1. Potent vasorelaxant analogs from chemical modification and biotransformation of isosteviol.
- Author
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Wonganan O, Tocharus C, Puedsing C, Homvisasevongsa S, Sukcharoen O, and Suksamrarn A
- Subjects
- Animals, Aorta metabolism, Cunninghamella chemistry, Cunninghamella metabolism, Diterpenes, Kaurane chemistry, Dose-Response Relationship, Drug, Male, Molecular Conformation, Muscle, Smooth metabolism, Rats, Rats, Sprague-Dawley, Structure-Activity Relationship, Vasodilator Agents chemistry, Aorta drug effects, Diterpenes, Kaurane metabolism, Diterpenes, Kaurane pharmacology, Muscle, Smooth drug effects, Vasodilator Agents metabolism, Vasodilator Agents pharmacology
- Abstract
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., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)
- Published
- 2013
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