Special Issue "Artemisinin (Qinghaosu): Commemorative Issue in Honor of Professor Youyou Tu on the Occasion of her 80th Anniversary"

Guest Editor
Dr. Geoff Brown
Department of Chemistry, The University of Reading, Whiteknights, Reading, RG6 6AD, UK
Website: http://www.reading.ac.uk/chemistry/about/staff/g-d-brown.asp
E-Mail:
Interests: *for Molecules specifically*: natural products; terpenes; biosynthesis; autoxidation chemistry; structure determination by NMR spectroscopy; prebiotic chemistry; *for Pharmaceuticals specifically*: natural products; antimalarial drugs; cannabinoids; NMR spectroscopy; metabonomics; oligosacharide structure determination

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Manuscript ID: Molecules-Artemisinin-20090512-Ferreira-us
Type of Paper: Review
Title: Flavonoid and Phenolics Antioxidants from Artemisia annua L. as Potential Synergizers of Artemisinin
Authors: Jorge F.S. Ferreira ^1,*, Davenand Luthria ² , Tomikazu Sasaki ³
Affiliations: ¹ USDA-ARS, Appalachian Farming Systems Research Center, 1224 Airport Rd., Beaver, WV 25813, USA; E-mail: Jorge.Ferreira@ars.usda.gov.
² Davenand Luthria, USDA-ARS, Food Composition and methods Development Lab, 10300 Baltimore Ave,. Bldg 161 BARC-East, Beltsville, MD 20705-2350, USA; E-mail: D.Luthria@ars.usda.gov
³ Department of Chemistry, Box 351700, University of Washington, Seattle, WA 98195-1700, USA; E-mail: sasaki@chem.washington.edu
Abstract: Since artemisinin was established as an active anti-malarial component from a diethyl ether extract of Artemisia annua in 1969, hundreds of papers have been published on the antimalarial effects of artemisinin and its semi-synthetic analogs, mainly dihydroartemisinin, artemether, arteether, and artesunate due to their better stability, higher bioavailability, and higher bioactivity against malaria. In the past decade, this work has been expanded to other bioactivities of artemisinin such as anti-cancer properties. Artemisinin, pharmacokinetics and bioavailability in animals and humans have not be well studied. Few, but growing, studies showing the potential synergistic effects of artemisinin with other compounds such as flavonoids and phenolics produced by A. annua have been reported. The growing idea that multi-component drug therapy might be better than monotherapy is illustrated by the recent resolution of the World Health Organization to support artemisinin-based combination therapies (ACTs), while phasing out monotherapy with artemisinins. In this critical review we will review the composition of phenolic phytochemicals extracted from A. annua. We will discuss the current research suggesting the possibility that artemisinin and its semi-synthetic analogs might become more potent if simultaneously delivered with natural antioxidant components (flavonoids and phenolics) present in A. annua traditional tea preparations and aqueous-alcoholic extracts for the treatment of malaria and other parasitic diseases that afflict humans and animals. These antioxidant molecules have been linked to suppression of the Cyt-P450 enzymes and p-glycoproteins, responsible for altering the absorption and metabolism of artemisinin in the body, and might also have immune modulatory activity in subjects afflicted with parasitic diseases. An approach for optimum extractions of both bioactive classes of phytochemicals (sesquiterpenoids and phenolics) from A. annua will be presented along with a brief discussion on influence of post harvest storage conditions on both groups of bioactive phytochemicals from A. annua.
Keywords: Artemisia annua, artemisinin, crude extracts, synergism, bioavailability, pharmacokinetics, extraction optimization, postharvest processing

Manuscript ID: Molecules- Artemisinin-20090517-Brown-uk
Title: The Biosynthesis of Artemisinin and the Phytochemistry of Artemisia annua L.
Type of Paper: Review
Author: Geoff Brown
Affiliation: Department of Chemistry, The University of Reading, Whiteknights, Reading, RG6 6AD, UK
Abstract: The Chinese medicinal plant Artemisia annua L. (Qinghao) is the only known source of the sesquiterpene, artemisinin (Qinghaosu), that is used in the treatment of malaria. Artemisinin is a highly oxygenated sesquiterpene, containing a unique 1,2,4-trioxane ring structure, which is responsible for the antimalarial activity of this natural product. The phytochemistry of A. annua is dominated by the presence of both sesquiterpenoids and flavonoids, as is the case for many other members of the Compositae family. A. annua is distinguished from other plants in this family, however, by the very large number of natural products which have been characterised (including around fifty amorphane and cadinane sesquiterpenes), as well as by the highly oxygenated nature of many of the terpene secondary metabolites. The discovery of an unusually wide variety of terpenoidal allylic hydroperoxidesfrom this species hasled to the proposal that the biogenesis of many of these highly oxygenated metabolites may be the result of oxidation reactions occurring at the tri-substituted double bond of a terpene precursor. Several studies into the biosynthesis of artemisinin were reported in the 1980’s and 1990’s, all of which required the prior synthesis of one or more sesquiterpene natural product in a radio-isotopically labelled form. These labelled precursors were then fed to either a homogenate or a cell-free preparation which was derived from the plant. Collectively, the results from these experiments were confusing, because they implied that an unfeasibly large number of different sesquiterpenes were all direct precursors to artemisinin. Some of these results were also contradictory, and as a result the complete biosynthetic pathway to artemisinin remained uncertain. More recent experiments, published within the last five years and employing stable isotopically-labelled precursors which were fed to intact A. annua plants, have provided a more conclusive picture of biosynthesis in this species. Thus, it has now been demonstrated that the sesquiterpene dihydroartemisinic acid is a late-stage precursor to artemisinin, while the closely related secondary metabolite, artemisinic acid, is not. In fact, feeding of these two precursors leads to the production of roughly half the sesquiterpenes which are known from A. annua. These experiments provide good circumstantial evidence for the hypothesis that many of the highly oxygenated terpenoids from A. annua arise by oxidation to an allylic hydroperoxide. In the particular case of artemisinin, it has now been shown explicitly by these in vivo experiments (as well as by additional in vitro studies) that the biosynthesis actually proceeds via a tertiary allylic hydroperoxide. Furthermore, there is evidence that the autoxidation of dihydroartemisinic acid to this allylic hydroperoxide is possibly a non-enzymatic process, and that the series of spontaneous rearrangement reactions which then convert the allylic hydroperoxide to the 1,2,4-trioxane ring of artemisinin, are almost certainly non-enzymatic in nature.