Using an ethnobotanical approach in combination with in vivo-guided fractionation as a means for lead discovery, cryptolepine was isolated as an antihyperglycemic component of Cryptolepis sanguinolenta. Two syntheses of cryptolepine, including an unambiguous synthesis, are reported. The hydroiodide, hydrochloride, and hydrotrifluoromethanesulfonate (hydrotriflate) salts of cryptolepine were synthesized, and a comparison of their spectral properties and their in vitro activities in a 3T3-L1 glucose transport assay is made. Cryptolepine and its salt forms lower blood glucose in rodent models of type II diabetes. While a number of bioactivities have been reported for cryptolepine, this is the first report that cryptolepine possesses antihyperglycemic properties.

In vivo bioassay-guided fractionation of the aqueous alcohol extract of the aerial parts of Bidens pilosa Sch. Bip. var. radiata (Asteraceae) using C57 BL/Ks-db/db mice as a model for type 2 diabetes, yielded two known polyacetylenic glucosides, identified as 2-beta-D-glucopyranosyloxy-1-hydroxy-5(E)-tridecene-7,9,11-+ ++triyne (1) and 3-beta-D-glucopyranosyloxy-1-hydroxy-6(E)-tetradecene-8,10,1 2-triyne (2). A 3:2 mixture of compounds 1 and 2 effected a significant drop in blood glucose.

Evidence has been published that a wide array of plant-derived active principles, representing numerous classes of chemical compounds, demonstrate activity consistent with their possible use in the treatment of patients with Type 2 diabetes mellitus (DM). Despite these interesting observations, to date, metformin is the only ethical drug approved for treatment of Type 2 DM derived from a medicinal plant. Why is this so, given the fact that higher plants are such a potential source of new drugs? The answer to this rhetorical question may lie in the reliance of most pharmaceutical companies on random, in vitro, mechanism-based, high throughput screening in the initial phases of plant drug research. In this article we describe an alternative pathway to discovery of drugs for the treatment of Type 2 DM: on based on an ethnomedical approach, involving ethnobotany and traditional medicine. In particular, we present evidence that cryptolepine, an indoloquinolone alkaloid isolated from Cryptolepis sanguinolenta, significantly lowers glucose when given orally to a mouse model of diabetes. The antihyperglycaemic effect of cryptolepine leads to a significant decline in plasma insulin concentration, associated with evidence of an enhancement in insulin-mediated glucose disposal. Finally, cryptolepine increases glucose uptake by 3T3-L1 cells. These data permit us to conclude that an ethnobotanical approach to drug discovery can identify a potentially useful drug for the treatment of Type 2 DM.

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