RESUMO
The synthesis and structure-activity relationship study of a series of compounds with heterocycles in place of the cis double bond in combretastatin A-4 (CA-4) are described. Substituted tosylmethyl isocyanides were found to be the key intermediates in construction of the heterocycles. Cytotoxicities of the heterocycle-based CA-4 analogues were evaluated against NCI-H460 and HCT-15 cancer cell lines. 3-Amino-4-methoxyphenyl and N-methyl-indol-5-yl were the best replacements for the 3-hydroxy-4-methoxyphenyl in CA-4. 4,5-Disubstituted imidazole was found to be the best for the replacement of the cis double bond in CA-4. Medicinal chemistry efforts led to the discovery of compounds 24h and 25f that were found to be 32 and 82% bioavailable, respectively, in rat. Evaluation of 24h and 25f against murine M5076 reticulum sarcoma in mice revealed that both compounds were orally efficacious with an increase in life span of 38.5 and 40.5%, respectively.
Assuntos
Antineoplásicos/síntese química , Imidazóis/síntese química , Estilbenos/química , Administração Oral , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Biopolímeros , Divisão Celular/efeitos dos fármacos , Cães , Ensaios de Seleção de Medicamentos Antitumorais , Haplorrinos , Humanos , Imidazóis/química , Imidazóis/farmacocinética , Imidazóis/farmacologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Camundongos , Camundongos Nus , Transplante de Neoplasias , Ratos , Relação Estrutura-Atividade , Transplante Heterólogo , Tubulina (Proteína)/química , Células Tumorais CultivadasRESUMO
Pharmacokinetic changes of oltipraz were investigated after intravenous and oral administration at a dose of 30 mg/kg to control Sprague-Dawley rats and rats with liver cirrhosis induced by dimethylnitrosamine. After intravenous administration in rats with liver cirrhosis, the area under the plasma concentration-time curve from time zero to time infinity (AUC) was significantly greater (1490 microg min/ml versus 2840 microg min/ml) than that in control rats. This was due to significantly slower total body clearance (CL) (20.2 ml/(min kg) versus 10.6 ml/(min kg)) in the rats. The slower CL was due to significantly slower CL(NR) (20.1 ml/(min kg) versus 10.5 ml/(min kg)) in rats with liver cirrhosis. The significantly slow CL(NR) was due to slower hepatic blood flow rate and significantly slower in vitro intrinsic oltipraz disappearance clearance (CL(int), 77.2 ml/min per whole liver versus 11.5 ml/min per whole liver) because the free (unbound in serum proteins) fraction of oltipraz was significantly greater (15.1% versus 31.3%) in the rats. After oral administration in rats with liver cirrhosis, the AUC was also significantly greater (354 microg min/ml versus 812 microg min/ml) and this was not due to increased absorption in the rats. This also could be due to slower hepatic blood flow rate and significantly slower CL(int) in the rats.