title: Potent vasorelaxant analogs from chemical modification and biotransformation of isosteviol.
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.
authors: Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok 10240, Thailand.
authors: Orawan
authors: O
authors: Wonganan
authors: Chainarong
authors: C
authors: Tocharus
authors: Chonticha
authors: C
authors: Puedsing
authors: Sureeporn
authors: S
authors: Homvisasevongsa
authors: Oratai
authors: O
authors: Sukcharoen
authors: Apichart
authors: A
authors: Suksamrarn
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism; D020093:Cunninghamella / Q000737:chemistry / Q000378:metabolism; D045786:Diterpenes, Kaurane / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D008968:Molecular Conformation; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014665:Vasodilator Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D045786:Diterpenes, Kaurane; D014665:Vasodilator Agents; C515747:isosteviol