Unlocking the potential of icaritin derivatives: Synthesis, characterization, and antiproliferative activity against MCF-7 breast cancer cells

Natural products serve as ideal templates for drug development, and screening compounds derived from natural products has been a prominent and viable approach for discovering new drugs, especially in the field of cancer treatment. Icaritin (ICT), a prenylated flavonol glycoside natural product, has demonstrated significant anti-breast cancer activity. In this study, we used ICT as a template to chemically synthesize 16 icariin derivatives and evaluated their effects on the proliferation of the human breast cancer cell line MCF-7 using the CCK-8 assay. Eight of these compounds exhibited significant antitumor activity (IC50 < 20 μM), with the most potent compounds being T14 (IC50 = 2.69 ± 0.28 μM) and T16 (IC50 = 4.72 ± 0.63 μM). Through a structure-activity relationship (SAR) study of ICT, we determined the key features for ICT's in vitro anti-breast cancer activity: the presence of the 8-prenyl group is not essential for activity; the 7-OH group is crucial for activity; replacing the 6-H with a Minnich base enhances activity; acetylation of the 7-OH, 5-OH, and 3-OH groups significantly increases activity; and the nature of the substituent at the 3-OH group plays a critical role in activity, with even minor changes to the substituent having a significant impact on activity.