Synthesis, cytotoxic activity and binding model analysis of novel isoxazole-docetaxel analogues with C3′-N modification

Structure–activity relationship (SAR) studies confirm that modifications at C-3′ position can lead to the development of highly potent novel taxoids. We designed and synthesized a series of novel isoxazole-docetaxel analogues A1–A5 by introducing isoxazolyl groups to C3′-N position. All of the synthesized compounds exhibited similar to better cytotoxic activities than docetaxel against human cancer cell lines, Hela, A2780, A549, MCF-7, and SK-OV-3. These compounds also possessed higher inhibition than docetaxel against drug-resistant cancer cell lines, A2780-MDR and MCF-7-MDR. Binding model analysis of A1–A5 molecule to microtubule (MT) showed that these compounds were anchored to the active site, explaining their inhibitory effects on MT in vitro. The calculated binding free energy values were in positive correlation with the IC50 values of A1–A5 compounds against cancer cells. These results strongly support the statement that the introduction of isoxazolyl groups to C-3′ position indeed improves the cytotoxic activities of taxoids.