Synthesis of C17-[5-methyl-1,3]-oxazoles by N-propargylation of triterpenic acids and evaluation of their cytotoxic activity

Abstract A series of unexpected triterpenic C17-[5-methyl-1,3]-oxazoles along with targeted N-propargylamides was synthesized by an interaction of acid chlorides with propargylamine hydrochloride. We proposed that the formation of methyl oxazole passes through an alternative pathway by the participation of the terminal alkyne carbon atom and acid chloride intermediate with following intramolecular rearrangements. The synthesized compounds were evaluated for their cytotoxicity at the U.S. National Cancer Institute. 28-Nor-17-(5-methyloxazol-2-yl)−2-cyano-2,4-seco-3-nor-lup-4(23),20(29)-diene has demonstrated the highest activity with GI50 ranged from 1.03 to 16.4 μM against different cancer cell lines. Molecular docking in Kelch domain of Keap1 protein was performed to study a possible molecular target. Thus, we have shown for the first time that triterpenic C17-[5-methyl-1,3]-oxazoles are alternative products of the interaction of triterpenic acid chlorides with propargylamine hydrochloride and they have an advantage over corresponding N-propargylamides as cytotoxic agents. Graphical Abstract