Thirty-three benzophenanthridine alkaloid derivatives (1a-1u and 2a-2l) were synthesized, and their cytotoxic activities against two leukemia cell lines (Jurkat Clone E6-1 and THP-1) were evaluated in vitro using a Cell Counting Kit-8 (CCK-8) assay. Nine of these derivatives (1i-l, 2a, and 2i-l) with IC50 values in the range of 0.18-7.94 μM showed significant inhibitory effects on the proliferation of both cancer cell lines. Analysis of the primary structure-activity relationships revealed that different substituent groups at the C-6 position might have an effect on the antileukemia activity of the corresponding compounds. In addition, the groups at the C-7 and C-8 positions could influence the antileukemia activity. Among these compounds, 2j showed the strongest in vitro antiproliferative activity against Jurkat Clone E6-1 and THP-1 cells with good IC50 values (0.52 ± 0.03 μM and 0.48 ± 0.03 μM, respectively), slightly induced apoptosis, and arrested the cell-cycle, all of which suggests that compound 2j may represent a potentially useful start point to undergo further optimization toward a lead compound.
Keywords: Zanthoxylum nitidum; antileukemia activity; benzophenanthridine alkaloid derivatives; cell cycle and apoptosis; synthesis.