No abstract

As part of an ongoing collaborative effort to discover new antimalarial agents from natural sources, we have tested 53 bisbenzylisoquinoline alkaloids for cytotoxicity against cultured mammalian cells and for antiplasmodial activity against chloroquine-sensitive and chloroquine-resistant clones of Plasmodium 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 majority exhibited some degree of cytotoxicity against human KB cells. More than half of the compounds tested, however, showed selective antiplasmodial activity, with >100-fold greater toxicity toward one or both of the P. falciparum clones, relative to cultured mammalian cells. The most selective alkaloids 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 stereochemistry, and the substitution patterns of these alkaloids and their in vitro antiplasmodial and cytotoxic activities are beginning to emerge.

Anew member of the naphthalene-isoquinoline series of alkaloids, ancistrotectorine (2), has been isolated from the leaves of the Thai medicinal plant Ancistrocladus tectorius (Ancistrocladaceae). The structure was deduced through single crystal X-ray crystallography and complete 'H-nmr spectroscopic assignments were made. Ancistrotectorine (2) is the second member of the 7,3 -linked naphthalene-isoquinoline alkaloid group to be isolated.Ancistrocladus is the only genus of the plant family Ancistrocladaceae and is composed of nearly 20 species distributed in tropical Asia, Malayasia, and West Africa (2). The genus is a source, together with two genera in the Dionchophyllaceae, of the naphthalene-isoquinoline group of alkaloids (3,4). Eighteen alkaloids in this series have been isolated to date, and the compounds may be grouped according to the location of the -bond joining the two units. Most of the alkaloids (ten) are linked 5-1' (5-12), whilst seven others are linked 7-1' (9, 13-15). The remaining alkaloid, ancistrocladidine (1) from Ancistrocladus heyneanus Wall. ( 16), is linked 7-3', and the crystallographic analysis of this alkaloid was recently presented (17). We report here the structure determination of a second alkaloid having a 7-3' linkage, ancistrotectorine (2) from the leaves of Ancistrocladus tectorius (Lour.) Merr.Previous work on the stem and twigs of A. tectorius has yielded ancistrocladeine (10), ancistrocladine (12), hamatine (12), and ancistrocline (12), subsequent to a demonstration that the species contained alkaloids (18). The roots of A. tectorius have been used to treat dysentery and malaria.After partition of the EtOH extract, the CHC13 fraction was chromatographed on alumina to afford ancistrotectorine (0.016% yield). From its uv spectrum, which displayed Xmax 234, 286, 306, 323, and 337 nm, ancistrotectorine was a member of the 'For the previous paper in this series see Mukhopadhyay et al. (1).

Gedunin from Cedrela odorata (Meliaceae), a potent in vitro antimalarial agent, was investigated for its in vivo efficacy in CD-1 mice infected with Plasmodium berghei. When orally administered at 50 mg kg -1 day -1 for 4 days, gedunin was able to suppress the parasitaemia level by 44%. However, no clear dose-response effects were observed in the 0-100 mg kg -1 day -1 dose range. Preliminary pharmacokinetics in Sprague-Dawley rats showed poor absorption. However, a binary treatment of 50 mg kg -1 day -1 gedunin with 25 mg kg -1 day -1 dillapiol, a cytochrome P450 inhibitor, increased parasitaemia clearance in mice to 75%. A clear dose-response was observed in the 0-50 mg kg -1 day -1 gedunin dose range when administration was combined with 25 mg kg -1 day -1 dillapiol. In addition, 7methoxygedunin, a semi-synthetic derivative which is more stable to degradation than gedunin, suppressed the level in mice by 67% at 50 mg kg -1 day -1 . When administered at this dose in combination with 25 mg kg -1 day -1 dillapiol, clearance increased to 80%. These results demonstrate the potential efficacy of antimalarial drugs and phytomedicines based on gedunin and the value of the combination therapy.