RESUMO
Thirteen methylpyrazoline analogs (1a-m) of combretastatin A-4 (CA-4, 2) were synthesized. The trans-geometry of the two substituted phenyl moieties was ascertained by a single crystal X-ray diffraction study of compound 1d. The cytotoxicities of the analogs against the growth of murine B16 melanoma and L1210 lymphoma cells in culture were measured using the MTT assay. One of the derivatives, 1j, which has the same substituents as CA-4 was the most active in the series with IC(50) values of 3.3 µM and 6.8 µM against the growth of L1210 and B16 cells, respectively. The activity of this analog against human cancer cell lines was confirmed in the NCI 60 panel. The other active analogs against L1210 were 1b and 1f, which gave IC(50) values in the 6-8 µM range. Compound 1j caused microtubule depolymerization with an EC(50) value of 4.1 µM. This compound has good water solubility of 372 µM. Molecular modeling studies using DFT showed that compound 1j adopts a "twisted" conformation mimicking CA-4 that is optimal for binding to the colchicine site of tubulin.
Assuntos
Antineoplásicos Fitogênicos/síntese química , Bibenzilas/síntese química , Microtúbulos/efeitos dos fármacos , Pirazóis/química , Estilbenos/síntese química , Moduladores de Tubulina/síntese química , Animais , Antineoplásicos Fitogênicos/farmacologia , Bibenzilas/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Leucemia L1210/tratamento farmacológico , Leucemia L1210/metabolismo , Leucemia L1210/patologia , Melanoma Experimental/química , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Camundongos , Microtúbulos/química , Microtúbulos/patologia , Simulação de Acoplamento Molecular , Estilbenos/farmacologia , Relação Estrutura-Atividade , Moduladores de Tubulina/farmacologiaRESUMO
Thirteen hydroxyethyl- analogs of combretastatin A-4 (CA-4) that contain the 1-(1'-hydroxyethyl)-1-(3",4",5"-trimethoxyphenyl)-2-(substituted phenyl)ethene framework were synthesized. Molecular modeling studies at the DFT level showed that compound 3j adopts a 'twisted' conformation mimicking CA-4. The cytotoxicity of the novel compounds against the growth of murine B16 melanoma and L1210 lymphoma cells in culture was measured using an MTT assay. Three analogs 3f, 3h, and 3j were active. Of these, 3j, which has the same substituents as CA-4 and IC(50) values of 16.1 and 4.1 µM against B16 and L1210 cells, respectively, was selected for further biological evaluation. The activity of 3j was verified by the NCI 60 cell line screen. Compound 3j causes microtubule depolymerization in A-10 cells with an EC(50) of 21.2 µM. Analog 3j, which has excellent water solubility of 479 µM, had antitumor activity in a syngeneic L1210 murine model.
