In vivo transformations of dihydro-epi-deoxyarteannuin B in Artemisia annua plants

Abstract

[15-13C2H3]-dihydro-epi-deoxyarteannuin B (4a) has been fed to intact Artemisia annua plants via the root and three labeled metabolites (17a-19a) have been identified by 1D- and 2D-NMR spectroscopies. The in vivo transformations of 4a in A. annua are proposed to involve enzymatically-mediated processes in addition to possible spontaneous autoxidation. In the hypothetical spontaneous autoxidation pathway, the tri-substituted double bond in 4a appears to have undergone 'ene-type' reaction with oxygen to form an allylic hydroperoxide, which subsequently rearranges to the allylic hydroxyl group in the metabolite 3α-hydroxy-dihydro-epi-deoxyarteannuin B (17a). In the enzymatically-mediated pathways, compound 17a has then been converted to its acetyl derivative, 3α-acetoxy-dihydro-epi-deoxyarteannuin B (18a), while oxidation of 4a at the 'unactivated' 9-position has yielded 9β-hydroxy-dihydro-epi-deoxyarteannuin B (19a). Although all of the natural products artemisinin (1), arteannuin K (7), arteannuin L (8), and arteannuin M (9) have been suggested previously as hypothetical metabolites from dihydro-epi-deoxyarteannuin B in A. annua, none were isolated in labeled form in this study. It is argued that the nature of the transformations undergone by compound 4a are more consistent with a degradative metabolism, designed to eliminate this compound from the plant, rather than with a role as a late precursor in the biosynthesis of artemisinin or other natural products from A. annua. © 2007 Elsevier Ltd. All rights reserved.