Microbial metabolism of artemisitene
Introduction
Artemisitene (1), an endoperoxide closely related to the known antimalarial sesquiterpene artemisinin (2), is a minor constituent of Artemisia annua (Asteraceae) (Acton & Klayman, 1985). Metabolism studies have traditionally used model systems to predict metabolic fates in humans. Microorganisms, particularly fungi, have been used successfully as in vitro models for the prediction of mammalian drug metabolism (Smith & Rosazza, 1975a, Smith & Rosazza, 1975b, Smith & Rosazza, 1982, Kieslich, 1976, Rosazza & Smith, 1979, Clark & Hufford, 1979, Clark & Hufford, 1991, Clark, McChesney, & Hufford, 1985). It is anticipated that the microbial metabolism of artemisitene (1) would produce significant quantities of metabolites that would be difficult to obtain from either animal systems or chemical synthesis. This work may also provide some new analogs that may serve as prospective candidates for antimalarial evaluation or as starting compounds for the semi-synthesis of other derivatives. This note reports on the microbial transformation of artemisitene (1) and the isolation and characterization of its metabolites.
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Results and discussion
Screening-scale studies of artemisitene (1) have shown that A. niger (NRRL 599) was the most efficient microorganism to metabolize this sesquiterpene into three metabolites. A preparative-scale fermentation was performed using artemisitene (1) as a substrate and compounds 3, 4 and 5 were isolated and purified by flash chromatography.
In metabolite 3, C15H22O5, the reduction of the olefinic carbons, C-11 and C-13, was established from the NMR data. It was observed that the C-13 methyl group
General
M.p.'s were determined in open capillary tubes using an Electrothermal 9100 capillary melting-point apparatus and are uncorr. IR spectra were recorded in KBr using a PYE Unicam infrared spectrophotometer and specific rotations were obtained at amb. temp. on a Perkin-Elmer digital polarimeter model 241MC. The and NMR spectra were obtained in CDCl3 on a Bruker DRX-500 NMR spectrometer operating at 500 and 125 MHz, respectively. The chemical shift values are reported as ppm referenced to
Acknowledgements
The authors thank Dr. Charles D. Hufford, School of Pharmacy, The University of Mississippi for recording the NMR spectra and Dr. Larry A. Walker of the National Center for the Development of Natural Products, The University of Mississippi, for evaluating the antimalarial activity.
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