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.
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