Design of semisynthetic derivatives of the Amaryllidaceae alkaloid ambelline and exploration of their in vitro cytotoxic activities

Abstract

Ambelline, an alkaloid from the Amaryllidaceae family with a crinane-type skeleton, has not yet demon-strated any outstanding biological activity. However, its analogues prepared by derivatization of the C-11 hydroxyl group show different interesting effects. Continuing our earlier work, twelve novel aromatic esters were developed (10, 14, 16, 17, 22-25, 30-33) and studied, together with previously synthesized derivatives (2-9, 11-13, 15, 18-21, 26-29) in terms of their cytotoxic activity. The cytotoxic potential was determined on a panel of nine human cancer cell lines and one noncancerous cell line to characterize their biological activity spectrum. To describe and foresee the structure-activity relationship for further research, substances synthesized and described in our previous work were also included in this cytotox-icity study. The most significant activity was associated with analogues having methyl (10), methoxy (14-17), or ethoxy (18) substitution on the phenyl condensed to ambelline. However, the 4-chloro-3-nitrobenzoyl derivative (32) showed the most promising IC50 values, ranging from 0.6 ± 0.1 μM to 9.9 ± 0.2 μM. In vitro cytotoxicity studies indicated the most potent antiproliferative activity of 32 in a dose -dependent and time-dependent manner. Besides, 32 was found to be effective in decreasing viability and triggering apoptosis of MOLT-4 T-lymphoblastic leukemia cells.