AUTHOR=Wang Ruo , Huang Renhong , Yuan Yaofeng , Wang Zheng , Shen Kunwei 

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

JOURNAL=Frontiers in Molecular Biosciences

VOLUME=10

YEAR=2023

URL=https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2023.1293763

DOI=10.3389/fmolb.2023.1293763

ISSN=2296-889X

ABSTRACT=<p>Eleven two-carbon tethered artemisinin–isatin hybrids (<bold>4a–k</bold>) 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 <bold>4a</bold> (IC<sub>50</sub>: 2.49–12.6 <italic>µ</italic>M) was superior to artemisinin (IC<sub>50</sub>: 72.4-&gt;100 <italic>µ</italic>M), dihydroartemisinin (IC<sub>50</sub>: 69.6–89.8 <italic>µ</italic>M), and Adriamycin (IC<sub>50</sub>: 4.46–&gt;100 <italic>µ</italic>M) 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 <italic>in silico</italic> studies were used to investigate the mechanism of the most promising hybrid <bold>4a</bold>. Target prediction, bioinformatics, molecular docking, and molecular dynamics revealed that the most promising hybrid <bold>4a</bold> may exert anti-breast cancer activity by acting on multiple targets such as <italic>EGFR</italic>, <italic>PIK3CA</italic>, and <italic>MAPK8</italic> and thus participating in multiple tumor-related signaling pathways.</p>