WO1993001824A1 - Therapie combinee utilisant des composes bioflavonoides avec des medicaments anticancer - Google Patents

Therapie combinee utilisant des composes bioflavonoides avec des medicaments anticancer Download PDF

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WO1993001824A1
WO1993001824A1 PCT/US1992/006087 US9206087W WO9301824A1 WO 1993001824 A1 WO1993001824 A1 WO 1993001824A1 US 9206087 W US9206087 W US 9206087W WO 9301824 A1 WO9301824 A1 WO 9301824A1
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group
compound
acyloxy
halogens
och
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PCT/US1992/006087
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English (en)
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Barry M. Markaverich
Rajender Singh Varma
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Baylor College Of Medicine
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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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
    • 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

Definitions

  • This invention relates to the use of a combination of anti-cancer drugs with bioflavonoid compounds and related compounds which include methyl p-hydroxyphenyllactate (MeHPLA), its analogs, chemical derivatives and chemically related compounds, phenylmethylene ketones, nitroalkenes, aurones, and chalcones as an enhanced anti-tumor agent and inhibitor of proliferative cell growth.
  • MeHPLA methyl p-hydroxyphenyllactate
  • anti-cancer drugs are typically described as cytotoxic agents which inhibit cancer cell division through a variety of mechanisms. Most of these drugs block tumor cell proliferation by inhibiting DNA synthesis and interfering with the progression of the cell cycle.
  • One popular class of anti-cancer drugs are the anti-metabolites such as arabinocytosylcytosine, 5-fluorouracil (5-FU), 6-mercaptopurine, 6- thioguanine and methotrexate (MTX) which block DNA synthesis through a variety of mechanisms.
  • MTX is an antimetabolite directed against dihydrofolate reductase; 5-FU inhibits tRNA methylation, rRNA maturation, nuclear RNA synthesis, and thymidylate synthetase which results in "thymidineless" cell death and causes DNA damage and strand breaks; and both 5-FU and MTX cause extensive hypermethylation of the nucleic acid.
  • Antibiotics such as bleomycin and adriamycin are DNA intercalating agents which cause DNA strand breaks and arrest of tumor cells in the G2 phase of the cell cycle.
  • Alkylating agents such as the nitrosoureas, cis-platinum and cyclophoshamide (CY), covalently bind to nucleic acids causing DNA-DNA and DNA-protein crosslinking which results in the .arrest of cells during the G2 phase of the cell cycle.
  • CY cyclophoshamide
  • MeHPLA methyl phydroxyphenyllactate
  • MeHPLA and related compounds appear to be cytostatic as opposed to cytotoxic agents.
  • MeHPLA and type II sites are present in essentially all non-malignant tissues that have been examined and occupancy of type II sites by MeHPLA in these tissues results in an arrest of cell proliferation. Therefore, drugs which mimic MeHPLA as cell regulatory agents such as RSV-101 and DHBA should not effect non-malignant tissues since type II sites in these cells are already occupied by endogenous MeHPLA.
  • mammary cancer preparations are deficient in MeHPLA and consequently have high levels of unoccupied nuclear type II sites.
  • These nuclear type II sites are available for binding drugs related to MeHPLA like DHBA and RSV-101, resulting in the inhibition of tumor cell proliferation in vitro and mouse mammary tumor growth in vitro.
  • treatments with DHBA and RSV-101 has not resulted in body weight loss, hair loss or other signs of generalized non-specific cytotoxicity.
  • these drugs appear to inhibit mammary cancer cell proliferation without many of the severe side effects normally observed with other standard cytotoxic chemotherapeutic drugs.
  • nuclear type II sites appear to be ubiquitous, it is suspected that MeHPLA related compounds will inhibit a broad spectrum of cancers. It has been observed that MeHPLA-related compounds inhibit melanoma, retinoblastoma, lymphoma, cervical cancer and a number of breast cancer cell types in tissue culture.
  • the present invention describes a combination therapy using
  • MeHPLA related drugs and standard chemotherapeutic agents such as the aforementioned antibiotics, alkylating agents and anti-metabolites.
  • This invention has significant benefit as compared to treatment with standard cytotoxic agents alone (which possess significant non-specific cytotoxicity). Combination therapy with both types of compounds will significantly inhibit cancer growth with a substantial reduction in severe non-specific generalized cytotoxicity.
  • An objective of the present invention is the provision of a combination of compounds for the treatment of cancer.
  • a further object of the present invention is a method of regulating cell growth and proliferation in normal and malignant cells by using a combination of compounds.
  • An additional object of the present invention is a procedure to inhibit the growth of proliferating cells which include a Type II nuclear estrogen binding site.
  • a further object of the present invention is a method of inhibiting the growth of estrogen responsive tissues.
  • An additional object of the present invention is the treatment of human breast cancer, and other malignancies which contain unbound nuclear Type II sites.
  • a method of regulating cell growth and proliferation in normal and malignant cells comprising the step of administering a therapeutic dose of a combination of compounds wherein at least one compound of the combination is selected from group I and at least one compound is selected from group II and wherein the compound from group I is selected from the group consisting of antimetabolites, antibiotics and alkylating agents and the compound from group II is selected from the group consisting of:
  • R 1 and R 4 are selected from the group consisting of H, OH, acylosy and halogens
  • R 2 , R 3 and R 6 are selected from the group consisting of H, OH, OCH 3 , amino, alkylamine and alkyl groups containing 1 to 6 carbons, acyloxy, and halogens
  • R 6 is selected from the group consisting of H, CH 3 , OH, OCH 3 , acyloxy and halogens
  • R' 1 and R' 2 are selected from the group consisting of H, OH, CH 3 , OCH 3 , amino, cyano, alkyl or alkylamine groups of 1 to 6 carbon atoms, acyloxy, halogens, ⁇ -azido and aziridine derivatives, 3,4-dihydroxyphenylmethylene, p- hydroxyphenylmethylene and other substituted phenyl groups
  • R' 3 , R' 4 , R' 5 , R" 1 and R" 2
  • OCH 3 amino, cyano, alkyl or alkylamine groups of 1 to 6 carbon atoms, acyloxy, halogens, ⁇ -azido, aziridine, acyloxy and halogen substituted derivatives.
  • the antimetabolites are selected from the group consisting of arabinocytosylcytosine, 6-mercaptopurine, 6-thioguanine, 5-fluorouracil, cytoxan, and methotrexate.
  • the antibiotics are selected from bleomycin, adriamycin and vinblastin and the alkylating agents are selected from nitrosoureas, cis-platinum and cyclophosphamide.
  • the following compounds can also be used as group II compounds: methyl p- hydroxyphenyllactate, analogues of methyl p-hydroxyphenyllactate, chemical derivatives of methyl p-hydroxyphenyllactate, and chemically related compounds such as the group consisting of the formula:
  • R 1 is selected from the group consisting of H, alkyl groups containing 1 to 6 carbons and aryl groups;
  • R 2 and R 3 are selected from the group consisting of H, OH and OCH 3 ;
  • R 4 is selected from the group consisting of H and an alkyl group of 1 to 6 carbons.
  • Group II compounds have consisted of: 2-(hydroxybenzylidene)-5-methyl- cyclopentanone (MV-1), 2, 6-bis(hydroxybenzylidene-4-methyl- cyclohexanone (MV-17), 2, 6-bis(3,4-dihydroxybenzylidene)-4- methylcylcohexanone (MV-18), 2,6-bis(3-methoxy-4-hydroxybenzylidene) cyclohexanone (RSV-101), 2,6-bis(3,4-dihydroxybenzyhdene) cyclohexanone (MV-3), 4-hydroxy- ⁇ -methyl- ⁇ -nitrostyrene (MV-N1), 3,4-dihydroxy- ⁇ - methyl- ⁇ -nitrostyrene (MV-N3), aurone (MV-19), 4'-hydroxyaurone (MV-
  • the compounds described herein can be used for inhibiting the growth of proliferating cells which include a Type II nuclear estrogen binding site.
  • Figure 1 shows the effects of the combination therapy on mouse mammary tumor growth.
  • biologically inhibiting or “inhibition” of the growth of proliferating cells as used herein means partial or total growth inhibition and also includes decreases in the rate of proliferation or growth of the cells.
  • the biologically inhibitory dose of the compounds of the present invention may be determined by assessing the effects of the test compound on malignant cell growth in tissue culture, uterine growth in the animal or tumor growth in the animal as previously described by Markaverich, et al., Cancer Research 43:3208-3211 (1983), or any other method known to those of ordinary skill in the art. These methods have also been fully described in U.S. Patent Application No. 219,680.
  • Administration of the compounds useful in the method of the present invention may be by topical, parenteral, oral, intranasal, intravenous, intramuscular, subcutaneous, or any other suitable means.
  • the dosage administered is dependent upon the age, weight, kind of concurrent treatment, if any, and nature of the malignancy or the pathological condition.
  • the effective compound useful in the method of the present invention may be employed in such forms as capsules, tablets, liquid solutions, suspensions, or elixirs, for oral administration, or sterile liquid forms such as solutions, suspensions or emulsions.
  • Any inert carrier is preferably used, such as saline, or phosphate-buffered saline, or any such carrier in which the compounds used in the method of the present invention have suitable solubility properties.
  • the compounds of the present invention may be administered in a biologically effective carrier.
  • the biologically effective carriers may include any solvent with which the compounds of the present invention are compatible and which are non-toxic to the individuals treated at the amounts administered.
  • the compounds of the present invention are administered as an encapsulated composition. Due to the low aqueous solubility of many of the compounds effective in carrying out the present invention they are encapsulated in cyclodextrin, liposomes or as silastic implants. However, the compounds of the present invention may be encapsulated by other methods and with other compounds by methods known to those skilled in the art.
  • agent is meant to include agents which decrease cell growth, or inhibit the proliferation of tumor cells when administered to said tumor cells in a effective dose.
  • Method of methyl 3-(4-hydroxyphenyl)-2-hydroxypropionate is also known as methyl p-hydroxyphenyllactate or MeHPLA.
  • MeHPLA is meant to also include its analogs, chemical derivatives, and chemically related compounds which bind to the nuclear Type II receptors and by so doing inhibit cell proliferation.
  • chemically related compounds refers to the derivatives and analogs of p-coumaric acid, p-hydroxyphenylbutanone, (4- hydroxyphenoxy)acetate and the arylpropenaldehydes, alkyl aryletheneyl ketones, aryl arylethenyl ketones, aryl butenaldehydes, alkyl arylpropenyl ketones and arylpropenyl ketones which are structurally related to
  • MeHPLA and disclosed herein.
  • These chemically related compounds include the cis and trans isomers of said compounds and their esters, ethers, ketones and derivatives containing S or N in place or O atoms. More specifically these structurally related analogs and derivatives include compounds where R 1 represents the methyl, ethyl, n-propyl, n-butyl, isopropyl tert-butyl or aryl group and R 2 and R 3 represent H, OH or OCH 3 groups and R 4 is H or an alkyl group of 1 to 6 carbons. Specific analogs of each class of these structurally related compounds to MeHPLA have been demonstrated to possess biological activity mimicing MeHPLA as an effective inhibitor of cell proliferation and tumor cell growth.
  • analogs and chemically related compounds effective in practicing the present invention include, but are not limited to, phenylmethylene ketones, nitroalkenes, aurones, and chalcones. Most preferably, these analogs are selected from the group consisting of the general formulas:
  • R 1 is selected from the group consisting of H, OH, acyloxy, alkyl groups containing 1 to 6 carbons, and aryl groups;
  • R 2 and R 3 are selected from the group consisting of H, OH and OCH 3 and
  • R 4 is selected from the group consisting of H, or alkyl group containing 1 to 6 carbons.
  • Preferred compounds which may be used to practice the present invention may be selected from the group consisting of methyl 3-(4- hydroxyphenyl)-2-hydroxypropionate, n-propyl 3-(4-hydroxyphenyl)-2- hydroxypropionate, n-butyl 3-(4-hydrorj ⁇ henyl)-2-hydroxypropionate, 3-(4- hydroxyphenyl)-2-propanoic acid, 4-(4-hydroxyphenyl)-2-butanone, 1-(4- hydroxyphenyl)-3-pentanone,methyl(4-hydroxyphenoxy)acetate,methyl3- (3,4-dihydroxyphenyl)-2-propenoate.
  • Another aspect of the invention is a method of regulating cell growth proliferation in normal and malignant cells comprising the step of administering a therapeutic dose of a combination of compounds, wherein at least one compound is selected from group I and one compound is selected from group II, and wherein the compound from group I is selected from the group consisting of antimetabolites, antibiotics and alkylating agents and the compound from group II is selected from the group consisting of:
  • R 1 and R 4 are selected from the group consisting of H and OH, acyloxy and halogens
  • R 2 , R 3 and R 6 are selected from the group consisting of H, OH, OCH 3 , amino, alkylamino and alkyl groups containing 1 to 6 carbons, acyloxy, and halogens
  • R 5 is selected from the group consisting of H, CH 3 , OH, OCH 3 , acyloxy and halogens
  • R' 1 and R' 2 are selected from the group consisting of H, CH 3 , OH, OCH 3 , amino, cyano, alkyl or alkylamino groups of 1 to 6 carbon atoms, acyloxy, halogen, ⁇ - azido and aziridine derivatives, 3,4-dihydroxyphenylmethylene, p- hydroxyphenylmethylene and other substituted phenyl groups
  • R' 3 , R' 4 , R' 5 , R" 1 and R" 2
  • Preferred compounds which may be used to practice the present invention maybe selected from phenylmethylene ketones, nitroalkenes, aurones and chalcones.
  • Examples of the type of group I compounds which can be used for antimetabolites include arabinocytosylcytosine, 6-mercaptopurine, 6- thioguanine, 5-fluorouracil, cytoxan, and methotrexate.
  • the compounds which can be used include bleomycin, adriamycin and vinblastin.
  • Some alkylating agents which can be used are nitrosoureas, cis-platinum and cyclophoshamide.
  • the preferable compounds include the phenyl methylene ketones selected from the group consisting of:
  • nitroalkenes the most preferable are:
  • aurones most preferable for practicing the present invention are:
  • chalcones most preferable for practicing the present invention are:
  • Preferred compounds which may be used to practice the present invention may be selected from the group consisting of methyl 3-(4- hydroxyphenyl)-2-hydroxypropionate, n-propyl 3-(4-hydroxyphenyl)-2- hydroxypropionate, n-butyl 3-(4-hydroxyphenyl)-2-hydroxypropionate, 3-(4- hydroxyphenyl)-2-propanoic acid, 4-(4-hydroxyphenyl)-2-butanone, 1-(4- hydroxyphenyl)-3-pentanone, methyl (4-hydroxyphenoxy) acetate, and methyl 3-(3,4-dihydroxyphenyl)-2-propenoate.
  • compounds are 1-(4-hydroxyphenyl)-3 ⁇ pentanone and 1-(4-hydroxyphenyl)-3-butanone. These compounds have been shown to bind to Type II sites and to have antitumor and anti- proliferative activity in the uterotropic assay.
  • Another group of compounds which show anti-proliferative activity in the rat uterus are methyl (4-hydroxyphenoxy) acetate and 2-(4- hydroxyphenoxy) ethyl methyl ether.
  • Preferred compounds which may be used to practice the present invention are:
  • Most preferred compounds of this group for practicing the present invention are 3-(4-hydroxyphenyl)-1-phenyl-2-propen-1-one and 4-(4- hydroxyphenyl)-3-buten-2-one, analogs, chemical derivatives and chemically related compounds and pharmaceutically acceptable salts thereof.
  • these antitumor agents are also useful as inhibitors of cell growth and proliferation in those cells which include a Type II nuclear estrogen binding site.
  • These compounds bind to Type II nuclear estrogen binding sites and regulate cell growth.
  • Specific proliferating cells which are sensitive to the binding of these compounds include estrogen responsive tissues such as uterus, mammary gland, uterine tumors and mammary tumors.
  • the above-described compounds inhibit the proliferative capacity of human breast cancer cells and thus provide an effective therapy for this disease.
  • Benign prostatic hyperplasia is another example of a proliferative tissue disease in which the above-described compounds can successfully be used in the treatment.
  • a further embodiment includes a method of regulating cell growth and proliferation in normal and malignant cells, comprising the step of administering a therapeutic dose of a combination of compounds, wherein at least one compound is selected from group I and at least one compound is selected from group II and wherein the compound from group I is selected from the group consisting of antimetabolites, antibiotics and alkylating agents and the compound from group II is selected from the group consisting of methyl p-hydroxyphenyllactate, its analogues, chemical derivatives and chemically related compounds.
  • Compounds of group II which are used include:
  • R 1 is from the group consisting of H, alkyl groups containing 1 to 6 carbons, and substituted or unsubstituted aryl groups; and R 2 and R 3 are selected from the group consisting of H, OH and OCH 3 .
  • Preferred compounds of this group which may be used to practice the present invention are:
  • mice bearing estrogen-independent mammary tumors were segregated into 6 experimental groups (5 mice per group) at the time of tumor transplantation. Eleven days following transplantation, the animals were treated with the MV-88, RSV- 101 or 5-FU administered in the drinking water.
  • MV-88 and RSV-101 were dissolved in the drinking water as a complex in a 2-hydroxypropyl ⁇ -cyclodextrin-vehicle by adding the drug in excess to an aqueous solution of 2-hydroxypropyl- ⁇ -cyclodextrin (Aldrich). The suspension was stirred at room temperature and the excess non-solubilized drug removed by centrifugation and ultrafiltration.
  • aqueous cyclodextrin-drug complex was lyophillized, weighed and dissolved in a known concentration of methanol and the drug concentration (mg drug/ mg dry cyclodextrin-drug complex) determined by high performance liquid chromatography (HPLC) utilizing a C 18 reversed phase column by methods known to those reasonably skilled in the art. Sample peak areas were compared to those of known concentrations of authentic standards. Typical values were 1 mg
  • MV-88 or RSV-101 per 11-15 mg dry cyclodextrin were used for determining the dosage of the drug-cyclodextrin complex to be dissolved in water for oral delivery.
  • An equivalent amount of 2- hydroxypropyl ⁇ -cyclodextrin was also added to the drinking water of the controls and 5-FU treated animals.
  • the concentration of the drug delivered to the animals was determined by measuring the volume of the drinking water consumed (miUiHters/day/Kg body weight/mouse) throughout the study.
  • MV-88, RSV-101 and 5-Fu were delivered at a daily rate of approximately 5mg/Kg/day/mouse in these studies.
  • Tumor size was monitored by measuring the tumors (length x width) with vernier calipers at the indicated times following treatment.
  • FU and RSV-101 + 5-FU treatment groups had palpable tumors demonstrating that treatment had indeed blocked the growth of this tumor as opposed to inhibiting its establishment.
  • combination therapy with MeHPLA related compounds and 5-FU is that relatively non-toxic agents (MV-88, RSV-101) can be combined with a cytotoxic drug (5-FU) to inhibit mammary cancer growth. Because of the enhancement of 5-FU activity by MeHPLA related compounds, the dose level of 5-FU required to inhibit mammary cancer growth could be reduced to decrease generalized systematic cytoxicity. Although combination therapy with a variety of cytotoxic anti-cancer drugs is in widespread use, these procedures are limited by a high degree of non-specific cytotoxicity and severe side effects.

Abstract

Méthode de régulation de la prolifération de cellules dans des tissus sains et des tissus malins qui consistent à administrer une dose thérapeutique d'une combinaison de ces composés. Au moins un des composés est choisi dans le groupe méthyl p-hydroxylphényllactate, ses analogues, des dérivés chimiques et des composés chimiques connexes. En outre, au moins un des composés est choisi dans le groupe des antimétabolites, antibiotiques et alkylants. Cette thérapie combinée a un effet plus marqué d'inhibition de la croissance et de la prolifération des cellules cancereuses, et des cellules non cancéreuses.
PCT/US1992/006087 1991-07-24 1992-07-17 Therapie combinee utilisant des composes bioflavonoides avec des medicaments anticancer WO1993001824A1 (fr)

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Cited By (9)

* Cited by examiner, † Cited by third party
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WO1996019209A1 (fr) * 1994-12-20 1996-06-27 Indena S.P.A. Chalcones et leurs esters a activite antiproliferative dans les tumeurs de l'uterus, de l'ovaire et du sein
WO2005077405A1 (fr) * 2004-02-06 2005-08-25 Cancer Treatment International Compositions et methodes de traitement du cancer par elevation systemique de lactate et depletion d'arginine
US7312191B2 (en) 2003-07-29 2007-12-25 Arizona Biomedical Research Commission Conjugated nitro alkene anticancer agents based on isoprenoid metabolism
WO2010110647A1 (fr) * 2009-03-27 2010-09-30 Biotropics Malaysia Berhad Aurones en tant que modulateurs de récepteur d'oestrogène et leur utilisation dans des maladies dépendantes des hormones sexuelles
WO2010110646A1 (fr) * 2009-03-27 2010-09-30 Biotropics Malaysia Berhad Aurones en tant qu'inhibiteurs sélectifs de pde et leur utilisation dans des affections et troubles neurologiques
WO2014022660A1 (fr) * 2012-08-03 2014-02-06 Georgia State University Research Foundation, Inc. Analogues de curcumine et procédés de fabrication et d'utilisation de ceux-ci
US8815232B2 (en) 2008-08-26 2014-08-26 Kyon Biotech Ag Compositions and methods for treating cancer
US10899727B2 (en) 2016-04-11 2021-01-26 Middle Tennessee State University Therapeutic aurones
KR20220029221A (ko) * 2020-09-01 2022-03-08 부산대학교 산학협력단 Pak1 억제활성을 갖는 신규 화합물 및 이의 용도

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CHEMICAL ABSTRACT, 1990, Markaverich and Nuclear Type II Binding Sites in Malignant Cells, Metabolic Fate and Mammary Tumorgrowth, 112: 194912. *
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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5808137A (en) * 1994-12-20 1998-09-15 Indena S.P.A. Chalcones and esters thereof with antiproliferative activity in uterus, ovary and breast tumors
CN1087609C (zh) * 1994-12-20 2002-07-17 因迪纳有限公司 有抗子宫、卵巢和乳腺肿瘤增生活性的查耳酮及其酯
WO1996019209A1 (fr) * 1994-12-20 1996-06-27 Indena S.P.A. Chalcones et leurs esters a activite antiproliferative dans les tumeurs de l'uterus, de l'ovaire et du sein
US7977315B2 (en) 2003-07-29 2011-07-12 Arizona Biomedical Research Commission Conjugated nitro alkene anticancer agents based on isoprenoid metabolism
US7312191B2 (en) 2003-07-29 2007-12-25 Arizona Biomedical Research Commission Conjugated nitro alkene anticancer agents based on isoprenoid metabolism
WO2005077405A1 (fr) * 2004-02-06 2005-08-25 Cancer Treatment International Compositions et methodes de traitement du cancer par elevation systemique de lactate et depletion d'arginine
US8815232B2 (en) 2008-08-26 2014-08-26 Kyon Biotech Ag Compositions and methods for treating cancer
WO2010110646A1 (fr) * 2009-03-27 2010-09-30 Biotropics Malaysia Berhad Aurones en tant qu'inhibiteurs sélectifs de pde et leur utilisation dans des affections et troubles neurologiques
WO2010110647A1 (fr) * 2009-03-27 2010-09-30 Biotropics Malaysia Berhad Aurones en tant que modulateurs de récepteur d'oestrogène et leur utilisation dans des maladies dépendantes des hormones sexuelles
WO2014022660A1 (fr) * 2012-08-03 2014-02-06 Georgia State University Research Foundation, Inc. Analogues de curcumine et procédés de fabrication et d'utilisation de ceux-ci
US9884825B2 (en) 2012-08-03 2018-02-06 Georgia State University Research Foundation, Inc. Curcumin analogs and methods of making and using thereof
US10899727B2 (en) 2016-04-11 2021-01-26 Middle Tennessee State University Therapeutic aurones
US11286245B2 (en) 2016-04-11 2022-03-29 Middle Tennessee State University Therapeutic aurones
KR20220029221A (ko) * 2020-09-01 2022-03-08 부산대학교 산학협력단 Pak1 억제활성을 갖는 신규 화합물 및 이의 용도
KR102609490B1 (ko) * 2020-09-01 2023-12-04 부산대학교 산학협력단 Pak1 억제활성을 갖는 신규 화합물 및 이의 용도

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