Antiplasmodial and cytotoxic activity of natural bisbenzylisoquinoline alkaloids

As part of an ongoing collaborative effort to discover new antimalarial age nts from natural sources, we have tested 53 bisbenzylisoquinoline alkaloids for cytotoxicity against cultured mammalian cells and for antiplasmodial a ctivity against chloroquine-sensitive and chloroquine-resistant clones of P lasmodium falciparum. The isolates from Cyclea barbata, Stephania pierrei, Stephania erecta, Pachygone dasycarpa, Cyclea atjehensis, Hernandia peltata , Curare candicans, Albertisia papuana, and Berberis valdiviana exhibited a wide range of biological potencies in antiplasmodial assays, and the major ity exhibited some degree of cytotoxicity against human KB cells. More than half of the compounds tested, however, showed selective antiplasmodial act ivity, with > 100-fold greater toxicity toward one or both of the P. falcip arum clones, relative to cultured mammalian cells. The most selective alkal oids were (-)-cycleanine (40), (+)-cycleatjehine (50), (+)-cycleatjehenine (49), (+)-malekulatine (3), (-)-repandine (13), and (+)-temuconine (2). As a result of these studies; relationships between the structures, the stereo chemistry, and the substitution patterns of these alkaloids and their in vi tro antiplasmodial and cytotoxic activities are beginning to emerge.