Synthesis and Antitumor Activities of Novel Mitochondria-Targeted Dihydroartemisinin Ether Derivatives

Cangcang Xu; Linfan Xiao; Peiyu Lin; Xiyue Yang; Xin Zou; Lingli Mu; Xiaoping Yang

doi:10.1021/acsomega.2c04562

Synthesis and Antitumor Activities of Novel Mitochondria-Targeted Dihydroartemisinin Ether Derivatives

ACS Omega. 2022 Oct 18;7(43):38832-38846. doi: 10.1021/acsomega.2c04562. eCollection 2022 Nov 1.

Authors

Cangcang Xu¹, Linfan Xiao¹, Peiyu Lin¹, Xiyue Yang¹, Xin Zou¹, Lingli Mu¹, Xiaoping Yang¹

Affiliation

¹ Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan 410013, China.

Abstract

Ten novel mitochondria-targeted dihydroartemisinin ether derivatives were designed, synthesized, and evaluated for antitumor activity against five cancer cell lines in vitro. Profoundly, compound D8-T (IC₅₀ = 56.9 nM) showed the most potent antiproliferative activity against the T24 cells with low cytotoxicity in normal human umbilical vein endothelial cells. High-performance liquid chromatography analysis confirmed that D8-T targeted mitochondria 6.3-fold higher than DHA. ATP content assay demonstrated that D8-T decreased the ATP level of bladder cancer cells. The effect of D8-T on cell apoptosis was determined by flow cytometry and western blot of Bax and Bcl-2. Surprisingly, the results indicated that D8-T did not induce bladder cancer cell apoptosis. In contrast, the cell cycle analysis and western blot of CDK4, CDK6, cyclin D1, and p21 demonstrated that the cancer cell cycle was arrested at the G1 phase after D8-T treatment. Furthermore, the consistent results were received by RNA-seq assay. These promising findings implied that D8-T could serve as a great candidate against bladder cancer for further investigation.