- High-level semi-synthetic production of the potent antimalarial artemisinin
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In 2010 there were more than 200 million cases of malaria, and at least 655,000 deaths. The World Health Organization has recommended artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated malaria caused by the parasite Plasmodium falciparum. Artemisinin is a sesquiterpene endoperoxide with potent antimalarial properties, produced by the plant Artemisia annua. However, the supply of plant-derived artemisinin is unstable, resulting in shortages and price fluctuations, complicating production planning by ACT manufacturers. A stable source of affordable artemisinin is required. Here we use synthetic biology to develop strains of Saccharomyces cerevisiae (baker's yeast) for high-yielding biological production of artemisinic acid, a precursor of artemisinin. Previous attempts to produce commercially relevant concentrations of artemisinic acid were unsuccessful, allowing production of only 1.6 grams per litre of artemisinic acid. Here we demonstrate the complete biosynthetic pathway, including the discovery of a plant dehydrogenase and a second cytochrome that provide an efficient biosynthetic route to artemisinic acid, with fermentation titres of 25 grams per litre of artemisinic acid. Furthermore, we have developed a practical, efficient and scalable chemical process for the conversion of artemisinic acid to artemisinin using a chemical source of singlet oxygen, thus avoiding the need for specialized photochemical equipment. The strains and processes described here form the basis of a viable industrial process for the production of semi-synthetic artemisinin to stabilize the supply of artemisinin for derivatization into active pharmaceutical ingredients (for example, artesunate) for incorporation into ACTs. Because all intellectual property rights have been provided free of charge, this technology has the potential to increase provision of first-line antimalarial treatments to the developing world at a reduced average annual price.
- Paddon,Westfall,Pitera,Benjamin,Fisher,McPhee,Leavell,Tai,Main,Eng,Polichuk,Teoh,Reed,Treynor,Lenihan,Jiang,Fleck,Bajad,Dang,Dengrove,Diola,Dorin,Ellens,Fickes,Galazzo,Gaucher,Geistlinger,Henry,Hepp,Horning,Iqbal,Kizer,Lieu,Melis,Moss,Regentin,Secrest,Tsuruta,Vazquez,Westblade,Xu,Yu,Zhang,Zhao,Lievense,Covello,Keasling,Reiling,Renninger,Newman
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p. 528 - 532
(2013/08/25)
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- COMPOSITIONS COMPRISING ARTEMISINIC ACID AND METHODS OF THEIR PREPARATION
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Provided herein are compositions comprising purified artemisinic acid and methods of their preparation. The artemisinic acid can be used, for example, for the preparation of artemisinin, an anti-malaria compound.
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Page/Page column 32-34
(2009/08/14)
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- CONVERSION OF AMORPHA-4,11-DIENE TO ARTEMISININ AND ARTEMISININ PRECURSORS
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The present invention relates to methods for the conversion of amorpha-4,11-diene to artemisinin and various artemisinin precursors.
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Page/Page column 19
(2008/06/13)
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- Cyclic peroxyacetal lactone, lactol and ether compounds
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A process for preparing a compound containing (a) peroxyacetal lactone, (b) peroxyacetal lactol or (c) peroxycacetal ether functionality comprising oxygenating in the presence of one or more oxidizing metal catalysts a compound containing (i) hydroperoxy alkene carboxylic acid, (ii) hydroperoxy alkene aldehyde, (iii) hydroperoxy alkene keto, (iv) hydroperoxy alkene alcohol functionality or (v) dialkyl acetals of compounds in (ii) and (iii) above. For example (I)→(II) wherein n=1,2 or 3; m=0, 1, 2,; p=0, 1, 2 or 3; R5 =--COOH, --C(O)R, --CROH, (α), where R is H, alkyl, aryl or arylalkyl; R1 are independently alkyl, arylalkyl or each R1 together with the group --O--C--O-- to which they are attached form a cyclic acetal; X=CR2 R 3, O, S, SO, SO2 where R2 and R3 are independently selected from H, optionally substituted alkyl, optionally substituted aryl, and wherein when n>1, X is independently selected and can be branched or straight chain and X together with a substituent Y can also form a ring; Y is a substituent selected from H; optionally substituted alkyl or aryl; Y can be on the same C atom as the hydroperoxy group and an y C atom may be disubstituted by Y and includes replacement of H atom(s) in "(CH2)m " by Y; R6 or R 7 is as defined for R above, H, OH, OR1 or together with the carbon atom to which they are attached form a keto group. The present invention is particularly important in its application to the preparation of biologically active compounds comprising the cyclic peroxyacetal lactone or lactol functionalities. One such biologically active compound is qinghaosu (Artemisinin).
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- Method of preparing (+)-deoxoartemisinin and selected analogues of (+)-deoxoartemisinin
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This invention is a new method for preparing compounds useful as antimalarial agents having the formula; STR1 wherein R is hydrogen, a linear, branched or cyclo lower alkyl group having 1 to 8 carbon atoms; aminoalkyl; branched aminoalkyl; hydroxyalkyl: alkylcarboxylate or alkylbenzoate groups having 1 to 5 carbon atoms in the alkyl chains; aryl; alkoxy-substituted aryl; heteroaryl; and pyridinium groups. The method comprises treating artemisinic acid with a methylating agent followed by a stereoselective reduction of the methylated compound, subjecting the reduced compound to a Grignard addition followed by chiral photoxidation with subsequent treatment with a cyclization agent.
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