Microbial Transformation of Isosteviol Lactone and Evaluation of the Transformation Products on Androgen Response Element

Abstract

Two filamentous fungi, Cunninghamella bainieri ATCC 9244 and Aspergillus niger BCRC 32720, were used to investigate the biotransformation of isosteviol lactone (4alpha-carboxy-13alpha-hydroxy-13,16- seco-ent-19-norbeyeran-16-oic acid 13,16-lactone) ( 2), which was derived by reacting isosteviol ( ent-16-oxobeyeran-19-oic acid) ( 1) with m-chloroperbenzoic acid. Incubation of 2 with C. bainieri afforded metabolites 3- 6, which involved isomerization, hydroxylation, and ring cleavage reactions followed by oxidation and selective O-methylation. Incubation of 2 with A. niger afforded mono-, di-, and trihydroxylated metabolites 3, 4, and 7- 12. The structures of 3- 12 were elucidated on the basis of spectroscopic analyses, and structures 3, 4, and 6 were confirmed by X-ray crystallographic studies. Compounds 2- 6, 8- 10, and 12 were assayed as androgen agonists using an ARE (androgen response element)-mediated luciferase reporter gene assay. Compounds 3, 6, and 10 were significantly active, with 6 showing more activity than testosterone.

Fungal transformation of isosteviol lactone and its biological evaluation for inhibiting the AP-1 transcription factor

“…Compounds 9-14 have not previously been reported. The results indicated that these three selected fungal strains also possess the characteristics of reaction selectivity on the ent-beyerane skeleton as we previously reported Chou et al, 2008). The reactions involved not only isomerization of the lactone ring but also regio-and stereoselective hydroxylation.…”

“…In a continuing investigation of the microbial transformation of isosteviol lactone (2) (Chou et al, 2008), the bioconversion of 2 with Mucor recurvatus, Aspergillus niger, and Absidia pseudocylindrospora was undertaken and led to isolation of compounds 3-14 ( Fig. 1).…”

“…niger afforded the five known compounds 1, 4, and 6-8. The structures of known metabolites were determined by comparison of the NMR spectroscopic data with values in the literature (de Oliveira and Strapasson, 1996;Chou et al, 2008). On the other hand, incubation of 2 with Abs.…”

“…Ghisalberti (1997) indicated that some highly oxygenated diterpenoids usually have higher levels of biological activity than their less-hydroxylated precursors. Previously, we studied the microbial transformation of 2 and evaluated the transformation products on the androgen response element (Chou et al, 2008).…”

Bioactivity Profile of the Diterpene Isosteviol and its Derivatives

“…This is the first finding to prove that stevioside may protect tumor promoting potency from microbiological products [41,118]. Thus, the microbial transformation is a significant technique for structurally modifying natural and synthetic compounds due to its significant regio- and stereoselectivities [119,120,121,122]. Fungi are widely used in microbial transformation studies since their versatile enzymatic reservoir allows them to modify a diverse array of molecules [119,120,121].…”