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

Abstract

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. The orientation of aryl rings in relation to isoxazole heterocycle was confirmed by X-ray crystallography. Targeted compounds were evaluated for antimitotic microtubule destabilizing activity using a phenotypic sea urchin embryo assay. 3-(4-Methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)isoxazole 13e and 13h with a single methoxy substituent were the most potent. Compound 13e showed strong cytotoxicity in NCI60 screen with GI₅₀ for NCI-H522 human lung cancer cell line of 0.023 μM.

Keywords: 3,4-Diarylisoxazoles; Microtubule destabilization; Nitrostilbenes; Sea urchin embryo.