A series of novel amyl ester tethered dihydroartemisinin-isatin hybrids 4a-d and 5a-h were designed, synthesized, and evaluated as anti-breast cancer agents. The synthesized hybrids were preliminarily screened against estrogen receptor-positive (MCF-7 and MCF-7/ADR) and triple-negative (MDA-MB-231 and) breast cancer cell lines. Three hybrids 4a,d and 5e not only were more potent than artemisinin and adriamycin against drug-resistant MCF-7/ADR and MDA-MB-231/ADR breast cancer cell lines, but also displayed non-cytotoxicity towards normal MCF-10 A breast cells, and the SI values were >4.15, indicating their excellent selectivity and safety profiles. Thus, hybrids 4a,d and 5e could act as potential anti-breast cancer candidates and were worthy of further preclinical evaluations. Moreover, the structure-activity relationships which may facilitate further rational design of more effective candidates were also enriched.
Keywords: breast cancer; dihydroartemisinin; drug resistance; hybrid molecules; isatin.
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