3-(5-)-Amino-o-diarylisoxazoles: Regioselective synthesis and antitubulin activity

• A regioselective synthesis of 5-amino- and 3-aminodiarylisoxazoles was developed.
• Easily available plant extracts were used as starting material.
• Evaluation for antimitotic antitubulin activity in the sea urchin embryo model.
• Molecules with unsubstituted 5-amino group were the most effective.
• The compounds were highly cytotoxic in NCI60 anticancer drug screen.

A regioselective synthesis of both 5-amino- and 3-aminodiarylisoxazoles substituted with polyalkoxyaryl pharmacophores has been validated. Starting materials for the synthetic scheme were easily available from plant extracts. The targeted molecules were further tested in the phenotypic sea urchin embryo assay to identify compounds with antimitotic microtubule destabilizing activity. Structure–activity relationship studies suggested that the structural features essential for potent antiproliferative activity include: 1) 5-aminoisoxazole bridge linking biaryl substituents (rings A and B); 2) unsubstituted 5-amino group; 3) 3,4,5-methoxy substituted benzene and 4-methoxy benzene pharmacophores as rings A and B, respectively. The most potent compounds also showed strong in vitro cytotoxicity in NCI60 anticancer drug screen against a panel of 60 human cancer cell lines, including multi-drug resistant cells.

Figure optionsDownload as PowerPoint slide