RESUMO
The synthesis and SAR of a series of pyrrolopyridazine MEK inhibitors are reported. Optimal activity was achieved by incorporation of a 4-phenoxyaniline substituent at C4 and an acylated amine at C6.
Assuntos
Inibidores Enzimáticos/farmacologia , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Piridazinas/síntese química , Pirróis/síntese química , Acilação , Aminas/química , Compostos de Anilina/química , Animais , Desenho de Fármacos , Humanos , Piridazinas/farmacologia , Pirróis/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
A unified approach for the construction of the potent marine antitumor agents (+)-tedanolide (1) and (+)-13-deoxytedanolide (2) is described. Highlights of the synthetic strategy include the development of a versatile bifunctional dithiane-vinyl iodide linchpin, the unorthodox use of the Evans-Tishchenko reaction, and a late-stage high-risk stereocontrolled introduction of the C(18,19) epoxide to achieve a total synthesis of (+)-13-deoxytedanolide (2).
Assuntos
Macrolídeos/síntese química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Química Orgânica/métodos , Lactonas/síntese química , Lactonas/química , Macrolídeos/química , Estrutura Molecular , Poríferos/química , EstereoisomerismoRESUMO
N-Acyl-2-aminothiazoles with nonaromatic acyl side chains containing a basic amine were found to be potent, selective inhibitors of CDK2/cycE which exhibit antitumor activity in mice. In particular, compound 21 [N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide, BMS-387032], has been identified as an ATP-competitive and CDK2-selective inhibitor which has been selected to enter Phase 1 human clinical trials as an antitumor agent. In a cell-free enzyme assay, 21 showed a CDK2/cycE IC(50) = 48 nM and was 10- and 20-fold selective over CDK1/cycB and CDK4/cycD, respectively. It was also highly selective over a panel of 12 unrelated kinases. Antiproliferative activity was established in an A2780 cellular cytotoxicity assay in which 21 showed an IC(50) = 95 nM. Metabolism and pharmacokinetic studies showed that 21 exhibited a plasma half-life of 5-7 h in three species and moderately low protein binding in both mouse (69%) and human (63%) serum. Dosed orally to mouse, rat, and dog, 21 showed 100%, 31%, and 28% bioavailability, respectively. As an antitumor agent in mice, 21 administered at its maximum-tolerated dose exhibited a clearly superior efficacy profile when compared to flavopiridol in both an ip/ip P388 murine tumor model and in a s.c./i.p. A2780 human ovarian carcinoma xenograft model.
Assuntos
Antineoplásicos/síntese química , Quinases relacionadas a CDC2 e CDC28/antagonistas & inibidores , Oxazóis/síntese química , Tiazóis/síntese química , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Quinases relacionadas a CDC2 e CDC28/metabolismo , Linhagem Celular Tumoral , Sistema Livre de Células , Cristalografia por Raios X , Ciclina E/metabolismo , Quinase 2 Dependente de Ciclina , Cães , Ensaios de Seleção de Medicamentos Antitumorais , Estabilidade de Medicamentos , Humanos , Técnicas In Vitro , Camundongos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Transplante de Neoplasias , Oxazóis/farmacocinética , Oxazóis/farmacologia , Fosforilação , Ratos , Proteína do Retinoblastoma/metabolismo , Relação Estrutura-Atividade , Tiazóis/farmacocinética , Tiazóis/farmacologia , Transplante HeterólogoRESUMO
In this communication we describe the first total synthesis of (+)-13-deoxytedanolide, an architecturally complex marine macrolide possessing significant antitumor activity. The cornerstone of the synthesis comprises a highly convergent dithiane coupling used to construct the carbon skeleton, followed by a novel use of the Evans-Tishchenko reduction to oxidize the C(1) aldehyde to an ester in the presence of the oxidatively labile dithiane.