A novel class of trans-methylpyrazoline analogs of combretastatins: Synthesis and in-vitro biological testing

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 IC50 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 IC50 values in the 6–8 μM range. Compound 1j caused microtubule depolymerization with an EC50 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.

Thirteen methylpyrazoline analogs (1a-m) of combretastatin A-4 (CA-4, 2) were synthesized. The mechanism of action of the most cytotoxic analog 1j was found to be microtubule depolymerization.Figure optionsDownload as PowerPoint slideHighlights
► trans-Methylpyrazoline analogs of combretastatin-A4 were synthesized in good yields.
► X-ray crystal structure performed on analog 1d.
► The phenyl moieties are locked in a trans configuration about the pyrazoline unit.
► The most active analog 1j caused major microtubule depolymerization similar to C-A4.
► 1j exhibited significant cytotoxicity against murine and human cancer cells.