Novel artemisinin derivatives with potent anticancer activities and the anti-colorectal cancer effect by the mitochondria-mediated pathway

Lan Lin; Wenyu Lu; Tianzhi Dai; Huan Chen; Tong Wang; Li Yang; Xuelian Yang; Ying Liu; Dequn Sun

doi:10.1016/j.bioorg.2020.104496

Novel artemisinin derivatives with potent anticancer activities and the anti-colorectal cancer effect by the mitochondria-mediated pathway

Bioorg Chem. 2021 Jan:106:104496. doi: 10.1016/j.bioorg.2020.104496. Epub 2020 Nov 24.

Authors

Lan Lin¹, Wenyu Lu², Tianzhi Dai², Huan Chen³, Tong Wang³, Li Yang³, Xuelian Yang³, Ying Liu⁴, Dequn Sun⁵

Affiliations

¹ School of Life Science and Engineering, Southwest University of Science and Technology, No. 59, Middle Section of Qinglong Avenue, Mianyang 621010, China; Institute of Materials, China Academy of Engineering Physics, Jiangyou 621907, China.
² School of Life Science and Engineering, Southwest University of Science and Technology, No. 59, Middle Section of Qinglong Avenue, Mianyang 621010, China; Marine College, Shandong University at Weihai, No. 180, Wenhua West Road, Weihai 264209, China.
³ School of Life Science and Engineering, Southwest University of Science and Technology, No. 59, Middle Section of Qinglong Avenue, Mianyang 621010, China.
⁴ Institute of Materials, China Academy of Engineering Physics, Jiangyou 621907, China. Electronic address: liuying2016@caep.cn.
⁵ School of Life Science and Engineering, Southwest University of Science and Technology, No. 59, Middle Section of Qinglong Avenue, Mianyang 621010, China. Electronic address: dqsun@swust.edu.cn.

PMID: 33288320
DOI: 10.1016/j.bioorg.2020.104496

Abstract

Many artemisinin derivatives have good inhibitory effects on malignant tumors. In this work, a novel series of artemisinin derivatives containing piperazine and fluorine groups were designed and synthesized and their structures were confirmed by ¹H NMR, ¹³C NMR and HRMS technologies. The in vitro cytotoxicity against various cancer cell lines was evaluated. Among the derivatives, compound 12h was found to exhibit not only the best activity against HCT-116 cells (IC₅₀ = 0.12 ± 0.05 μM), but also low toxicity against normal cell line L02 (IC₅₀ = 12.46 ± 0.10 μM). The mechanisms study revealed that compound 12h caused the cell cycle arrest in G1 phase, induced apoptosis in a concentration-dependent manner, significantly reduced mitochondrial membrane potential, increased intracellular ROS and Ca²⁺ levels, up-regulated the expression of Bax, cleaved caspase-9, cleaved caspase-3, and down-regulated the expression of Bcl-2 protein. A series of analyses confirmed that 12h can inhibit HCT-116 cells migration and induce apoptosis by a mechanism of the mitochondria-mediated pathway in the HCT-116 cell line. The present work indicates that compound 12h may merit further investigation as a potential therapeutic agent for colorectal cancer.

Keywords: Anti-cancer activity; Artemisinin derivatives; Colorectal cancer; Mitochondria-mediated pathway; Piperazine and fluorine groups.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Artemisinins / chemical synthesis
Artemisinins / chemistry
Artemisinins / pharmacology*
Cell Cycle Checkpoints / drug effects
Cell Movement / drug effects
Cell Proliferation / drug effects
Colorectal Neoplasms / drug therapy*
Colorectal Neoplasms / metabolism
Colorectal Neoplasms / pathology
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Mitochondria / drug effects*
Mitochondria / metabolism
Molecular Structure
Structure-Activity Relationship
Tumor Cells, Cultured

Substances

Antineoplastic Agents
Artemisinins
artemisinin