Computational modeling and target synthesis of monomethoxy-substituted o-diphenylisoxazoles with unexpectedly high antimitotic microtubule destabilizing activity.

The ability of monomethoxy-substituted o-diphenylisoxazoles 2a-d to interact with the colchicine site of tubulin was predicted using computational modeling, docking studies, and calculation of binding affinity. The respective molecules were synthesized in high yields by three steps reaction using easily available benzaldehydes, acetophenones, and arylnitromethanes as starting material. The calculated antitubulin effect was confirmed in vivo in a sea urchin embryo model.

Sea Urchin Embryo Model As a Reliable in Vivo Phenotypic Screen to Characterize Selective Antimitotic Molecules. Comparative evaluation of Combretapyrazoles, -isoxazoles, -1,2,3-triazoles, and -pyrroles as Tubulin-Binding Agents.

A series of both novel and reported combretastatin analogues, including diarylpyrazoles, -isoxazoles, -1,2,3-triazoles, and -pyrroles, were synthesized via improved protocols to evaluate their antimitotic antitubulin activity using in vivo sea urchin embryo assay and a panel of human cancer cells. A systematic comparative structure-activity relationship studies of these compounds were conducted. Pyrazoles 1i and 1p, isoxazole 3a, and triazole 7b were found to be the most potent antimitotics across all tested compounds causing cleavage alteration of the sea urchin embryo at 1, 0.

Regioselective synthesis of 3,4-diaryl-5-unsubstituted isoxazoles, analogues of natural cytostatic combretastatin A4.

4,5-Diarylisoxazoles are potent antiproliferative tubulin-targeting agents. Their isomeric 3,4-diaryl-5-unsubstituted isoxazoles are hardly accessible. The synthesis of 3,4-diaryl-5-unsubstituted isoxazoles 13 was designed based on a condensation of arylbenzaldehydes, arylnitromethanes, and ethoxycarbonylmethylpyridinium bromide followed by a selective one-step transformation of intermediate 3,4-diaryl-5-ethoxycarbonyl-4,5-dihydroisoxazole 2-oxides 8.