Two-carbon tethered artemisinin-isatin hybrids: design, synthesis, anti-breast cancer potential, and in silico study

Ruo Wang; Renhong Huang; Yaofeng Yuan; Zheng Wang; Kunwei Shen

doi:10.3389/fmolb.2023.1293763

Two-carbon tethered artemisinin-isatin hybrids: design, synthesis, anti-breast cancer potential, and in silico study

Front Mol Biosci. 2023 Oct 19:10:1293763. doi: 10.3389/fmolb.2023.1293763. eCollection 2023.

Authors

Ruo Wang^#¹, Renhong Huang^#¹, Yaofeng Yuan², Zheng Wang¹, Kunwei Shen¹

Affiliations

¹ Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Laboratory of Molecule Synthesis and Function Discovery (Fujian Province University), Department of Chemistry, Fuzhou University, Fuzhou, China.

^# Contributed equally.

Abstract

Eleven two-carbon tethered artemisinin-isatin hybrids (4a-k) were designed, synthesized, and evaluated for their antiproliferative activity against MCF-7, MDA-MB-231, and MDA-MB-231/ADR breast cancer cell lines, as well as cytotoxicity toward MCF-10A cells in this paper. Among them, the representative hybrid 4a (IC₅₀: 2.49-12.6 µM) was superior to artemisinin (IC₅₀: 72.4->100 µM), dihydroartemisinin (IC₅₀: 69.6-89.8 µM), and Adriamycin (IC₅₀: 4.46->100 µM) against the three tested breast cancer cell lines. The structure-activity relationship revealed that the length of the alkyl linker between artemisinin and isatin was critical for the activity, so further structural modification could focus on evaluation of the linker. The in silico studies were used to investigate the mechanism of the most promising hybrid 4a. Target prediction, bioinformatics, molecular docking, and molecular dynamics revealed that the most promising hybrid 4a may exert anti-breast cancer activity by acting on multiple targets such as EGFR, PIK3CA, and MAPK8 and thus participating in multiple tumor-related signaling pathways.

Keywords: artemisinin; breast cancer; drug resistance; hybrid molecules; in silico study; isatin.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by the National Natural Science Foundation of China (82002773 and 82072897).