Synthesis and Antitumor Activity of a Series of Novel 1-Oxa-4-azaspiro[4,5]deca-6,9-diene-3,8-dione Derivatives.

A series of novel 1-oxa-4-azaspiro[4.5]deca-6,9-diene-3,8-diones were designed and synthesized by using 4-aminophenol and α-glycolic acid or lactic acid as starting materials in three or four steps. The key step is the metal-catalyzed oxidative cyclization of the amide to 1-oxa-4-azaspiro[4.5]deca-6,9-diene-3,8-diones ( and ), the reaction conditions of which are investigated and optimized. The anticancer activity of 17 1-oxa-4-azaspiro[4.5]deca-6,9-diene-3,8-dione derivatives was evaluated. Preliminary results showed that 15 compounds have moderate to potent activity against human lung cancer A549, human breast cancer MDA-MB-231, and human cervical cancer HeLa cancer cell lines. Among them, compounds and were the most potent against A549 cell line with 0.18 and 0.19 µM of IC, respectively; compounds , , and showed the most potent cytotoxicity against MDA-MB-231 cell line with 0.08, 0.08, and 0.09 µM of IC, respectively, while the activities of , , and against HeLa cell line were the most potent with 0.15, 0.14, and 0.14 µM of IC, respectively. Compound is a promising candidate for further development, which emerged as the most effective compound overall against the three tested cancer cell lines.