Fungal Transformation of Artemisinin

Date Added: February 04, 2009 05:57:55 AM

Author: Anonymous

Artemisinin is a naturally occurring a sesquiterpene lactone that provides anti-malarial activity when used against chloroquine-resistant parasites. In our efforts to produce rationally designed anti-malarial agents, we have focused on substitution of a methylene position of the artemisinin skeleton, heretofore difficultly accessed positions of modification. We have identified and exploited the ability of various microorganisms from different genres to transform artemisinin and 10-deoxyartemisinin. These microorganisms were grown in 2,500 mL flasks, each containing 500 mL of Sabouraud-dextrose/peptone medium at 28°C while shaking at 180 rpm. After 48 hours, the cultures were dosed with artemisinin (or 10-deoxyartemisinin) to a final concentration of 500 mg/mL and returned to the incubators (using the afore-mentioned conditions) for 15 days. High-performance liquid chromatography (HPLC) revealed both artemisinin- and 10-deoxyartemisinin-containing cultures were each transformed to a major metabolite by a single fungus from family Cunninghamellaceae. Samples were collected using semi-preparative HPLC, and the metabolites were identified using electrospray ionization mass spectra (LC/ESI/MS) and proton nuclear magnetic resonance (NMR) spectra. HPLC analysis of the ethyl acetate extract from cultures dosed with artemisinin showed the major metabolite at 13.8 min. LC/ESI/MS and NMR analysis showed the transformation product to be a enantioselectively formed hydroxyl metabolite of artemisinin, 89.6 % of total peak area, [MH]+ = m/z 299. HPLC analysis of the ethyl acetate extract from cultures dosed with 10-deoxoartemisinin showed the major metabolite at 13.5 min. LC/ESI/MS and NMR analysis showed the transformation product to be a hydroxy-10-deoxyartemisinin, 92.8 % of total peak area, [MH]+ = m/z 285. The hydroxy-derivatives of artemisinin and 10-deoxyartemisinin biotransformations have valuable pharmaceutical properties, also quantitative structure-activity relationships studies suggest that steric bulk on the b-face of artemisinin will likely increase anti-malarial activity.

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