Arabian Journal of Chemistry (Nov 2022)
Discovery of 29-O-acyl-toosendanin-based derivatives as potent anti-cancer agents
Abstract
Structural modification of natural products is an effective strategy to discover potent lead compounds with improved medicinal performance. Toosendanin (TSN), a natural limonoid with diverse pharmacological properties, was selected as the starting material for structural modification to obtain more active anti-cancer agents in the current study. A library containing 25 structurally diverse derivatives (including 12 new ones) were constructed on the basis of the structure-guided modification of TSN. Subsequent cytotoxic assay of this library discovered that compounds 14, 18, and 25 showed more significant antiproliferative activity than the precursor TSN in MDA-MB-468 cell model and so as compounds 14, 17–19, 21, and 25 in Hela cell model. Among them, the new derivative 29-O-(6-chloronicotinoyl)-toosendanin (25) exhibited the most potent antiproliferative activity (IC50s 0.05–0.06 μM), being more active than TSN (IC50s 0.14–0.24 μM) and even the first-line drug adriamycin (IC50s ∼ 0.07 μM) in both tested cancer cell lines. The SARs study uncovered that the hemiacetal group, the 14,15-epoxy ring, 1-OH, 7-OH, 3-OAc, and 12-OAc were viewed as the essential active groups and the 29-OH was the critically active modification position of TSN for the enhancement of cytotoxicity. The discovering of 25 from TSN-based derivatives might serve as a lead compound for anti-cancer chemotherapy, which may shed light on rationally design TSN-based derivatives for obtaining more potent anti-tumor agents.