Synthesis and biological evaluation of new geiparvarin derivatives.

New geiparvarin derivatives modified at the unsaturated alkenyloxy bridge, where a hydrogen atom replaces the 3'-methyl group, were synthesized and evaluated against a panel of human tumor cell lines in vitro. These compounds demonstrated an increase in growth inhibitory activity relative to the parent compound, geiparvarin. The activity increased even further in the series of demethylated compounds, with the introduction of a methyl group at the 1'-position of the alkenyloxy chain. In contrast, a remarkable decrease in activity was observed with the introduction of a methyl group at the 2'-position. Interestingly, the new derivatives fully inhibited the growth of drug-resistant cell lines, suggesting that they are not subject to pump-mediated drug efflux. On the basis of their cytotoxic profiles, the most active compounds (R)-4 and (R)-5 were selected for further biological evaluation in comparison with the lead compound. The new derivatives strongly induce apoptosis in a promyelocytic leukemia cell line (HL-60) mediated by depolarization of mitochondrial transmembrane potential and mitochondrial production of reactive oxygen species (ROS).