WO2005040189A1 - Nouvelles sapogenines dammarane, utilisation de ces dernieres en tant qu'agents anticancereux - Google Patents

Nouvelles sapogenines dammarane, utilisation de ces dernieres en tant qu'agents anticancereux Download PDF

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WO2005040189A1
WO2005040189A1 PCT/CA2004/001873 CA2004001873W WO2005040189A1 WO 2005040189 A1 WO2005040189 A1 WO 2005040189A1 CA 2004001873 W CA2004001873 W CA 2004001873W WO 2005040189 A1 WO2005040189 A1 WO 2005040189A1
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cancer
group
lower alkyl
ppd
formula
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PCT/CA2004/001873
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Winter Huang
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Panagin Pharmaceuticals Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • 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 relates to novel biologically active dammarane sapogenins, their use in anti-cancer applications. More particularly, the invention pertains to a novel group of dammarane sapogenins obtained by chemical cleavage of dammarane saponins extracted from panax ginseng, panax quinquefol, panax notoginseng and other species in acanthopanax plants family, and a novel preparation of anti-cancer agent containing one or more of these sapogenins for the treatment of cancer.
  • Dammarane saponins are compounds that organically exist in various species of acanthopanax plants. Sapogenins, on the other hand, do not naturally exist in the ginseng plant but can only be derived through chemical structure modification by cleavage and/or semi- synthesis of dammarane saponins.
  • ginsenoside Rg3 [3-O-[ ⁇ -D-glucopyranosyl (l-»2)- ⁇ -D- glucopyranosyl]-20(s)- protopanaxadiol] inhibits the activity of various cancer cells (Shinkai K et al (1996) Jpn J Cancer Res. 87: 357-62), including, human prostate cancer cells, in vitro, (Liu WK et al. (2000) Life Sci. 67(11): 1297-306), lung metastasis in mice (Iishi H et al. (1997) Clin Exp Metastasis 15: 603-11), and peritoneal metastasis in rats (Mochizuki M et al. (1995) Biol Pharm Bull. 18: 1197-202).
  • U.S. Patent No. 5,919,770 also discloses a metabolite of ginseng saponin produced by human intestinal bacteria, Mc[20-O-[ ⁇ -L- arabinofuranosyl (l-»6)-P-D-glucopyranosyl)- protopanaxadiol], that inhibits the vascularization of tumors and extravasation of cancer cells.
  • U.S. Patent Application No. 09/957,082 discloses the ability of protopanaxadiol and protopanaxadiol, two known sapogenins, to reverse multi-drug resistance in cancers.
  • An object of the present invention is to provide a group of novel dammarane sapogenins and their anti-cancer uses thereof.
  • R 3 is a substituent selected from the group of -H, lower alkyl, lower alkenyl, or lower alkynyl; is a substituent selected from the group of -H, -OH, -OR or -OCOR, wherein R is lower alkyl or aryl;
  • R 5 is a substituent selected from the group of
  • heterocyclic group may be further substituted with a substituent selected from the group of -OH, -OR or -OCOR, wherein R is lower alkyl or aryl, lower alkyl and substituted lower alkyl, wherein the substituents are selected from the group of lower alkyl, lower alkoxy, and hydroxy; with the proviso that when R 5 is 4-(2-methyl-2-butenyl), R 3 is methyl, and R_ t is -OH, and then R] is other than OH.
  • the present invention also provides these dammarane sapogenin compounds for use in the preparation of a medicament for treatment of a cancer and/or malignant disease.
  • the invention provides a method for the prophylaxis or treatment of a cancer and/or malignant disease comprising administering to a patient an effective amount of one or more these novel dammarane sapogenins.
  • Figure la, lb, and lc are graphs which show the effect of Protopanaxadiol (PPD) and Protopanaxatriol (PPT) derivatives on lung cancer cells;
  • FIG. 1a, 2b, and 2c are graphs which show the effect of Protopanaxadiol (PPD) and Protopanaxatriol (PPT) derivatives on breast cancer cells;
  • PPD Protopanaxadiol
  • PPT Protopanaxatriol
  • Figure 3 (a, b, c, d, e, f, g, h, i, and j) are graphs which show the effect of Protopanaxadiol (PPD) and Protopanaxatriol (PPT) derivatives on breast cancer MCF7MDR cells and breast cancer MCF7 cells;
  • PPD Protopanaxadiol
  • PPT Protopanaxatriol
  • FIG. 4a, 4b, and 4c are graphs which show the enhanced effect of Protopanaxadiol (PPD) and Protopanaxatriol (PPT) derivatives with Paclitaxel on breast cancer MCF7 cells;
  • PPD Protopanaxadiol
  • PPT Protopanaxatriol
  • FIG. 5a, 5b, and 5c are graphs which show the enhanced effect of Protopanaxadiol (PPD) and Protopanaxatriol (PPT) derivatives with Paclitaxel on breast cancer MCF7MDR cells; and
  • Figure 6a, 6b, and 6c are graphs which show the enhanced effect of Protopanaxadiol (PPD) and Protopanaxatriol (PPT) derivatives with Cisplatin on breast cancer MCF7MDR cells.
  • PPD Protopanaxadiol
  • PPT Protopanaxatriol
  • Figure 7a and 7b provide graphical representations of cell viability of human glioma tumor cells (U87) treated with various Protopanaxadiol (PPD) and Protopanaxatriol (PPT) derivatives; and
  • Figure 8a, 8b, 8c, and 8d provide graphical representations of the cell viability pancreatic cancer cells treated with various Protopanaxadiol (PPD) and Protopanaxatriol (PPT) derivatives
  • halogen refers to fluorine, bromine, chlorine, and iodine atoms.
  • hydroxyl refers to the group -OH.
  • thiol or “mercapto” refers to the group -SH, and -S(O)0-2.
  • lower alkyl refers to a straight chain or branched, or cyclic, alkyl group of one to ten carbon atoms. This term is further exemplified by such groups as methyl, ethyl, n- propyl, i-propyl, n-butyl, t-butyl, 1-butyl (or 2-methylpropyl), cyclopropylmethyl, i-amyl, n- amyl, hexyl and the like.
  • substituted lower alkyl refers to lower alkyl as just described including one or more groups such as hydroxyl, thiol, alkylthiol, halogen, alkoxy, amino, amido, carboxyl, cycloalkyl, substituted cycloalkyl, heterocycle, cycloheteroalkyl, substituted cycloheteroalkyl, acyl, carboxyl, aryl, substituted aryl, aryloxy, hetaryl, substituted hetaryl, aralkyl, heteroaralkyl, alkyl alkenyl, alkyl alkynyl, alkyl cycloalkyl, alkyl cycloheteroalkyl, cyano. These groups may be attached to any carbon atom of the lower alkyl moiety.
  • alkynyl refers to the group -C ⁇ C-R'; where R' is selected from hydrogen, halogen, lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl or the like as defined.
  • alkoxy refers to the group -OR, where R is lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroalkyl, heteroarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl as defined below.
  • acyl refers to the group -C(O)R, where R is hydrogen, lower alkyl substituted lower alkyl, aryl, substituted aryl.
  • Carboxyl refers to the group -C(O)OR, where R may independently be hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, hetaryl, substituted hetaryl and the like as defined.
  • aryl or “Ar” refer to an aromatic carbocyclic group having at least one aromatic ring (e.g., phenyl or biphenyl) or multiple condensed rings in which at least one ring is aromatic, (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl, 9-fluorenyl etc.).
  • substituted aryl refers to aryl optionally substituted with one or more functional groups, e.g., halogen, hydroxyl, thiol, lower alkyl, substituted lower alkyl, trifluoromethyl, alkenyl, alkenyl, alkylalkenyl, alkyl alkynyl, alkoxy, alkylthio, acyl, aryloxy, amino, amido, carboxyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted heterocycle, heteroalkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, nitro, sulfamido or cyano.
  • functional groups e.g., halogen, hydroxyl, thiol, lower alkyl, substituted lower alkyl, trifluoromethyl, alkenyl, alkenyl, alkylalkenyl, alky
  • heterocycle refers to a saturated, unsaturated, or aromatic carbocyclic group having a single ring (e.g., morpholino, pyridyl or furyl) or multiple condensed rings (e.g., naphthpyridyl, quinoxalyl, quinolinyl, indolizinyl, indanyl or benzo[b]thienyl) and having at least one hetero atom, such as N, O or S, within the ring.
  • a single ring e.g., morpholino, pyridyl or furyl
  • multiple condensed rings e.g., naphthpyridyl, quinoxalyl, quinolinyl, indolizinyl, indanyl or benzo[b]thienyl
  • hetero atom such as N, O or S
  • substituted heterocycle refers to heterocycle optionally substituted with, halogen, hydroxyl, thiol, lower alkyl, substituted lower alkyl, trifluoromethyl, alkenyl, alkenyl, alkylalkenyl, alkyl alkynyl, alkoxy, alkylthio, acyl, aryloxy, amino, amido, carboxyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted heterocycle, heteroalkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, nitro, sulfamido or cyano and the like.
  • cycloalkyl refers to a cyclic or polycyclic alkyl group containing 3 to 15 carbon atoms.
  • these may be multiple condensed rings in which one of the distal rings maybe aromatic (e.g. tetrahydronaphthalene, etc.).
  • substituted cycloalkyl refers to a cycloalkyl group comprising one or more substituents with, e.g halogen, hydroxyl, thiol, lower alkyl, substituted lower alkyl, trifluoromethyl, alkenyl, alkenyl, alkylalkenyl, alkyl alkynyl, alkoxy, alkylthio, acyl, aryloxy, amino, amido, carboxyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted heterocycle, heteroalkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, nitro, sulfamido or cyano and the like.
  • cycloheteroalkyl refers to a cycloalkyl group wherein one or more of the ring carbon atoms is replaced with a heteroatom (e.g., N, O, S or P).
  • substituted cycloheteroalkyl refers to a cycloheteroalkyl group as herein defined which contains one or more substituents, such as halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, hetaryl, substituted hetaryl, nitro, cyano, alkylthio, thiol, sulfamido and the like.
  • This invention relates to a group of novel dammarane sapogenin compounds with following Formula I:
  • R 3 is a substituent selected from the group of -H, lower alkyl, lower alkenyl, or lower alkynyl; is a substituent selected from the group of -H, -OH, -OR or -OCOR, wherein R is lower alkyl or aryl;
  • R 5 is a substituent selected from the group of
  • heterocyclic group maybe further substituted with a substituent selected from the group of -OH, -OR or -OCOR, wherein R is lower alkyl or aryl, lower alkyl and substituted lower alkyl, wherein the substituents are selected from the group of lower alkyl, lower alkoxy, and hydroxy; with the proviso that when R 5 is 4-(2-methyl-2-butenyl), R 3 is methyl, and R-t is -OH, and then R t is other than OH.
  • This invention relates to a physically obtained group of novel dammarane sapogenin compounds as follow: - 3 ⁇ ,12 ⁇ ,22-trihydroxy-22-de-isopentenyl-dammarane (PPD Derivative 1); - 3 ⁇ ,12 ⁇ ,20S,25-tetrahydroxy-dammarane (PPD Derivative 2); - 3 ⁇ ,12 ⁇ ,20s,26-tetrahydroxy-dammar-24z-ene (PPD Derivative 3); - 3 ⁇ , 12 ⁇ , 20s, 26-tetrahydroxy-dammar-24E-ene (PPD Derivative 4) D - 3 ⁇ ,6 ⁇ ,12 ⁇ ,20S-tetrahydroxy-25-hydroperoxy-dammarane-23-ene (PPT Derivative 1); - 3 ⁇ ,6 ⁇ ,12 ⁇ ,20S,24R-pentahydroxy-dammar-25-ene (PPT Derivative 2); - 6 ,12 ⁇ ,20S-trihydroxy-dammar-24-
  • the present invention provides versatile synthetic routes to the dammarane sapogenins and analogues thereof.
  • the nature of the substituents should be chosen such that the substituents do not prevent a desired reaction proceeding.
  • One skilled in the art would be cognizant of what groups would be detrimentally affected by reaction conditions, for example, strong bases, bases, free radicals, reductants and oxidants. Where possible one skilled in the art would exploit the use of protecting groups.
  • the term "protecting group” as used herein is a term well-known in the art and refers to substituents on functional groups.
  • P may be independently hydrogen or a hydroxyl protecting group.
  • hydroxyl protecting groups examples include ethers, such as benzyl (Bn), >-methoxybenzyl (pMB), triphenylmethyl (Tr), allyl (All), methoxymethyl (MOM), benzyloxymethyl (BOM), 2-methoxyethoxymethyl (MEM), and tetrahydropyranyl (THP) ethers.
  • ethers such as benzyl (Bn), >-methoxybenzyl (pMB), triphenylmethyl (Tr), allyl (All), methoxymethyl (MOM), benzyloxymethyl (BOM), 2-methoxyethoxymethyl (MEM), and tetrahydropyranyl (THP) ethers.
  • hydroxyl protecting groups include silyl ethers, such as trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), t- butyldimethylsilyl (TBDMS), and t-butyldiphenylsilyl (TBDPS).
  • TMS trimethylsilyl
  • TES triethylsilyl
  • TIPS triisopropylsilyl
  • TDMS t- butyldimethylsilyl
  • TDPS t-butyldiphenylsilyl
  • ester which includes acetate (Ac), benzoate (Bz), and pivaloate (Pv).
  • the resulting ozonide intermediate is not isolated, but is instead further reacted with a mild reducing agent such as dimethylsulfide (Me 2 S) or zinc in acetic acid (Zn/HOAc), to produce the resulting aldehyde product.
  • a mild reducing agent such as dimethylsulfide (Me 2 S) or zinc in acetic acid (Zn/HOAc
  • [052] may be conveniently prepared by reacting a compound of Formula III with m- chloroperbenzoic acid (mCPBA) in a solvent such as CH 2 C1 2 , typically at temperatures at or around 0°C.
  • mCPBA m- chloroperbenzoic acid
  • An alternative method for synthesizing the epoxide employs reacting compounds of Formula I with dimethyldioxirane (DMD) in acetone at room temperature.
  • DMD dimethyldioxirane
  • [054] may be conveniently prepared by reacting a compound of Formula III under mild oxymercuration conditions with mercuric acetate Hg(OAc) 2 in solvents such as mixtures of aqueous tetrahydrofuran or aqueous acetone, followed by in situ reaction with sodium borohydride NaBH in aqueous sodium hydroxide to provide the desired hydroxyl product.
  • solvents such as mixtures of aqueous tetrahydrofuran or aqueous acetone
  • R"' is alkyl or aryl
  • R"' may be conveniently prepared by a method analogous to the mild oxymercuration conditions described above through reaction of Hg(OAc) 2 with a compound of Formula II in a solvent which is an alcohol of the formula (R'"OH).
  • borane BH 3
  • borane derivatives such as disiamylborane and 9-BBN (9- borabicyclo[3.3.1]nonane)
  • solvents such as tetrahydrofuran
  • hydroxyl groups may be further derivatized with alkylating or acylating agents to provide compounds of Formula IV-a, IV-b:
  • W is an alkyl or acyl group.
  • the hydroxyl groups may be alkylated with a variety of alkylating agents, according to the formula WX, where W is an alkyl group and X is a leaving group.
  • said leaving groups include halides, including I, Br, or Cl, or alternatively a sulfonate ester, including, but not limited to toluene sulfonate (OTs), methanesulfonate (OMs) and trifluoromethanesulfonate (OTf).
  • OTs toluene sulfonate
  • OMs methanesulfonate
  • OTf trifluoromethanesulfonate
  • These alkylation reactions generally proceed under basic conditions, the bases typically employed include, but are not limited to, sodium or potassium hydrides, sodium or potassium hydroxides, and sodium or potassium carbonates.
  • the solvents commonly used to carry out the alkylating reactions include, but are not limited to, tetrahydrofuran (THF), dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and dichloromethane (CH C1 ).
  • W is an alkyl group.
  • alkylations typically take place at temperatures between -78 to 0°C, in solvents that include, but are not limited to dichloromethane (CH C1 2 ), in the presence of an acid catalyst such as boron trifluoride etherate (BF 3 • OEt 2 ).
  • an acid catalyst such as boron trifluoride etherate (BF 3 • OEt 2 ).
  • Appropriate conditions and combinations of reagents and solvents needed for the synthesis of the desired compound can easily be determined by a worker skilled in the relevant arts.
  • hydroxyl groups may also be derivatized with acylating agents using a number of well-established methods known to a worker skilled in the arts.
  • Acylating agents may include acyl halides of the formula: o R ⁇ X wherein R is an alkyl or aryl group.
  • R is an alkyl or aryl group.
  • reactions often take place in combination with an added base, typically, but not limited to pyridine and/or 4-(N,N- dimethylamino)pyridine (DMAP) in a solvent which may include, but is not limited to, CH 2 C1 2 , DMF, pyridine and CH 3 CN.
  • DMAP 4-(N,N- dimethylamino)pyridine
  • a solvent which may include, but is not limited to, CH 2 C1 2 , DMF, pyridine and CH 3 CN.
  • the desired product may be further isolated from the reaction mixture using purification procedures well known to a skilled artisan. These methods may; include, but are not limited to, medium pressure liquid chromatography, high pressure liquid chromatography (HPLC), size exclusion chromatography, ion exchange chromatography and/or crystallization.
  • the PPD and PPT derivatives of the present invention exhibit various biochemical properties including one or more of the following: the ability to inhibit the growth of cancer cells, the ability to increase or restore sensitivity of a cancer cell to one or more chemotherapeutic drugs; and the ability to cross the blood-brain barrier.
  • Compounds of the present invention can be assayed to demonstrate the extent of their activities using standard techniques well known to workers skilled in the art. Exemplary testing methods are outlined herein and are not intended to limit the scope of the present invention.
  • PPD and PPT derivatives according to the present invention can inhibit the growth of cancer cells.
  • Compounds of the present invention may be tested for their activity as anti-cancer agents in cell or in vivo assays substantially as described herein or in variants of such assays using appropriate cell lines and conditions as would be readily appreciated by a worker skilled in the art.
  • Compounds of this invention may be assayed for anti-cancer activity by conventional methods, including for example, the methods described below.
  • Cytotoxicity may be measured using a standard method for adherent cell lines such as the microculture tetrazolium assay (MTT). Details of this assay have been published (Alley, M C et al, Cancer Research 48:589-601, 1988). Exponentially growing cultures of tumor cells such as the LNCaP prostate cancer cells or the MS-1 mesothelioma cancer cells are used to make microtiter plate cultures. Cells are seeded at 1.2xl0 3 cells per well in 96-well plates, and grow overnight at 37°C. Test compounds are added. Cells are then incubated for 24 hours.
  • MTT microculture tetrazolium assay
  • the MTT dye is added (3 -(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide in saline). This mixture is incubated at 37°C for 5 hours, and then 50 ⁇ l of 25% SDS, pH2 is added to each well. After an overnight incubation, the absorbance of each well at 550 nm is read using an ELISA reader. The values for the mean ⁇ SD of data from replicated wells are calculated, using the formula % T/C (% viable cells treated/control). 1 OD of treated cells OD of control cells x 100 + % T/C. The concentration of test compound that gives a T/C of 50% growth inhibition is designated as the IC 50 value.
  • An alternative method of evaluating anti-cancer activity of the compounds of the present invention involves determining the effect of a test compound on the viability of cancer cells. Exponentially growing cancer cells are treated with various concentrations of the test compound. Examples of cell lines that can be used in this method include MS-1, LNCaP, H460, and MCF-7 which are readily obtainable from Canadian Life Technologies Inc., Burlington, ON. The cells are further incubated for 24 h and stained with a molecule that allows a distinction between viable and non-viable cells, for example crystal violet. The absorbency of the stained cells at 590nm are then measured. The percent viability of treated cells is then compared to that of control cells. Average absorbency of the control wells (A c ) without any treatment is calculated, average absorbency of each treatment group (A-n) is determined, and then the average cell viability of each treatment group (V;) is derived using the following formula:
  • a decrease in viability in the treated cells in comparison to the control cells is indicative of anti-cancer activity.
  • Another method of evaluating anti-cancer activity of the compounds of the present invention involves monitoring the effect of the compounds on cell cycle progression. Exponentially growing cancer cells are treated with various concentrations of the test compound. The cells are further incubated for 24 h. The number of cells is then determined by flow cytometry and values compared to control cells. A decrease in relative growth of treated cells in comparison to untreated cells is indicative of anti-cancer activity.
  • Compounds of this invention may be further tested in pre-clinical assay for in vivo activity which is indicative of clinical utility.
  • Such assays are conducted with nude mice into which tumor tissue, preferably of human origin, has been transplanted (xenografted), as is well known in this field. Test compounds are evaluated for their anti-tumor efficacy following administration to the xenograft-bearing mice.
  • mice sarcoma cells are hyperdermically transplanted into the mice to form tumor tissue in the recipient mice.
  • the mice are treated with the test compounds given orally, using a gastric catheter, at various dosages. Compounds are given daily for 8 days.
  • Tumor weights are measured 24 hours after the last administration of the test compounds.
  • Multidrug resistance is characterized by the development of resistance to several structurally unrelated anticancer drugs and is a major cause of failure of cancer chemotherapy.
  • Certain PPD and PPT derivatives according to the present invention can increase or restore the sensitivity of a cancer cell to one or more chemotherapeutic drugs.
  • a suitable cell-based assay for assessing the ability of a candidate compound to restore sensitivity of cancer cells to chemotherapeutic drug substances in vitro is as follows. Cancer cell lines (CCL), e.g.
  • CTD cancer therapeutic drug substances
  • e.g., Paclitaxel; Cisplatin; and Mitoxantrone are developed in accordance with the methods described by Twentyman et al., Br. J. Cancer, 54 . 253 (1986).
  • CCL-MDR Cell lines resistant to multiple CTDS
  • CCL-S non-drug resistant cell lines
  • CCL-S non-drug resistant cell lines
  • cells are cultured ab initio in the presence of varying concentrations of both CTDS and test PPD derivatives.
  • the ratio of CTDS (e.g. Mitoxantrone) required to inhibit cell proliferation by 50% in the absence of test PPD derivatives compared with that obtained in the presence of test PPD derivatives is taken as a measure of increased sensitivity of the CCL line (CCL-MDR or CCL-S) to CTDS which has been induced by the PPD derivatives.
  • tests described herein are examples of standard tests that can be used to measure the activity of the compounds of the present invention.
  • a wide variety of tests for measuring anti-cancer or anti- neoplastic activity, ability to increase or restore drug sensitivity, and ability to cross the blood- brain barrier are well known and can be used to demonstrate the characteristics of the PPD and PPT derivatives of the present invention.
  • the PPD and PPT derivatives are used in the treatment of patients having pathological conditions associated with abnormal cell proliferation, i.e., cancers.
  • the pathological conditions include the abnormal cell proliferation of both primary and metastatic malignant cells of various tissues and/or organs, comprising, with no limitation being implied, muscle, bone or connective tissues, skin, brain, lungs, sex organs, lymphatic or renal systems, mammary or blood cells, liver, digestive tract, pancreas and thyroid or adrenal glands.
  • pathological conditions can also include solid tumors, cancers of the ovary, breast, brain, prostate, colon, stomach, kidney or testicles, Kaposi's sarcoma, cholangioma, chorioma, neuroblastoma, Wilms' tumor, Hodgkin's disease, melanomas, multiple myelomas, lymphatic leukemias and acute or chronic granulocytic lymphomas.
  • Compounds of this invention may be use for treatment and prevention of oncogene mediated cancers and malignant diseases, to treat or prevent tumour growth and metastasis invasion in general, and to prevent or reverse multidrug resistance and thereby facilitate cancer and tumor treatment with conventional, e.g. cytotoxic, anti-cancer agents.
  • the PPD and PPT derivatives are used to treat primary cancers that are usually resistant to conventional chemotherapeutics, including without limitation: pancreatic cancer, lung cancer, stomach cancer, esophagus cancer, colon and rectum cancer, brain cancer, ovary cancer, liver cancer, kidney cancer, larynx cancer, bone cancer, multiple myeloma, and melanoma.
  • the PPD and PPT derivatives are used to treat multi-drug resistant cancers developed from initial chemotherapy, including without limitation, the above cancers as well as: breast cancer, prostate cancer, bladder cancer, cancer in body of uterus, oral cavity cancer, thyroid cancer, cervix cancer, testis cancer, non- Hodgkin's lymphoma, leukemia, Hodgkin's disease, skin cancer, and soft tissue cancer.
  • the PPD and PPT derivatives are used to treat advanced and metastatic cancers that are usually drug resistant, including the above cancers when in an advanced and/or metastatic stage.
  • the PPD and PPT derivatives according to the present invention can be used either alone or in combination with other pharmacologically active compounds, for example together with chemotherapeutic drugs. Characteristically when the PPD and PPT derivatives are used to prevent or reverse multidrug resistance of tumor and other malignant cells, they are used in combination with chemotherapeutic drugs, i.e., cytostatic or cytotoxic agents.
  • chemotherapeutic drugs i.e., cytostatic or cytotoxic agents.
  • compositions Comprising the PPD and PPT Derivatives
  • compositions comprising one or more dammarane sapogenins (the PPD or PPT derivatives) and one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and, if desired, other active ingredients.
  • dammarane sapogenins the PPD or PPT derivatives
  • non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and, if desired, other active ingredients.
  • the compounds of the invention may be administered by any conventional route, in particular nasally, enterally, preferably orally, e.g. in the form of tablets or capsules, or parenterally e.g. in the form of injectable solutions or suspensions or in a suppository form.
  • Unit dosage forms contain, for example of from about 0.05 mg to 20 g of the compound of the invention per 70 kg bodyweight per day.
  • the invention also provides a pharmaceutical composition comprising an effective amount of the compounds in association with a pharmaceutically acceptable diluent or carrier. Such compositions may be manufactured in conventional manner.
  • compositions comprising the compounds of the present invention as an active ingredient and that can be used especially in the treatment of the diseases mentioned above include compositions for enteral, such as nasal, buccal, rectal or especially oral, administration and parenteral, such as intravenous, intramuscular or subcutaneous, administration to warm-blooded animals, especially human beings.
  • the compositions comprise the active ingredient on its own or preferably together with a pharmaceutically acceptable carrier.
  • the dosage of the active ingredient depends on the disease to be treated, and on species, age, and individual physical conditions, individual pharmacokinetic conditions, and the mode of administration. The dosage can be readily determined by a worker skilled in the art using standard methods in light of the above considerations, for example, as disclosed in the Physician's Desk Reference (PDR) published by Medical Economics Co. Inc. or Oradell, N.J.
  • PDR Physician's Desk Reference
  • the pharmaceutical compositions may comprise from approximately 1 % to approximately 95% active ingredient, forms of administration in single dose form preferably comprising from approximately 20% to approximately 90% active ingredient and forms of administration that are not in single dose form preferably comprising from approximately 5% to approximately 20% active ingredient.
  • Unit dose forms are, for example, dragees, tablets, ampoules, vials, suppositories or capsules.
  • Other forms of administration are, for example, ointments, creams, pastes, foams, tinctures, lipsticks, drops, sprays, dispersions, etc.
  • capsules comprising from approximately 0.05 g to approximately 2 g of the active ingredient.
  • compositions are prepared in a manner known er se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilizing procedures.
  • Solutions of the active ingredient, and also suspensions or dispersions, especially isotonic aqueous solutions, dispersions or suspensions are preferably used, it being possible, for example in the case of lyophilized compositions that contain the active ingredient alone or together with a carrier, for example mannitol, for such solutions, suspensions or dispersions to be made up prior to use.
  • the pharmaceutical compositions may be sterilized and/or may comprise excipients, for example preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating the osmotic pressure and/or buffers, and are prepared in a manner known per se, for example by means of conventional dissolving or lyophilizing procedures.
  • the solutions or suspensions may comprise viscosity-increasing substances, such as sodium carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin.
  • Suspensions in oil comprise as the oil component vegetable, synthetic or semi- synthetic oils customary for injection purposes.
  • liquid fatty acid esters that contain as acid component a long-chained fatty acid having from 8 to 22, especially from 12 to 22, carbon atoms, for example lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid, or corresponding unsaturated acids, for example oleic acid, elaidic acid, erucic acid, brassidic acid or linoleic acid, if desired with the addition of antioxidants, for example vitamin E, ⁇ -carotene or 3,5-di-tert-butyl-4-hydroxytoluene.
  • the alcohol component of those fatty acid esters has a maximum of 6 carbon atoms and is a mono- or poly-hydric, for example a mono-, di- or tri-hydric, alcohol, for example methanol, ethanol, propanol, butanol or pentanol or the isomers thereof, but especially glycol and glycerol.
  • fatty acid esters are therefore to be mentioned: ethyl oleate, isopropyl myristate, isopropyl palmitate, "Labrafil M 2375” (polyoxyethylene glycerol trioleate, Gattefosse, Paris), “Labrafil M 1944 CS” (unsaturated polyglycolised glycerides prepared by alcoholysis of apricot kernel oil and consisting of glycerides and polyethylene glycol ester; Gattefosse, France), “Labrasol” (saturate olyglycolised glycerides prepared by alcoholysis of TCM and consisting of glycerides and polyethylene glycol ester; Gattefoss ⁇ , France) and/or "Miglyol 812" (triglyceride of saturated fatty acids with a chain length of C8 to C12, H ⁇ ls AG, Germany), but especially vegetable oils, such as cottonseed oil, almond oil, olive oil, castor oil
  • the injection compositions are prepared in customary manner under sterile conditions; the same applies also to introducing the compositions into, for example, ampoules or vials and to sealing the containers.
  • compositions for oral administration can be obtained, for example, by combining the active ingredient with one or more solid carriers, if desired granulating a resulting mixture, and processing the mixture or granules, if desired, and if necessary by the addition of additional excipients, to form tablets or dragee cores.
  • Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starches, for example corn, wheat, rice or potato starch, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the above-mentioned starches, also carboxymethyl starch, crosslinked polyvinylpyrrolidone, or alginic acid or a salt thereof, such as sodium alginate.
  • fillers such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate
  • binders such as starches, for example corn, wheat,
  • Additional excipients are especially flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol, or derivatives thereof.
  • Carriers that will protect the compound against rapid release may also be used in pharmaceutical compositions that may be used in a time release formulation, for example, implants, and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used as a slow release polymer, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid and polylactic polyglycolic copolymers (PLG).
  • Dragee cores can be provided with suitable, optionally enteric, coatings, there being used Utter alia concentrated sugar solutions which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the production of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Colourings or pigments may be added to the tablets or dragee coatings, for example for identification purposes or to indicate different doses of active ingredient.
  • suitable, optionally enteric, coatings there being used Utter alia concentrated sugar solutions which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the production of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose
  • Orally administrable pharmaceutical compositions also include dry-filled capsules consisting of gelatin, and also soft, sealed capsules consisting of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the dry-filled capsules may contain the active ingredient in the form of granules, for example in admixture with fillers, such as corn starch, binders and/or glidants, such as talc or magnesium stearate, and optionally stabilisers.
  • the active ingredient is preferably dissolved or suspended in suitable liquid excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, to which stabilisers and detergents, for example of the polyoxyethylene sorbitan fatty acid ester type, may also be added.
  • suitable liquid excipients such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, to which stabilisers and detergents, for example of the polyoxyethylene sorbitan fatty acid ester type, may also be added.
  • oral forms of administration are, for example, syrups prepared in customary manner which comprise the active ingredient, for example, in suspended form and in a concentration of about 5 % to 20 %, preferably about 10 %, or in a similar concentration that provides a suitable single dose, for example, when administered in measures of 5 or 300ml, comprising from approximately 0.05 mg to approximately 2 g of the active ingredient.
  • syrups prepared in customary manner which comprise the active ingredient, for example, in suspended form and in a concentration of about 5 % to 20 %, preferably about 10 %, or in a similar concentration that provides a suitable single dose, for example, when administered in measures of 5 or 300ml, comprising from approximately 0.05 mg to approximately 2 g of the active ingredient.
  • powdered or liquid concentrates for the preparation of shakes, for example in milk. Such concentrates may also be packaged in single dose quantities.
  • Suitable rectally administrable pharmaceutical compositions are, for example, suppositories that consist of a combination of the active ingredient and a suppository base.
  • Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.
  • aqueous solutions of an active ingredient in water-soluble form for example in the form of a water-soluble salt, or aqueous injection suspensions that contain viscosity-increasing substances, for example sodixxm carboxymethylcellulose, sorbitol and/or dextran, and, if desired, stabilisers.
  • the active ingredient optionally together with excipients, can also be in the form of a lyophilisate and can be made into a solution prior to parenteral administration by the addition of suitable solvents.
  • the compounds for use in the invention can be administered, prophylactically or therapeutically, as such or in the form of pharmaceutical compositions, preferably in an amount effective against the said diseases, to a warm-blooded animal, for example a human being, requiring such treatment, the compounds being used especially in the form of pharmaceutical compositions.
  • a warm-blooded animal for example a human being, requiring such treatment
  • the compounds being used especially in the form of pharmaceutical compositions In such treatment an individual of about 70 kg bodyweight will be administered a daily dose of from approximately O.Olmg to approximately 5g, preferably from approximately 0.05 mg to approximately 2 g, of a compound.
  • the invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention.
  • a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention.
  • Associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
  • the pharmaceutical compositions of the present invention may be employed in conjunction with other therapeutic compounds.
  • Cytotoxicity was measured using a standard microculture tetrazolium assay (MTT) (Alley, M C et al, Cancer Research 48:589-601, 1988). Exponentially growing cultures of tumor cells, including multi-drug resistant cell lines, were used to make microtiter plate cultures. Cells were seeded at 1.2xl0 3 cells per well in 96-well plates, and grown overnight at 37°C. Test compounds, e.g., aPPT derivatives, were then added. Cells were treated for 24 hours.
  • MTT microculture tetrazolium assay
  • the MTT dye was added (3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide in saline) in accordance with the standard practice known in the art.
  • EXAMPLE 1 Effects of PPD and PPT derivatives on lung cancer cells.
  • FIG. 1 Figure la, lb, and lc show the comparison of the effect of the various concentrations of PPD and PPT derivatives on human lung cancer H460 cells).
  • Each cell line was treated with 2.5, 5, 7.5, 10, 15, 20, 25, 3035, and 40 ⁇ M of PPD and PPT derivatives for 24 hours prior to determining cell viability. It is clear that PPD and PPT derivatives caused cancer cell death in a dose-response fashion and reached near 100% cell killing at high concentrations.
  • EXAMPLE 2 Effects of PPD and PPT derivatives on breast cancer cells.
  • Figure 2a, 2b, and 2c show the comparison of the effect of the various concentrations of PPD and PPT derivatives on human breast cancer MCF7 cells.
  • Each cell line was treated with 2.5, 5, 7.5, 10, 15, 20, 25, 30 35, and 40 ⁇ M of PPD and PPT derivatives for 24 hours prior to determining cell viability. It is clear that PPD and PPT derivatives caused cancer cell death in a dose-response fashion and reached near 100% cell killing at high concentrations.
  • EXAMPLE 3 Comparative Effects of PPD and PPT derivatives to Paclitaxel on both breast cancer MCF7MDR cells and MCF7 cells.
  • Multi-drug resistant human breast cancer MCF7MDR cells and the parental non-drug resistant MCF7 cells were treated with various concentrations of PPD and PPT derivatives or Paclitaxel and the viability of the cells were examined using MTT assay at 24 hours post treatment.
  • Figure 3 (a, b, c, d, e, f, g, h, i, and j) show the comparison of the effect of the various concentrations of PPD and PPT derivatives on both multi-drug resistant human breast cancers MCF7MDR cells and parental non-drug resistant human breast cancer MCF7 cells.
  • Each cell line was treated with 2.5, 5, 7.5, 10, 15, 20, 25, 30 35, and 40 ⁇ M of PPD and PPT derivatives for 24 hours prior to determining cell viability.
  • PPD Protopanaxadiol
  • EXAMPLE 4 PPD and PPT derivatives enhance the efficacy of Paclitaxel on breast cancer MCF7 cells.
  • FIG. 4a, 4b, and 4c show that PPD and PPT derivatives enhance the efficacy of Paclitaxel on cancer cells.
  • EXAMPLE 5 PPD and PPT derivatives enhance the efficacy of Paclitaxel on breast cancer MCF7MDR cells.
  • FIG. 5a, 5b, and 5c show that PPD and PPT derivatives enhance the efficacy of Paclitaxel on multi-drug resistant cancer cells.
  • EXAMPLE 6 PPD and PPT derivatives enhance the efficacy of Cisplatin on breast cancer MCF7MDR cells.
  • FIG. 6a, 6b, and 6c show that PPD and PPT derivatives enhance the efficacy of Cisplatin on multi-drug resistant cancer cells.
  • Figure 7a, 7b provide graphical representations of cell viability of human glioma tumor cells (U87) treated with various Protopanaxadiol (PPD) and Protopanaxatriol (PPT) derivatives;
  • PPD Protopanaxadiol
  • PPT Protopanaxatriol
  • FIG. 8 (a, b, c, d) provide graphical representations of the cell viability pancreatic cancer cells treated with various Protopanaxadiol (PPD) and Protopanaxatriol (PPT) derivatives;
  • EXAMPLE 9 Anti-Cancer Effect of Protopanaxadiol (PPD) and Protopanaxatriol (PPT) derivatives on Various Cancer Cells
  • L6W represents a human breast cancer cell line
  • L6M represents its multi-drug resistant daughter cell line.
  • Human breast-cancer cells MDA435/LCC6 cells, both wild-type (MDA435/LCC6W, L6W) and drug resistant (MDA435/LCC6M, L6M) strains were incubated with paclitaxel alone, or with 40 ⁇ g/ml of PPD and PPT derivatives in the presence of paclitaxel at various concentrations. Cytotoxicity was measured 24 hours after the treatment, and the IC50s calculated from this data; the IC50 is the dose of a given drug that requires killing 50% of cancer cells. As shown in Table 2, 3.
  • the resistant index is therefore IC50 (L6M) /IC50( 6 W)- hi the presence of 40 Dg of PPD and PPT derivatives, the resistant index for drug resistant cell L6M is much smaller than 1.
  • the reversed index showed that the multi- drug resistant pgp+ cells became much more sensitive to paclitaxel than the pgp- parental cells following the PPD and PPT derivatives treatment.

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Abstract

La présente invention concerne un groupe de nouveaux composés de sapogénine dammarane et leur utilisation dans des applications anticancéreuses. De manière plus spécifique, cette invention se rapporte à un nouveau groupe de sapogénine dammarane: le dérivé PPD 1, 2, 3, 4 et le dérivé PPT 1, 2, 3, 4 et 5. Cette invention concerne également une nouvelle application desdites sapogénines pour le traitement anticancéreux qui consiste à les utiliser séparément ou ensemble et/ou conjointement à d'autres médicaments. Lesdites nouvelles sapogénines dammarane présentent un étonnant effet anticancéreux quand on les applique.
PCT/CA2004/001873 2003-10-27 2004-10-27 Nouvelles sapogenines dammarane, utilisation de ces dernieres en tant qu'agents anticancereux WO2005040189A1 (fr)

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KR100828192B1 (ko) * 2006-05-10 2008-05-08 주식회사 진생사이언스 담마란계 화합물을 유효성분으로 포함하는 신장 보호용약학 조성물
CN102875628A (zh) * 2012-10-30 2013-01-16 中国药科大学 具有抗菌活性的(20S,24S)-ocotillol型人参皂苷类衍生物、其制备方法及用途
WO2014178802A1 (fr) * 2013-04-29 2014-11-06 Alkoçlar Redal Can Composition de protopanaxtriol pour le traitement du cancer de la prostate et de l'hyperplasie prostatique bénigne
CN104352505A (zh) * 2014-11-14 2015-02-18 南通大学 原人参三醇及其衍生物在制备治疗肝病药物中的应用
CN104447931A (zh) * 2014-11-14 2015-03-25 南通大学 原人参三醇衍生物及其制备方法与应用
CN105640968A (zh) * 2016-01-14 2016-06-08 孙妙囡 一种人参皂苷组合物及其应用
CN106317155A (zh) * 2016-08-23 2017-01-11 吉首大学 一种还原性葫芦烷型三萜及其制法和用途
CN109575099A (zh) * 2018-11-19 2019-04-05 沈阳药科大学 达玛烷皂苷元衍生物及其制备方法和应用
CN111087441A (zh) * 2020-01-08 2020-05-01 黑龙江中医药大学 核桃青皮中一种新的三萜化合物的制备方法和应用
CN111349134A (zh) * 2020-04-23 2020-06-30 黑龙江中医药大学 核桃青皮中一种达玛烷型三萜化合物及其制备方法和应用
US10722442B2 (en) 2018-10-17 2020-07-28 Amorepacific Corporation Skin brightening composition comprising novel ginsenoside
CN111690033A (zh) * 2020-07-05 2020-09-22 沈阳药科大学 达玛烷皂苷元衍生物和制备方法及应用
US11000538B2 (en) 2018-10-31 2021-05-11 Amorepacific Corporation Composition for enhancing exercise ability or anti-fatigue comprising novel ginsenoside
US11000537B2 (en) 2018-10-17 2021-05-11 Amorepacific Corporation Composition comprising novel ginsenoside
US11576923B2 (en) 2019-09-27 2023-02-14 Amorepacific Corporation Composition for improving skin elasticity comprising novel ginsenoside
US11633413B2 (en) 2019-09-27 2023-04-25 Amorepacific Corporation Composition for preventing or improving menopausal symptom comprising novel ginsenoside

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KR100828192B1 (ko) * 2006-05-10 2008-05-08 주식회사 진생사이언스 담마란계 화합물을 유효성분으로 포함하는 신장 보호용약학 조성물
CN102875628A (zh) * 2012-10-30 2013-01-16 中国药科大学 具有抗菌活性的(20S,24S)-ocotillol型人参皂苷类衍生物、其制备方法及用途
CN102875628B (zh) * 2012-10-30 2015-12-02 中国药科大学 具有抗菌活性的(20S，24S)-ocotillol型人参皂苷类衍生物、其制备方法及用途
WO2014178802A1 (fr) * 2013-04-29 2014-11-06 Alkoçlar Redal Can Composition de protopanaxtriol pour le traitement du cancer de la prostate et de l'hyperplasie prostatique bénigne
CN104352505A (zh) * 2014-11-14 2015-02-18 南通大学 原人参三醇及其衍生物在制备治疗肝病药物中的应用
CN104447931A (zh) * 2014-11-14 2015-03-25 南通大学 原人参三醇衍生物及其制备方法与应用
CN105640968A (zh) * 2016-01-14 2016-06-08 孙妙囡 一种人参皂苷组合物及其应用
CN105640968B (zh) * 2016-01-14 2019-03-19 孙妙囡 一种人参皂苷组合物及其应用
CN106317155A (zh) * 2016-08-23 2017-01-11 吉首大学 一种还原性葫芦烷型三萜及其制法和用途
US11000537B2 (en) 2018-10-17 2021-05-11 Amorepacific Corporation Composition comprising novel ginsenoside
US10722442B2 (en) 2018-10-17 2020-07-28 Amorepacific Corporation Skin brightening composition comprising novel ginsenoside
US11000538B2 (en) 2018-10-31 2021-05-11 Amorepacific Corporation Composition for enhancing exercise ability or anti-fatigue comprising novel ginsenoside
CN109575099A (zh) * 2018-11-19 2019-04-05 沈阳药科大学 达玛烷皂苷元衍生物及其制备方法和应用
US11576923B2 (en) 2019-09-27 2023-02-14 Amorepacific Corporation Composition for improving skin elasticity comprising novel ginsenoside
US11633413B2 (en) 2019-09-27 2023-04-25 Amorepacific Corporation Composition for preventing or improving menopausal symptom comprising novel ginsenoside
CN111087441A (zh) * 2020-01-08 2020-05-01 黑龙江中医药大学 核桃青皮中一种新的三萜化合物的制备方法和应用
CN111087441B (zh) * 2020-01-08 2021-06-22 黑龙江中医药大学 核桃青皮中一种三萜化合物的制备方法和应用
CN111349134A (zh) * 2020-04-23 2020-06-30 黑龙江中医药大学 核桃青皮中一种达玛烷型三萜化合物及其制备方法和应用
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