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Chen, Jichao and Wang, Tianyu and Xu, Shengtao and Zhang, Pengfei and Lin, Aijun and Wu, Liang and Yao, Hequan and Xie, Weijia and Zhu, Zheying and Xu, Jinyi (2017) Discovery of novel antitumor nitric oxide-donating b-elemene hybrids through inhibiting the PI3K/Akt pathway. European Journal of Medicinal Chemistry, 135 . pp. 414-423. ISSN 1768-3254

Abstract

A series of novel furoxan-based NO-donating b-elemene hybrids were designed and synthesized to improve the anticancer efficacy of natural b-elemene. The bioassay results indicated that all of the target compounds exhibited significantly improved antiproliferative activities against three cancer cell lines (SGC-7901, HeLa and U87) compared to parent compound b-elemene. Interestingly, these compounds displayed excellent sensitivity to U87 cells with IC50 values ranging from 173 to 2 nM. Moreover, most compounds produced high levels of NO in vitro, and the antitumor activity of 11a in U87 cells was markedly attenuated by an NO scavenger (hemoglobin or carboxy-PTIO). Further mechanism studies revealed that 11a caused the G2 phase arrest of the cell cycle and induced apoptosis of U87 cells by preventing the activation of the PI3K/Akt pathway. Moreover, 11a significantly suppressed the tumor growth in H22 liver cancer xenograft mouse model with a tumor inhibitory ratio (TIR) of 64.8%, which

was superior to that of b-elemene (TIR, 49.6%) at the same dose of 60 mg/kg. Together, the remarkable biological profiles of these novel NO-donating b-elemene derivatives may make them promising candidates for the intervention of human cancers.

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