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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.

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Eleven bisbenzylisoquinoline (BBIQ) alkaloids were studied for in vitro trypanocidal activity against trypomastigote forms of the Y strain of Trypanosoma cruzi. The inhibitory activity of these compounds against trypanothione reductase (TR), a target enzyme for chemotherapy against Chagas disease, was also studied. Six BBIQ alkaloids (antioquine, cepharanthine, daphnoline, limacine, cycleanine and (-) curine) displayed a 50% lethal concentration (LC50) against T. cruzi of less than 100 microM. Daphnoline and curine, with LC50 values of 10 microM, are attractive for further investigation as potential anti-Chagasic drugs. Kinetic analyses suggested the BBIQ alkaloids are mixed inhibitors of TR. These compounds are reasonably potent inhibitors of TR; the best TR inhibitor, cepharanthine, had an IC50 of 15 microM, which is in the same order of magnitude as its LC50 against T. cruzi. The similar magnitudes of the IC50 and LC50 values suggest that inhibition of TR could contribute to the trypanocidal activity exhibited by the BBIQ alkaloids.

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A methanol extract of leaves and twigs from Ardisia iwahigensis demonstrated toxicity toward brine shrimp as well as LNCaP, ZR-75-1, and Lu1 human cancer cells in culture. A novel alkenylphenol, (Z)-1,16-bis(3-hydroxy-5-methoxyphenyl)-10-hexadecene-1,15-dione (ardisenone) (1), was isolated from the extract by bioassay-directed fractionation. This compound demonstrated moderate cytotoxicity against BC1, Lu1, Col2, KB, KB-V1, and LNCaP cell lines.

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Analysis of the alkaloidal fraction of the stem bark extract of Pachygone dasycarpa (Menispermaceae) resulted in the isolation of 10 known bisbenzylisoquinolines, (+)-tetrandrine, (+)-penduline, (+)-fangchinoline, (+)-atherospermoline, (+)-N-methyl-7-O-demethylpeinamine, (+)-daphnoline, (4-)-isotrilobine (1), (+)-cocsuline (2), (+)-tricordatine (3), (+)-2'-norcocsuline, and the new alkaloid (+)-12-O-methyltricordatine (4). The last bisbenzylisoquinoline alkaloid isolated, (+)-angchibangkine (5), is the first member of this alkaloid class found to possess three diphenyl ether bridges in the 7-6',8-7', and 11-12' positions. Structure elucidation of these alkaloids and of (+)-O-methylangchibangkine (6) was achieved by analysis of spectral data. Compounds 4-6 show antiplasmodial activity against Plasmodium falciparum.

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Five bisbenzylisoquinoline (BBI) alkaloids, curine, cycleanine, isotet:andrine, limacine and pheanthine were tested for trypanocidal activity in C 3H He mice infected with Y or CL strain of Trypanosoma cruzi. The activity was compared with the baseline drug, benznidazole. Oral treatment was more effective with curine at 10 mg/kg or with cycleanine at 2 mg/kg daily for 10 days in mice infected with Y or CL strain. In these groups, the parasitemias were negative after 5-7 weeks after inoculation and mortality time 50 (MT(50)) was significantly higher than untreated mice. Benznidazole was effective in mice infected with CL strain but not in mice infected with Y strain. The other BBI showed a relative efficacy against both strains. The effect of BBI alkaloids could be due to a blocking of the Ca2+ channel for the regulation of T. cruzi infectivity to invade host cells or their selective immunosuppressive properties.

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A MeOH extract of Nectandra salicifolia trunk bark, obtained during a diversity-based plant collection in a lower montane rainforest in Costa Rica, showed activity in an in vitro antiplasmodial assay measuring incorporation of [3H]-labeled hypoxanthie by Plasmodium falciparum. In addition to 15 known alkaloids isolated from samples of trunk bark, roots, and leaves/twigs of this species, a new bisbenzylisoquinoline alkaloid (+)-costaricine [(+)-12-O-methyllindoldhamine] (1) was isolated from bark (0.038% yield) and from roots (0.001%). (+)-Costaricine was active in the antiplasmodial assay, with IC50 values of 50 ng/mL vs. the chloroquine-sensitive D6 clone and 294 ng/mL vs. the chloroquine-resistant W2 clone of P. falciparum.

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Continuing studies of the alkaloidal fraction from the roots of Cyclea barbata afforded two new bisbenzylisoquinoline alkaloids, namely, (-)-2'-norlimacine [1] and (+)-cycleabarbatine [2]. The known (+)-tetrandrine-2'-beta-N-oxide [3], for which the configuration of the N-oxide function is now assigned, was identified, as were (+)-berbamine, (-)-repandine, (+)-cycleanorine, (+)-daphnandrine, (-)-curine, (+)-coclaurine, and (-)-N-methylcoclaurine.

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Novel isoquinoline alkaloids were evaluated for their effect on the kinetics of a soybean lipoxygenase type I using linoleic acid as substrate. Some of these alkaloids were found to increase the initial reaction velocity, this property seems related to phenolic groups present in the molecule. The effect of these compounds on the soybean lipoxygenase activity was compared to that of others products which are known to affect this reaction. A reaction mechanism is then proposed: it appeared, in this reaction a correlative structure-activity of phenolic compounds we tested.

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