic compound(s) (chemotherapy), or else in combination with a radiation treatment.
  • a compound according to the invention may be use in combination with one or more anticancer active agent(s) and/or with radiotherapy.
  • Figure 1 X-Ray Structure of 5,6-Dehydro-7-deacetoxy-7-oxogedunin determined by X-ray diffraction.
  • Figure 2 Effect of 5,6-dehydro-7-deacetoxy-7-oxogedunin (1) on viability of breast cancer cells. Abscissa: from the left to the right non-treated cells (DMSO); cells treated with Paclitaxel (positive control); cells treated with 5,6-dehydro-7-deacetoxy-7-oxogedunin (1). Ordinate: absorbance measured at 570 nm. Error bars represent the standard deviation from three independent experiments.
  • Figure 3 Percentage of mitotic cells after treatment with gedunin, paclitaxel or 5,6-dehydro-7-deacetoxy-7-oxogedunin (1) after 0, 24, 48, 72 or 96 hours of treatment. Abscissa: treatment duration (hours). Ordinate: % of mitotic cells.
  • Figure 4 Impact of 5,6-dehydro-7-deacetoxy-7-oxogedunin (1) on cell death in cancer cells. Abscissa: from the left to the right non-treated cells (DMSO); cells treated with Paclitaxel (positive control); cells treated with 5,6-dehydro-7-deacetoxy-7-oxogedunin (1). Ordinate: % of cancer cells Annexin V positive (% apoptotic/necrotic cells). Error bars represent the standard deviation from three independent experiments.
  • Figure 5 Clonogenicity assays of breast cancer cell lines MDAMB-468. From the left to the right: cancer cells in a well cell culture after 14 days and no treatment; treated with Paclitaxel or treated with 5,6-dehydro-7-deacetoxy-7-oxogedunin (1).
  • Paclitaxel purity > 97%) and 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) were purchased from Sigma- Aldrich.
  • Annexin-V binding assay kit was purchased from Miltenyi Biotec. Column chromatography was performed on silica gel (63-200 ⁇ , 40-63 ⁇ ) from Merck. Solvents for chromatography were distilled before use.
  • NMR spectroscopic data were recorded at 303K on a Bruker Avance III 500 spectrometer fitted with a 5mm i.d. 13 C/1H cryoprobe tuned to the recording frequency of 500.13 MHz (for 1H) and 125.76 MHz (for 13 C).
  • the spectra are referenced to the solvent in which they were run (7.26 ppm for 1H CDC1 3 and 77.16 ppm for 13 C CDC1 3 ).
  • Chemical shifts are expressed as ⁇ values in parts per million (ppm) and the coupling constants (J) are given in Hertz (Hz).
  • X-ray spectra The X-ray data set was collected on a Kappa CCD diffractometer (Bruker Nonius B.V), using the Mo-KL2,3 radiation, at 293K. Cell line
  • Air-dried C. procera seeds were ground to give a powder (1.5 kg).
  • the crude extract (15 g) was taken into CH 2 CI 2 and applied to a silica gel column (63-200 ⁇ , 70-230 mesh, 8 x 40 cm) eluted sequentially with n-hexane/CH 2 Cl 2 (v/v 50:50, 3 L), CH 2 C1 2 (2 L), CH 2 C1 2 /CHC1 3 (v/v 50:50, 2 L) and finally CHC1 3 (3 L). Following solvent removal, five fractions were obtained (A 1 -A5).
  • Fraction B 3 (frns. 89-183 pooled and dried, 2.6 g) yielded a residue (2.6 g) which was taken into EtOAc and applied to a silica gel column (40-63 ⁇ , 240-400 mesh, 4,5 x 55 cm) eluted with a gradient of n-hexane/EtOAc (v/v 90: 10 (500 mL); 80:20 (1.5 L); 75:25 (1.5 L); 50:50 (2 L) to obtain four fractions (C 1 -C4).
  • Sub fraction Bi (frns. 1-7 pooled and dried, 3 g) was applied to silica gel eluted with a gradient of petroleum ether/EtOAc (v/v 90: 10 (800 mL); 80:20 (1.5 L); 75:25 (2 L) to obtain 7 sub-fractions (Ci -C 7 ).
  • EXAMPLE 2 Effect of 5,6-dehvdro-7-deacetoxy-7-oxogedunin (1) on viability of breast cancer cells and comparison with gedunin
  • Cancer cells (6000 per well) were seeded in a 96 flat-well plate and treated for 72 hours with vehicle (DMSO), 5,6-dehydro-7-deacetoxy-7-oxogedunin in increasing concentrations (from 80 nM to 100 ⁇ ). Paclitaxel was used as positive control at a fixed concentration (100 nM).
  • IC50 corresponding to the concentration of 5,6-dehydro-7-deacetoxy-7-oxogedunin (1) needed to reduce cell growth by 50% in MDA-MB-468 cell lines following 72 hours incubation is determined using the MTT assay, calculated using GraphPad Prism software. Data from 3 independent experiments are presented as mean ⁇ standard error, using a one-tailed paired t-test.
  • MDA-MB-468 cell line showed sensitivity to 5,6-dehydro-7-deacetoxy-7- oxogedunin showing IC50 of 14.4 ⁇ .
  • the percentage of mitotic cells upon treatment with gedunin, paclitaxel or 5,6-dehydro-7-deacetoxy-7-oxogedunin (1) has been measured by immunofluorescence double marking using Iodure Propidium (DNA content) / MPM2 marking (epitopes generated by CDK1 activity), by flow cytometric analysis. Mitotic cells are indeed 4n DNA and MPM2 positive.
  • Data are obtained after 24, 48, 72 and 96 hours following administration of gedunin (10 ⁇ ), paclitaxel (10 nM) or 5,6-dehydro-7-deacetoxy-7-oxogedunin (1) (10 ⁇ ) (see figure 3).
  • the most significant accumulation is observed after treatment with the compound (1) according to the invention.
  • This effect is in particular maintained beyond 72 hours, contrary to the treatment with gedunin or paclitaxel that show low percentages of mitotic cells and decreasing after 48 hours. Therefore, it can be conclude that the 5,6-dehydro-7-deacetoxy-7-oxogedunin is more effective in inducing mitotic blockade of the tumor cells than gedunin and paclitaxel, and thus to induce cell death of the cancerous cells and to limit the tumor growth.
  • Cell death (apoptotis and/or necrosis) was assessed using the Annexin-V binding assay kit and performed according to manufacturer's instructions.
  • Flow cytometry analysis was performed on a FACS Calibur using the CellQuestPro software in the CytoCell flow cytometry facility (SFR Bonamy, FED4203/Inserm UMS 016/CNRS 3556). Fluorescence was measured at 488 nm.
  • the line was treated with 10 ⁇ of 5,6-dehydro-7-deacetoxy-7-oxogedunin (1) for 48 hours with DMSO as negative control and cell death quantified using the Annexin-V binding assay analysed by flow cytometry. Paclitaxel (100 nm) was used as positive control.
  • EXAMPLE 5 Clonogenicity assays of breast cancer cell lines MDA-MB-468 Clonogenicity was assessed essentially as described in Franken et al. ⁇ Kouame
  • Paclitaxel 100 nM was used as positive control.

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Abstract

La présente invention concerne de nouveaux composés dérivés de limonoïdes pour le traitement et/ou la prévention de la croissance de cellules cancéreuses, en particulier pour le traitement du cancer du sein. Le cancer du sein est un cancer qui se développe à partir de tissu mammaire. C'est le cancer invasif le plus fréquent chez les femmes. Les inventeurs ont désormais découvert de nouveaux dérivés de type limonoïde, qui possèdent une activité anticancéreuse élevée, avec, simultanément, une faible toxicité. Ils ont démontré que ces nouveaux dérivés sont efficaces contre des lignées cellulaires de cancer du sein. En particulier, la présente invention concerne des composés de formule (I) pour utilisation pour le traitement du cancer du sein. En particulier, les inventeurs ont testé les composés sur la lignée cellulaire MDA-MB-468 et, en particulier, l'impact des composés sur la phase mitotique et sur la mort cellulaire dans des cellules cancéreuses a été analysé.
PCT/EP2017/062166 2016-05-20 2017-05-19 Dérivés de limonoïdes pour le traitement et/ou la prévention de la croissance de cellules du cancer du sein WO2017198849A1 (fr)

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EPEP16305580 2016-05-20

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007117466A2 (fr) 2006-03-31 2007-10-18 Massachusetts Institute Of Technology Celastrol, gédunine, et dérivés de ceux-ci, utilisés comme inhibiteurs de hsp90

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007117466A2 (fr) 2006-03-31 2007-10-18 Massachusetts Institute Of Technology Celastrol, gédunine, et dérivés de ceux-ci, utilisés comme inhibiteurs de hsp90

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
GARY E. L. BRANDT ET AL., JOURNAL OF MEDICINAL CHEMISTRY, vol. 51, no. 20, 2008, pages 6495 - 6502
GARY E. L. BRANDT ET AL: "Gedunin, a Novel Hsp90 Inhibitor: Semisynthesis of Derivatives and Preliminary Structure-Activity Relationships", JOURNAL OF MEDICINAL CHEMISTRY, vol. 51, no. 20, 23 October 2008 (2008-10-23), US, pages 6495 - 6502, XP055312347, ISSN: 0022-2623, DOI: 10.1021/jm8007486 *
KOUARNE PB-K ET AL., PHYTOTHER RES., vol. 27, 2013, pages 835 - 840
MBAYE DIOUM ET AL: "A Ring-D-Seco-Tetranortriterpenoid from Seeds of Carapa procera Active against Breast Cancer Cell Lines", PLANTA MEDICA, vol. 82, no. 11/12, 25 May 2016 (2016-05-25), DE, pages 967 - 972, XP055312343, ISSN: 0032-0943, DOI: 10.1055/s-0042-107797 *
NAKAYAMA S ET AL., BREAST CANCER RESEARCH, vol. 11, 2009, pages R12
NSIAMA TK ET AL., PHYTOCHEMISTRY, vol. 72, 2011, pages 1854 - 1858
TAN Q-G ET AL., CHEM. REV., vol. 111, 2011, pages 7437 - 7522
TAYTOR DAH ET AL., PROGRESS IN THE CHEMISTRY OF ORGANIC NATURAL PRODUCTS, 1984
TIENABE K NSIAMA ET AL: "Rings D-seco and B,D-seco tetranortriterpenoids from root bark of", PHYTOCHEMISTRY, vol. 72, no. 14, 11 July 2011 (2011-07-11), pages 1854 - 1858, XP028256722, ISSN: 0031-9422, [retrieved on 20110604], DOI: 10.1016/J.PHYTOCHEM.2011.05.014 *

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