Microbial transformation of isosteviol and bioactivities against the glucocorticoid/androgen response elements.
Preparative-scale fermentation of isosteviol ( ent-16-oxobeyeran-19-oic acid) (1) with Mucor recurvatus MR 36, Absidia pseudocylindrospora ATCC 24169, and Aspergillus niger BCRC 32720 afforded nine known metabolites ( 2, 3, 5-10, and 14) and nine new metabolites ( 4, 11-13, and 15-19). The reactions involved stereoselective introduction of OH groups at positions C-1, -6, -7, -9, -11, -12, -15, and -17 as well as further ketonization at the C-1 and C-7 positions. The structures of the metabolites were established on the basis of 1D and 2D NMR and IR supported by HRFABMS. GRE (glucocorticoid response element)- and ARE (androgen response element)-mediated luciferase reporter gene assays were used to screen for the biological activities of 1 and its metabolites. Compounds 7, 13, 16, and 18 showed significantly enhanced GRE-mediated luciferase activity, but at levels less than that induced by either methylprednisolone or dexamethasone. On the other hand, compounds 3, 4, 12, 13, 14, and 18 showed significant effects on ARE-mediated luciferase activity; in particular, 3, 12, 14, and 18 were more active than testosterone.
Chang
Shwu-Fen
SF
Department of Medicinal Chemistry, College of Pharmacy, Taipei Medical University, Taiwan, Republic of China.
Yang
Li-Ming
LM
Lo
Chia-Hsin
CH
Liaw
Jia-Horng
JH
Wang
Li-Hsuan
LH
Lin
Shwu-Jiuan
SJ
D020095:Absidia / Q000378:metabolism; D000818:Animals; D001234:Aspergillus niger / Q000378:metabolism; D001711:Biotransformation; D045786:Diterpenes, Kaurane / Q000737:chemistry / Q000378:metabolism*; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D015394:Molecular Structure; D009089:Mucor / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D011944:Receptors, Androgen / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism
D045786:Diterpenes, Kaurane; D011944:Receptors, Androgen; D011965:Receptors, Glucocorticoid; C515747:isosteviol; D013739:Testosterone; D008156:Luciferases