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1.
Bioorg Med Chem ; 23(10): 2360-7, 2015 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-25882531

RESUMO

We have published p53-MDM2 interaction inhibitors possessing a novel dihydroimidazothiazole scaffold. Although our lead compound 1 showed strong antitumor activity with single oral administration on a xenograft model using MV4-11 cells harboring wild-type p53, it needed a higher dose (200mg/kg) for distinct efficacy. We executed further optimization with the aim of improvement of potency and physicochemical properties. Thus optimal compounds were furnished by introducing fluorine moieties onto the phenyl ring at the C-6 position and the pyrrolidine part at the C-2 substituent; and modifying the terminal piperazine to 4,7-diazaspiro[2,5]octane variants. Furthermore, replacing 4-chlorophenyl on the C-5 position with pyridyl variant decreased nonspecific cytotoxicity significantly. Our exploration afforded DS-5272 indicating excellent antitumor efficacy from a dose of 25mg/kg on SJSA-1 xenografted models with high safety and good PK profiles, which has appropriate potency as a clinical candidate.


Assuntos
Antineoplásicos/síntese química , Neoplasias Ósseas/tratamento farmacológico , Imidazóis/síntese química , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Sarcoma/tratamento farmacológico , Tiazóis/síntese química , Proteína Supressora de Tumor p53/antagonistas & inibidores , Administração Oral , Animais , Antineoplásicos/farmacologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Descoberta de Drogas , Flúor/química , Expressão Gênica , Humanos , Imidazóis/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Ligação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Pirrolidinas/química , Sarcoma/genética , Sarcoma/metabolismo , Sarcoma/patologia , Tiazóis/farmacologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Bioorg Med Chem ; 21(14): 4319-31, 2013 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-23685175

RESUMO

We have discovered and reported potent p53-MDM2 interaction inhibitors possessing dihydroimidazothiazole scaffold. Our lead showed strong activity in vitro, but did not exhibit antitumor efficacy in vivo for the low metabolic stability. In order to obtain orally active compounds, we executed further optimization of our lead by the improvement of physicochemical properties. Thus we furnished optimal compounds by introducing an alkyl group onto the pyrrolidine at the C-2 substituent to prevent the metabolism; and modifying the terminal substituent of the proline motif improved solubility. These optimal compounds exhibited good PK profiles and significant antitumor efficacy with oral administration on a xenograft model using MV4-11 cells having wild type p53.


Assuntos
Antineoplásicos/síntese química , Desenho de Fármacos , Imidazóis/síntese química , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Tiazóis/síntese química , Proteína Supressora de Tumor p53/antagonistas & inibidores , Administração Oral , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Humanos , Imidazóis/química , Imidazóis/farmacologia , Concentração Inibidora 50 , Ligação Proteica/efeitos dos fármacos , Tiazóis/química , Tiazóis/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Bioorg Med Chem Lett ; 23(3): 728-32, 2013 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-23266121

RESUMO

With the aim of discovering potent inhibitors of the p53-MDM2 interaction and thus obtaining a potent anticancer drug, we have pursued synthesis and optimization of dihydroimidazothiazole derivatives, which have been discovered via scaffold hopping by mimicing the mode of interaction between MDM2 and Nutlins. Upon the discovery we encountered a problem involving the chemical instability of the scaffold, that is, susceptibility to oxidation which led to imidazothiazole. In order to solve this problem and to obtain further potent compounds, we executed medicinal research and thus furnished the optimal compounds by incorporating the methyl group onto the C-6 position to avoid the oxidation, and by modifying the C-2 moiety of the additional proline motif, which furnished high potency. The incorporation of the pyrrolidine moiety at the C-2 position raised another hydrophobic interaction site with MDM2 protein, which was generated by the induced-fitting observed by co-crystal structure analysis. These optimal molecules showed significant improvement in potency when compared with the early lead (+)-1 or Nutlin-3a.


Assuntos
Imidazóis/química , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Tiazóis/química , Tiazóis/farmacologia , Proteína Supressora de Tumor p53/antagonistas & inibidores , Humanos , Interações Hidrofóbicas e Hidrofílicas , Concentração Inibidora 50 , Ligação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Estereoisomerismo , Proteína Supressora de Tumor p53/metabolismo
4.
Bioorg Med Chem Lett ; 22(20): 6338-42, 2012 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-22995624

RESUMO

Starting with Nutlins as an initial lead, we designed and generated bicyclic scaffolds aiming to place cis-bischlorophenyl moiety at the equivalent location where the hydrophobic interaction with MDM2 could be expected. As a result, we discovered novel MDM2 inhibitors possessing a dihydroimidazothiazole scaffold. Further exploration of the side chains on the dihydroimidazothiazole scaffold aided by molecular modeling resulted in compounds exhibiting almost comparable in vitro potency to Nutlin-3a.


Assuntos
Desenho de Fármacos , Mapas de Interação de Proteínas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Tiazóis/química , Tiazóis/farmacologia , Proteína Supressora de Tumor p53/antagonistas & inibidores , Humanos , Imidazóis/química , Imidazóis/farmacologia , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/metabolismo
5.
Bioorg Med Chem Lett ; 19(2): 305-8, 2009 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-19091560

RESUMO

The synthesis and evaluation of new analogues of thieno[2,3-d]pyrimidin-4-yl hydrazones are described. 2-Pyrdinecarboxaldehyde [6-(tert-butyl)thieno[2,3-d]pyrimidine-4-yl]hydrazone derivatives have been identified as cyclin-dependent kinase 4 (CDK4) inhibitors. The potency, selectivity profile, and structure-activity relationship of this series of compounds are discussed.


Assuntos
Ciclina D1/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Hidrazonas/síntese química , Hidrazonas/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidrazonas/química , Inibidores de Proteínas Quinases/química , Pirimidinas/química , Relação Estrutura-Atividade
6.
Bioorg Med Chem Lett ; 14(12): 3209-15, 2004 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-15149677

RESUMO

To improve the metabolic stability of 3, which exhibited both in vitro antitumor activity and in vivo efficacy by both iv and po administration, we designed and synthesized new taxane analogues. Most of the synthetic compounds maintained excellent antitumor activity and were scarcely metabolized by human liver microsomes. And some compounds exhibited potent antitumor effects against B16 melanoma BL6 in vivo by both iv and po administration similarly to 3.


Assuntos
Antineoplásicos/química , Taxoides/química , Animais , Antineoplásicos/metabolismo , Antineoplásicos/uso terapêutico , Humanos , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/metabolismo , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Taxoides/metabolismo , Taxoides/uso terapêutico
7.
Bioorg Med Chem ; 11(20): 4431-47, 2003 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-13129580

RESUMO

It was shown that a new taxane analogue 3, which exhibited both in vitro antitumor activity and in vivo efficacy by both i.v. and p.o. administration, was prone to be metabolized by human liver microsomes. We identified a major metabolite, M-1, generated by human liver microsomes as 20a, a hydroxylated compound at the pyridine ring of 3. To improve the metabolic stability of 3, we designed and synthesized new taxane analogues based on the structure of M-1, and obtained some compounds that maintained excellent antitumor activity and were scarcely metabolized by human liver microsomes.


Assuntos
Taxoides/síntese química , Acetais/síntese química , Acetais/metabolismo , Acetais/farmacologia , Animais , Antineoplásicos , Divisão Celular/efeitos dos fármacos , Desenho de Fármacos , Estabilidade de Medicamentos , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Relação Estrutura-Atividade , Taxoides/metabolismo , Taxoides/farmacologia
8.
Cancer Sci ; 94(5): 459-66, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12824894

RESUMO

DJ-927 is a novel taxane, which was selected for high solubility, non-neurotoxicity, oral bioavailability, and potent antitumor activity. In this study, we compared the in vitro and in vivo efficacy of DJ-927 with those of paclitaxel and docetaxel. DJ-927 exhibited stronger cytotoxicity than paclitaxel and docetaxel in various tumor cell lines, especially against P-glycoprotein (P-gp)-expressing cells. The cytotoxicity of DJ-927, unlike those of other taxanes, was not affected by the P-gp expression level in tumor cells, or by the co-presence of a P-gp modulator. When intracellular accumulation of the three compounds was compared, intracellular amounts of DJ-927 were much higher than those of paclitaxel or docetaxel, particularly in P-gp-positive cells. In vivo, DJ-927 showed potent antitumor effects against two human solid tumors in male BALB/c-nu/nu mice, and yielded significant life-prolongation in a murine liver metastasis model with male C57BL/6 mice, in which neither paclitaxel nor docetaxel was effective. The results demonstrate the superior efficacy of orally administered DJ-927 over intravenously administered paclitaxel or docetaxel against P-gp-expressing tumors, probably due to higher intracellular accumulation. A phase I clinical trials of DJ-927 is currently ongoing in the US.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/uso terapêutico , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Neoplasias Experimentais/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Ensaio de Unidades Formadoras de Colônias , Docetaxel , Humanos , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Neoplasias Experimentais/metabolismo , Paclitaxel/uso terapêutico , Taxoides/uso terapêutico , Células Tumorais Cultivadas/efeitos dos fármacos , Células Tumorais Cultivadas/transplante
9.
Bioorg Med Chem Lett ; 13(2): 185-90, 2003 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-12482420

RESUMO

We synthesized novel water-soluble and orally active taxane analogues, 7-deoxy-9beta-dihydro-9,10-O-acetal taxanes. Cytotoxicities of the synthetic compounds were greater than those of paclitaxel and docetaxel, especially against resistant cancer cell lines expressing P-glycoprotein. In addition, some compounds showed potent antitumor effects against B16 melanoma BL6 in vivo by both iv and po administration.


Assuntos
Antineoplásicos Fitogênicos/síntese química , Paclitaxel/análogos & derivados , Paclitaxel/síntese química , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indicadores e Reagentes , Melanoma Experimental/tratamento farmacológico , Camundongos , Conformação Molecular , Transplante de Neoplasias , Paclitaxel/farmacologia , Solubilidade , Células Tumorais Cultivadas
10.
Chem Pharm Bull (Tokyo) ; 50(10): 1398-400, 2002 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12372874

RESUMO

A new method for the synthesis of 7-deoxytaxane analogues has been established through hydrogenation of Delta(6,7)-taxane derivatives. Among several catalysts examined, Pd-C was found to be a most effective catalyst for the preparation of target compound.


Assuntos
Hidrocarbonetos Aromáticos com Pontes/síntese química , Taxoides , Hidrocarbonetos Aromáticos com Pontes/química , Hidrogenação
11.
Bioorg Med Chem Lett ; 12(20): 2815-9, 2002 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-12270153

RESUMO

To investigate structure-activity relationships of the 9,10-acetal-9beta-dihydro taxoids, we modified the 7-hydroxyl groups of the 9,10-acetonide-3'-(4-pyridyl) analogue to deoxy, methoxy, alpha-F, and 7beta,8beta-methano group. As a result of this study, we found that the 7-deoxy analogue was the strongest among these analogues. In addition, we found that the 7-deoxy-3'-(4-pyridyl) and 7-deoxy-3'-(2-pyridyl) analogues showed stronger activity against cell lines expressing P-glycoprotein than the corresponding 3'-phenyl analogue.


Assuntos
Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/farmacologia , Paclitaxel/análogos & derivados , Paclitaxel/farmacologia , Taxoides , Hidrocarbonetos Aromáticos com Pontes/química , Fenômenos Químicos , Físico-Química , Cromatografia Líquida de Alta Pressão , Ensaios de Seleção de Medicamentos Antitumorais , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Paclitaxel/síntese química , Solubilidade , Estereoisomerismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
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