Synthesis and biological activities of novel mitochondria-targeted artemisinin ester derivatives

Cangcang Xu; Linfan Xiao; Xia Zhang; Tao Zhuang; Lingli Mu; Xiaoping Yang

doi:10.1016/j.bmcl.2021.127912

Synthesis and biological activities of novel mitochondria-targeted artemisinin ester derivatives

Bioorg Med Chem Lett. 2021 May 1:39:127912. doi: 10.1016/j.bmcl.2021.127912. Epub 2021 Mar 7.

Authors

Cangcang Xu¹, Linfan Xiao¹, Xia Zhang², Tao Zhuang³, Lingli Mu⁴, Xiaoping Yang⁵

Affiliations

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, China.
² Department of Laboratory Medicine, School of Medicine, Hunan Normal University, Changsha, Hunan, China.
³ Systems Biology Theme, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China.
⁴ Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China. Electronic address: moulingli@sina.com.
⁵ Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China. Electronic address: Xiaoping.Yang@hunnu.edu.cn.

PMID: 33691167
DOI: 10.1016/j.bmcl.2021.127912

Abstract

A series of novel artemisinin ester derivatives were designed and synthesized for targeting mitochondria. Cytotoxicity against SMMC-7721, HepG2, OVCAR3, A549 and J82 cancer cell lines was evaluated. Compound 2c (IC₅₀ = 3.0 μM) was the most potent anti-proliferative molecule against the OVCAR3 cells with low cytotoxicity in normal HUVEC cells. The mechanism of action of compound 2c was further investigated by analyzing cell apoptosis, mitochondrial membrane potential (Δψm) and intracellular ROS generation. The results indicated that compound 2c targeted mitochondria and induced cell apoptosis. ROS and heme attributed to the cytotoxicity and cell apoptosis of compound 2c. These promising findings indicated the compound 2c could serve as a great candidate against ovarian cancer for further investigation.

Keywords: Antitumor; Apoptosis; Novel artemisinin ester derivatives; ROS; Δψm.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Artemisinins / chemical synthesis
Artemisinins / chemistry
Artemisinins / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Esters / chemical synthesis
Esters / chemistry
Esters / pharmacology*
Humans
Mitochondria / drug effects*
Mitochondria / metabolism
Molecular Structure
Reactive Oxygen Species / metabolism
Structure-Activity Relationship

Substances

Antineoplastic Agents
Artemisinins
Esters
Reactive Oxygen Species