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Title: Microbial Metabolism. Part 10. Metabolites of 7,8 Dimethoxyflavone and 5-Methoxyflavone

item HERATH, WIMAL - University Of Mississippi
item MIKELL, JULIE - University Of Mississippi
item KHAN, IKHLAS - University Of Mississippi

Submitted to: Natural Product Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/6/2009
Publication Date: 10/13/2009
Citation: Herath, W., Mikell, J.R., Khan, I.A. 2009. Microbial Metabolism. Part 10. Metabolites of 7,8 Dimethoxyflavone and 5-Methoxyflavone . Natural Product Research. 23(13):1231-1239.

Interpretive Summary: Experiments with human liver microsomes had shown that the fully methylated flavanoids resist oxidative metabolism compared to their partially methylated and unmethylated analogs.13) However, a considerable variation of resistance had been observed among them.8,13) Stability of 7-methoxyflavone for example was increased or decreased by additional methoxy groups. The variation was from highly susceptible 7, 3'-dimethoxyflavone to the more stable 5, 7-dimethoxyflavone.13) The study which had been conducted with 15 flavones indicated the importance of positions rather than the number of methoxy groups towards oxidation.13) This investigation was an attempt to determine the susceptibility of 7, 8-dimethoxyflavone towards metabolism and to identify its metabolites prospectively with microorganisms as predictive models for mammalian drug metabolism. Of the forty microbial cultures screened, many were capable of transforming 1 to a limited number of metabolites with each organism. TLC comparisons of the EtOAc extracts of the culture filtrates showed relatively higher biotransformational efficiency with M. ramannianus yielding all metabolites generated by other organisms. The exception was compound 7, formed with A. flavus. About 25% conversion of 1 to the respective metabolites was observed indicating moderate susceptibility towards oxidative metabolism. It yielded five compounds, 2-6. In compounds 4-7, demethylation occurred at position 7. The 8-position methoxy group however, remained unchanged during all the transformations. 5-Methoxyflavone which was highly resistant to human microsomal oxidation13) underwent transformation to metabolites 9 (7.47 %) and 10 (71.92 %) when fermented with B. bassiana and A. alliaceus respectively.

Technical Abstract: Microbial transformation of 7, 8-dimethoxyflavone (1) by Mucor ramannianus (ATCC 9628) produced five metabolites: 7, 8-dimethoxy-4'-hydroxyflavone (2), 3', 4'-dihydroxy-7, 8-dimethoxyflavone (3), 7, 3'-dihydroxy-8-methoxyflavone (4), 7, 4'-dihydroxy-8-methoxyflavone (5) and 8-methoxy-7, 3', 4'-trihydroxyflavone (6). It was however, completely converted to a single metabolite, 7-hydroxy-8-methoxyflavone (7) by Aspergillus flavus (ATCC 9170). 5-Methoxyflavone (8) when fermented with Beauveria bassiana (ATCC 7159) gave a single product, 5-methoxyflavanone (9). Conversion of 8 with Aspergillus alliaceus (ATCC 10060) yielded the metabolite, 4'-hydroxy-5-methoxyflavone (10). The structures of the compounds, 2-7 and 9-10 were established by spectroscopic methods.