Potent vasorelaxant analogs from chemical modification and biotransformation of isosteviol

Isosteviol (1) has been reported to exhibit moderate vasorelaxant activity. In order to enhance the bioactivity of this compound, chemical modification of 1 to the dihydro analog, ent-16β-hydroxybeyeran-19-oic acid (2), was undertaken. Compound 2 was then converted to the corresponding acetate derivative, ent-16β-acetoxybeyeran-19-oic acid (3). Biotransformation of compounds 1–3 by the fungus Cunninghamella echinulata NRRL 1386 was investigated and the metabolites 4–9 were obtained. The substrates and their metabolites were subjected to in vitro rat aorta relaxant activity evaluation. The metabolite 4, ent-7α-hydroxy-16-ketobeyeran-19-oic acid, exhibited the most highly potent activity, with EC50 of 3.46 nM, whereas the parent compound 1 showed relatively low activity (EC50 57.41 nM). A 17-fold increase in vasorelaxant activity of the analog 4 relative to compound 1 is of particular significant. Compound 4 exerted vasorelaxant activity at particularly low concentration and the vasorelaxant profile reached maximum at relatively low concentration, especially when compared with acetylcholine, the positive control.

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► Chemical modification and microbial transformation of isosteviol gave eight analogs.
► Some of the modified compounds showed superior vasorelaxant activity on rat aortic ring.
► The 7-hydroxylated analog exhibited the most potent activity.
► It was 17-fold more active than the parent compound, isosteviol.