Design and synthesis of kidjoranin neoglycoside derivatives as potent anticancer agents.

Kidjoranin (1), one of the major C21-steroidal aglycones isolated from Cynanchum otophyllum in our previous work, was used as the substrate for the preparation of a series of 3β-O-neoglycoside derivatives via the CdCO3-mediated Koenigs-Knorr reaction. The resulting compounds were evaluated for cytotoxicity against a panel of human cancer cell lines (MCF-7, HCT-116, HeLa, and HepG2). Among them, compounds 2b, 2l, and 4a displayed significant cytotoxic effects, with IC50 values ranging from 6.00 to 9.41 μM, 2.58 to 3.20 μM, and 3.02 to 4.48 μM, respectively. Preliminary mechanistic studies revealed that compound 4a could induce apoptosis and lead to cell cycle arrest at the S phase in a dose-dependent manner. Furthermore, exploratory molecular docking was also performed to probe possible binding modes of 4a with PI3Kα, STAT3, and Cyclin D1. Collectively, these findings indicate that C-3 glycosylation of kidjoranin may represent a viable approach for developing new anticancer candidates.