Identification of intermediates and enzymes involved in the early steps of artemisinin biosynthesis in Artemisia annua.

An important group of antimalarial drugs consists of the endoperoxide sesquiterpene lactone artemisinin and its derivatives. Only little is known about the biosynthesis of artemisinin in Artemisia annua L., particularly about the early enzymatic steps between amorpha-4,11-diene and dihydroartemisinic acid. Analyses of the terpenoids from A. annua leaves and gland secretory cells revealed the presence of the oxygenated amorpha-4,11-diene derivatives artemisinic alcohol, dihydroartemisinic alcohol, artemisinic aldehyde, dihydroartemisinic aldehyde and dihydroartemisinic acid. We also demonstrated the presence of a number of biosynthetic enzymes such as the amorpha-4,11-diene synthase and the--so far unknown--amorpha-4,11-diene hydroxylase as well as artemisinic alcohol and dihydroartemisinic aldehyde dehydrogenase activities in both leaves and glandular trichomes. From these results, we hypothesise that the early steps in artemisinin biosynthesis involve amorpha-4,11-diene hydroxylation to artemisinic alcohol, followed by oxidation to artemisinic aldehyde, reduction of the C11-C13 double bond to dihydroartemisinic aldehyde and oxidation to dihydroartemisinic acid.

Occurrence, biological activity and synthesis of drimane sesquiterpenoids.

In this review the names, structures and occurrence of all new drimanes and rearranged drimanes which have been published between January 1990 and January 2003 have been collected. Subjects that have been treated are biosynthesis, analysis, biological activities, with special attention to cytotoxic activity and antifeedant and insecticidal activity and mode of action. An important part of the review deals with the synthesis of drimanes. This part has been subdivided into syntheses by transformation of natural products, syntheses starting from chiral compounds obtained by enzymatic resolution, syntheses by cationic polyolefin cyclizations, syntheses from trans-decalones, syntheses by radical cyclizations and syntheses by cycloaddition reactions. The review contains about 350 references.