WO2008070176A1 - Novel hydrophilic derivatives of 2-aryl-4-quinolones as anticancer agents - Google Patents
Novel hydrophilic derivatives of 2-aryl-4-quinolones as anticancer agents Download PDFInfo
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- WO2008070176A1 WO2008070176A1 PCT/US2007/025056 US2007025056W WO2008070176A1 WO 2008070176 A1 WO2008070176 A1 WO 2008070176A1 US 2007025056 W US2007025056 W US 2007025056W WO 2008070176 A1 WO2008070176 A1 WO 2008070176A1
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- Prior art keywords
- cancer
- phosphate derivative
- compound
- och
- derivative according
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- 239000002246 antineoplastic agent Substances 0.000 title description 9
- PMZDQRJGMBOQBF-UHFFFAOYSA-N quinolin-4-ol Chemical compound C1=CC=C2C(O)=CC=NC2=C1 PMZDQRJGMBOQBF-UHFFFAOYSA-N 0.000 claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims description 89
- 229910052739 hydrogen Inorganic materials 0.000 claims description 68
- 206010028980 Neoplasm Diseases 0.000 claims description 54
- 239000007787 solid Substances 0.000 claims description 41
- 201000011510 cancer Diseases 0.000 claims description 39
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 29
- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 claims description 27
- 206010006187 Breast cancer Diseases 0.000 claims description 15
- 208000026310 Breast neoplasm Diseases 0.000 claims description 15
- 208000032839 leukemia Diseases 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
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- 208000029742 colonic neoplasm Diseases 0.000 claims description 13
- 239000004480 active ingredient Substances 0.000 claims description 12
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- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 11
- 206010038389 Renal cancer Diseases 0.000 claims description 11
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 11
- 201000010982 kidney cancer Diseases 0.000 claims description 11
- 201000005202 lung cancer Diseases 0.000 claims description 11
- 208000020816 lung neoplasm Diseases 0.000 claims description 11
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- 206010005949 Bone cancer Diseases 0.000 claims description 6
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- JGABMVVOXLQCKZ-UHFFFAOYSA-N 2-phenyl-1h-quinolin-4-one Chemical compound N=1C2=CC=CC=C2C(O)=CC=1C1=CC=CC=C1 JGABMVVOXLQCKZ-UHFFFAOYSA-N 0.000 claims description 5
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000002467 phosphate group Chemical class [H]OP(=O)(O[H])O[*] 0.000 claims 20
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- 229910019142 PO4 Inorganic materials 0.000 abstract description 20
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- 230000001093 anti-cancer Effects 0.000 abstract description 3
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- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 description 1
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- 239000012267 brine Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 238000003570 cell viability assay Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229960005309 estradiol Drugs 0.000 description 1
- 229930182833 estradiol Natural products 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- JAFSQOZJLSKULO-UHFFFAOYSA-N n-(6-acetyl-1,3-benzodioxol-5-yl)selenophene-2-carboxamide Chemical compound CC(=O)C1=CC=2OCOC=2C=C1NC(=O)C1=CC=C[se]1 JAFSQOZJLSKULO-UHFFFAOYSA-N 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 1
- 210000003200 peritoneal cavity Anatomy 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229940124606 potential therapeutic agent Drugs 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000004550 quinolin-6-yl group Chemical group N1=CC=CC2=CC(=CC=C12)* 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- MABNMNVCOAICNO-UHFFFAOYSA-N selenophene Chemical compound C=1C=C[se]C=1 MABNMNVCOAICNO-UHFFFAOYSA-N 0.000 description 1
- WAQBFLCVNNZBQR-UHFFFAOYSA-N selenophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=C[se]1 WAQBFLCVNNZBQR-UHFFFAOYSA-N 0.000 description 1
- LPNFPTALNNSHRL-UHFFFAOYSA-N selenophene-3-carboxylic acid Chemical compound OC(=O)C=1C=C[se]C=1 LPNFPTALNNSHRL-UHFFFAOYSA-N 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 238000013414 tumor xenograft model Methods 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D421/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms
- C07D421/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing two hetero rings
- C07D421/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/60—Quinoline or hydrogenated quinoline ring systems
Definitions
- the present invention relates to novel phosphate derivatives of 2-aryl-4-quino!ones, and novel intermediates, 2-selenophene 4-quinolones and ⁇ /, ⁇ /-dialkylaminoalkyl derivatives of 2-phenyl-4-quinolones; and in particular to their uses in treating human cancers.
- R 6 , R 3 ' F, Cl, OCH 3
- Preferred embodiments of the present invention include (but not limited thereto) the following items:
- a phosphate derivative of 2-aryl-4-quinolone having the following formulas Ia, Ib or Ic:
- R 2 ', R 3 ', R4 1 , Rs' and R 6 ' independently are H, (CH 2 )nCH 3 , (CH 2 ) n YH, Y(CH 2 ) n CH 3 , Y(CH 2 ) n YH, Y(CH 2 ) n NR 8 R 9 , X, (CH 2 ) n NR 8 R 9 ,
- n is an integer of 0-4, Y is 0 or S, X is F, Cl, or Br 1 and R 8 and R 9 independently are H, (CH 2 ) n YH, (CH 2 ) n N(C n H 2n+ i)(C m H 2m+1 ) or (CH 2 ) n CH 3 , wherein n and Y are defined as above, and m is an integer of 0-4; R 2 , R 3 , R 4 and R 5 independently are H, (CH 2 ) n CH 3 , (CH 2 ) n YH,
- R 3 and R 4 together is -Y(CH 2 ) n Y-, wherein n, Y, X, R 8 and R 9 are defined as above; and R 1 and R 1 1 independently are H, Li + , Na + , K + , N + R 8 R 9 R 10 Rn or benzyl wherein R 10 and R 11 independently are H, (CH 2 ) n YH, (CH 2 ) n N(C n H 2n+1 )(C m H 2m+1 ) or (CH 2 ) n CH 3 , n, m, R 8 and R 9 are defined as above.
- R 2 , R 3 , R 4 , and R 5 are all H; or one of R 2 , R 3 , R 4 , and R 5 is F, OCH 3 , Y(CH 2 ) n CH 3 or (CH 2 J n NR 8 Rg, and the others thereof are H; or R 2 and R 5 are H, and R 3 and R 4 together is -O(CH 2 ) n O-, wherein n, Y 1 R 8 and R 9 are defined as in Item 1.
- R 2 , R 3 and R 5 are H; and R 5 ' is F, and R 2 ', R 3 ', R 4 ' and R 6 'are H.
- R 4 , and R 5 are all H; or one of R 2 , R 3 , R 4 and R 5 is F or OCH 3 , and the others thereof are H; or R 2 and R 5 are H, and R 3 and R 4 together is -0(CH 2 J n O-, wherein n is defined as in Item 1.
- a pharmaceutical composition for the killing of solid cancer cells which comprises a therapeutically effective amount of a phosphate derivative of 2-aryl-4-quinolone as set forth in any one of Item 1 to Item 19 or a pharmaceutically acceptable salt thereof, as an active ingredient, in admixture with a pharmaceutically acceptable carrier or diluent for the active ingredient, wherein the solid cancer cells comprise human breast cancer, colon cancer, lung cancer, melanoma, ovarian cancer, renal cancer, stomach cancer, prostate cancer, ileocecal carcinoma, glioblastoma, bone cancer, epidermoid carcinoma of the nasopharynx, hepatoma or leukemia cancer.
- composition according to Item 20 wherein the solid cancer cells are human breast cancer, colon cancer, lung cancer, renal cancer, hepatoma, or leukemia cancer
- R 2 ', R 3 ' and R 4 ' independently are H, (CH 2 ) n CH 3 , (CH 2 ) n YH, Y(CH 2 )nCH 3 , Y(CH 2 ) n YH, Y(CH 2 ) n NR 8 R 9l X, or (CH2) n NR 8 R 9 , wherein n is an integer of 0-4, Y is O or S, X is F, Cl, or Br, and Re and R 9 independently are H, (CH 2 ) n YH, (CH 2 ) n N(C n H 2n+ i )(C m H 2m+1 ) or (CH 2 ) n CH 3 , wherein n and Y are defined as above, and m is an integer of 0-4; R 2 , R 3 , R 4 and R 5 independently are H, (CH 2 ) n CH 3 , (CH 2 ) n YH, Y(CH 2
- R 3 and R 4 together is -Y(CH 2 J n Y-, wherein n, Y, X, R 8 and R 9 are defined as above.
- R 2 , R 3 , R 4 , and R 5 are all H; or one of R 2 , R 3 , R 4 and R 5 is F or OCH 3 , and the others thereof are H; or R 2 and R 5 are H, and R 3 and R 4 together is -O(CH 2 ) n O-, wherein n is defined as in Item 19.
- R 2 ', R 3 ' and R 4 ' are all H; or one of R 2 ', R 3 ' and R 4 ' is F or OCH 3 , and the others thereof are H.
- a pharmaceutical composition for the killing of solid cancer cells which comprises a therapeutically effective amount of a compound of 2-selenophene 4-quinolone as set forth in any one of Item 23 to Item 27 or a pharmaceutically acceptable salt thereof, as an active ingredient, in admixture with a pharmaceutically acceptable carrier or diluent for the active ingredient, wherein the solid cancer cells comprise human breast cancer, colon cancer, lung cancer, melanoma, ovarian cancer, renal cancer, stomach cancer, prostate cancer, ileocecal carcinoma, glioblastoma, bone cancer, epidermoid carcinoma of the nasopharynx, hepatoma or leukemia cancer.
- R 2 ', R 3 ', R 4 1 , R 5 ' and R 6 ' independently are H, (CH 2 )nCH 3 , (CH 2 ) n YH,
- n is an integer of 0-4, Y is O or S, X is F, Cl, or Br, and R 8 and Rg independently are H, (CH 2 ) n YH, (CH 2 ) n N(C n H 2n+1 )(C m H 2m+1 ) or (CH 2 ) n CH 3 , wherein n and Y are defined as above, and m is an integer of 0-4; R 2 , R 3 , R 4 and R 5 independently are H, (CH 2 ) n CH 3 , (CH 2 ) n YH, Y(CH 2 ) n CH 3 , Y(CH 2 )nYH, Y(CH 2 ) n NR 8 R 9 , X, (CH 2 ) n NR 8 R 9 , or R 3 and R 4 together is -Y(CH 2 ) n Y-, wherein n, Y 1 X, R 8 and R 9 are defined as above; provided that one of
- a pharmaceutical composition for the killing of solid cancer cells which comprises a therapeutically effective amount of a compound of 2-phenyl 4-quinolone as set forth in any one of Item 30 to Item 35 or a pharmaceutically acceptable salt thereof, as an active ingredient, in admixture with a pharmaceutically acceptable carrier or diluent for the active ingredient, wherein the solid cancer cells comprise human breast cancer, colon cancer, lung cancer, melanoma, ovarian cancer, renal cancer, stomach cancer, prostate cancer, ileocecal carcinoma, glioblastoma, bone cancer, epidermoid carcinoma of the nasopharynx, hepatoma or leukemia cancer.
- Fig. 1 shows effects of compound 1-1 and compound 1-1 -b on MCF7 tumor growth in a mouse xenograft model.
- Female SCID mice received injections of MCF7 transfectants to induce tumor xenografts. Mice were divided into five groups. The second to fifth groups were given i.p. with compounds 1-1 (15 mg/kg), 1-1 (30 mg/kg), 1-1 -b (22.5 mg/kg), and 1-1 -b (45 mg/kg), respectively, three times per week. Data are expressed as mean of tumor weights (g) ⁇ S. E. M. * p ⁇ 0.05 compared with the control.
- Fig. 2 shows effect of compound 1-1 -b on animal survival.
- BALB/c mice were intraperitoneal ⁇ injected with CT-26 tumor cells for 7 days before beginning the treatments with compound 1-1 -b (5 mg/kg/day and 10 mg/kg/day QD x 7).
- Fig. 3 shows effect of quinolone derivatives on the viability of human breast cancer cells.
- MCF7 cells were treated with DMSO (Control) or various concentrations (0.125 ⁇ M to 10 ⁇ M) of quinolone derivative for 48 hours and subsequent cell viability was measured by MTT assay. Results from three separate experiments were averaged and are presented as mean ⁇ standard error as shown.
- Example 7 a novel intermediate, 2-selenophene 4-quinolone (l-7-d), was synthesized. 2-selenophene-4-quinolone (l-7-d) was reacted with tetrabenzyl pyrophosphate in the presence of alkali, the corresponding phosphoric acid dibenzyl ester (l-7-e) was obtained.
- l-7-d 2-selenophene 4-quinolone
- HBr (3ml) was added while the solution was heated to 60 0 C, and the mixture was heated to 90 0 C for 3h. After the reaction was complete, the reaction mixture was poured into water, and extracted with EtOAc. The acid layer was neutralized to pH 7-8 by adding 10% NaHCO 3 , and extracted with EtOAc (100ml x 5). The organic layer was dried over MgSO 4 , and evaporated. The residue was recrystallized from n-hexane-EtOAc to afford l-8-d as gray solid (55mg, 59.9%).
- 1-10-c (530mg, 2mmol), ⁇ /-bromo-succinimide (NBS, 360mg, 2 mmol), and 2,2'-azobis(isobutyronitrile) (AIBN, 30 mg, 0.19 mmol) were added to a dry round bottom flask, which was purged with argon. 50 ml of dry benzene was added to the reaction mixture in an argon atmosphere with stirring at room temperature for 30 min, and then refluxed at 80 0 C for 1 h and then cooled to room temperature to give 1-10-d, which, without further purification, was treated with diethylamine (3.0 ml, 29.0 mmole), and then refluxed for 1 h.
- diethylamine (3.0 ml, 29.0 mmole
- mice Female GALB/cAnN-Foxn1.E SCID mice (18-20 g; 6-8 weeks of age) were purchased from the National Animal Center and maintained in pressurized ventilated cage according to institutional regulations. The mice were implanted subcutaneously with estradiol (0.7mg) 2 days before tumor transplantation. MCF-7 cells (2 ⁇ 10 6 ) were inoculated s.c. into the right flank of the mice. After appearance of a 150-mm 3 tumor nodule, 30 tumor-bearing mice were randomly divided into five groups for treatment with vehicle (PBS), 1-1 or 1-1 -b. The first groups only received vehicle. The second to fifth groups were given i.p.
- PBS vehicle
- 1-1 or 1-1 -b vehicle
- mice 30 male 6-week-old Balb/c mice, were purchased from the National Animal cancer and maintained in pressurized ventilated cage according to institutional regulations.
- II-2 Results 11-2-1 Appearance of mice after treatment
- mice in the excipient control group showed overt ascites, while mice receiving orally 1-1 -b (5 mg/kg/day, QD x 7) and 1-1 -b (10 mg/kg/day, QD x 7) exhibited reduced ascites development.
- II-2-2 The average life span of mice after treatment As shown in Fig. 2, all mice in the excipient control group were dead
- MTT solution (2 mg/ml, Sigma Chemical Co.) was added to each well to make a final volume of 500 ⁇ and incubated for 1 h at
- compound l-7-d In vitro cytotoxic activity of compound l-7-d was tested in HCT-116, Hep G2, NCI-H226, A549, A498 and HL-60 cells. As shown in Table 1 , compound l-7-d demonstrates significant inhibition against most of the six cancer cell lines and most notably, is quite active against HCT-116 and HL-60 cells. Compound l-7-d shows an IC 50 of 0.9 ⁇ M against HCT-116 and an IC 50 of 0.5 ⁇ M against HL-60 cell. Compound l-7-d is an attractive candidate for development as a novel anti-cancer agent.
- IC 50 value means the concentration causing 50% growth-inhibitory effect.
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Abstract
Description
Claims
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CA2670292A CA2670292C (en) | 2006-12-07 | 2007-12-07 | Novel hydrophilic derivatives of 2-aryl-4-quinolones as anticancer agents |
NZ577130A NZ577130A (en) | 2006-12-07 | 2007-12-07 | Novel hydrophilic derivatives of 2-aryl-4-quinolones as anticancer agents |
US12/448,088 US8440692B2 (en) | 2006-12-07 | 2007-12-07 | Hydrophilic derivatives of 2-aryl-4-quinolones as anticancer agents |
KR1020097014196A KR101139413B1 (en) | 2006-12-07 | 2007-12-07 | Novel hydrophilic derivatives of 2-aryl-4-quinolones as anticancer agents |
CN2007800447969A CN101583280B (en) | 2006-12-07 | 2007-12-07 | Novel hydrophilic derivatives of 2-aryl-4-quinolones as anticancer agents |
EP07853279A EP2096924B1 (en) | 2006-12-07 | 2007-12-07 | Novel hydrophilic derivatives of 2-aryl-4-quinolones as anticancer agents |
AU2007328034A AU2007328034B2 (en) | 2006-12-07 | 2007-12-07 | Novel hydrophilic derivatives of 2-aryl-4-quinolones as anticancer agents |
JP2009540310A JP5102843B2 (en) | 2006-12-07 | 2007-12-07 | Novel hydrophilic derivatives of 2-aryl-4-quinolones as anticancer agents |
US13/892,576 US9023867B2 (en) | 2006-12-07 | 2013-05-13 | Hydrophilic derivatives of 2-selenophene-4-quinolones as anticancer agents |
US13/892,545 US9029394B2 (en) | 2006-12-07 | 2013-05-13 | 2-phenyl-4-quinolones as anticancer agents |
US13/892,522 US9023866B2 (en) | 2006-12-07 | 2013-05-13 | 2-selenophene-4-quinolones as anticancer agents |
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US13/892,545 Division US9029394B2 (en) | 2006-12-07 | 2013-05-13 | 2-phenyl-4-quinolones as anticancer agents |
US13/892,522 Division US9023866B2 (en) | 2006-12-07 | 2013-05-13 | 2-selenophene-4-quinolones as anticancer agents |
US13/892,576 Division US9023867B2 (en) | 2006-12-07 | 2013-05-13 | Hydrophilic derivatives of 2-selenophene-4-quinolones as anticancer agents |
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EP (3) | EP2096924B1 (en) |
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CN (1) | CN101583280B (en) |
AU (1) | AU2007328034B2 (en) |
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WO2012009519A1 (en) | 2010-07-15 | 2012-01-19 | Efficient Pharma Management Corp. | Synthesis and anticancer activity of aryl and heteroaryl-quinolin derivatives |
WO2012066578A2 (en) | 2010-11-18 | 2012-05-24 | Kasina Laila Innova Pharmaceuticals Private Limited | Substituted 4-(selenophen-2(or 3)-ylamino)pyrimidine compounds and methods of use thereof |
US11820747B2 (en) | 2021-11-02 | 2023-11-21 | Flare Therapeutics Inc. | PPARG inverse agonists and uses thereof |
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KR101460207B1 (en) * | 2011-12-07 | 2014-11-11 | 세종대학교산학협력단 | Anticancer agents containing selenophene-fused aromatic compounds |
US9624235B2 (en) * | 2012-01-31 | 2017-04-18 | University of Pittsburgh—of the Commonwealth System of Higher Education | Compounds and methods for inhibition of AP endonuclease-1/redox factor-1 (HAPE1) activity |
CN102675200B (en) * | 2012-05-16 | 2014-04-09 | 中国药科大学 | 2-phenyl-4-carbostyril compounds with antineoplastic activity, and preparation method and usage thereof |
EP3302488B1 (en) * | 2015-06-03 | 2020-09-30 | Tairx, Inc. | Novel use of aryl-quinolin derivatives as inhibitors of vasculogenic mimicry |
WO2016201257A2 (en) * | 2015-06-10 | 2016-12-15 | The Johns Hopkins University | Compositions and methods for identifying adp-ribosylated sites by mass spectrometry |
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