Artemisinins

Interaction of biomolecules with ginghaosu (artemisinin) and its derivatives in the presence of Fe(II) ion—an exploration of antimalarial mechanism 99PAC1139. 

Antimalarial drug artemisinine, sesquiterpenic 8-lactone with 1,2,5-trioxane (endoperoxide) fragment 98CSR273. 

Chemistry and biological activity of artemisinin (sesquiterpene y-lactone with oxepane fragment and transannular peroxide bridge) and related antimalari-als 99H(51)1681. 

Trioxane 210 has been used as a model system by Gu and coworkers to study the antimalarial drug artemisinin 211 (Scheme 137) [97CPL234, 99JST103]. It is the boat/twist form rather than the chair conformer of 210 that describes the subunit in 211. Moreover, geometric parameters and vibrational frequencies can only reliably be computed at the DFT level and by post-Hartree-Fock methods. B3-LYP/6-31G calculations on the conformers of 3,3,6,6-tetramethyl-1,2,4,5-tetroxane show that the chair conformer is stabilized with respect to the twisted conformer by about -2.8 kcal/mol [00JST85]. No corresponding boat conformer was found. 

Artemisinin and its derivatives, artesunate and arthemether, kill both asexual and sexual blood stages (Fig. 2). However, artemisinins are quickly eliminated from the body, resulting in parasite recrudescence, and are therefore combined with schizontocides that have a longer biological half-life, such as amodiaquine,... 

Antiprotozoal Drugs. Figure 5 Artemisinin combination therapy (ACT) Adding a 3-days artesunate course to mefloquine cleats the parasitaemia much more rapidly (A — A). The remaining parasites are exposed to higher mefloquine levels in ACT (B) compared to mefloquine monotherapy (B (with permission White, 1997 Antimicrob Agents Chemother 41 1413-1422). 

Ashley EA, White NJ (2005) Artemisinin-based combinations. Curr Opin Infect Dis 18 531—536... 

Both artemisinin and artemether undergo deoxygenation on treatment with zinc in AcOH <96HCA1475>, but Fe(II) salts rupture the peroxy linkage and lead to rearranged products... 

Phosphorus ylides C-substituted and stabifized by elements of group 16 are often used for the synthesis of natural substances. For example, the synthesis of simpHfied analogs of artemisinin, used against chloroquine-resistant malaria, has been recently described from methoxymethylphosphonium yhde 120 [127,128]. The later is able to convert afiphatic nitriles into a-functionafized ketones 122 which are the precursors of the target compounds. Starting from the aromatic ni-... 

Ryd6n A-M, Kayser O (2007) Chemistry, biosynthesis and biological activity of artemisinin and related natm-al peroxides. 9 1-31... 

Chemistry, Biosynthesis and Biological Activity of Artemisinin and Related Natural Peroxides A.-M. Ryden O. Kayser... 

Alkylation of dianions occurs at the more basic carbon. This technique permits alkylation of 1,3-dicarbonyl compounds to be carried out cleanly at the less acidic position. Since, as discussed earlier, alkylation of the monoanion occurs at the carbon between the two carbonyl groups, the site of monoalkylation can be controlled by choice of the amount and nature of the base. A few examples of the formation and alkylation of dianions are collected in Scheme 1.7. In each case, alkylation occurs at the less stabilized anionic carbon. In Entry 3, the a-formyl substituent, which is removed after the alkylation, serves to direct the alkylation to the methyl-substituted carbon. Entry 6 is a step in the synthesis of artemisinin, an antimalarial component of a Chinese herbal medicine. The sulfoxide serves as an anion-stabilizing group and the dianion is alkylated at the less acidic a-position. Note that this reaction is also stereoselective for the trans isomer. The phenylsulfinyl group is removed reductively by aluminum. (See Section 5.6.2 for a discussion of this reaction.)... 

Scheme 10.6 gives some examples of the Ramberg-Backlund reaction. Entry 1 was used to prepare analogs of the antimalarial compound artemisinin for biological evaluation. The reaction in Entry 2 was used to install the side chain in a synthesis of the chrysomycin type of antibiotic. Entries 3 and 4 are examples of formation of C-glycosides. 

There is an expanding body of evidence to suggest that sesquiterpene lactones inhibit the synthesis NO synthetase. One such compound is an ambrosanolides-type sesquiterpene known as cumanin characterized from Ambrosia psilostachya. This sesquiterpene inhibit the enzymatic activity of NO synthetase with an IC50 value of 9.38 xM (49). Another example is the well-known artemisinin, a sesquiterpene used as an alternative drug in the treatment of severe and multidrug-resistant malaria, which inhibits NO synthesis in cytokine-stimulated human astrocytoma T67 cells (50). 

Aldieri E, Atragene D, Bergandi L, et al. Artemisinin inhibits inducible nitric oxide synthase and nuclear factor NF-kB activation. FEBS Lett 2003 552(2—3) 141—144. 

Besides their essential roles in nature, isoprenoids are of commercial importance in industry. Some isoprenoids have been used as flavors, fragrances, spices, and food additives, while many are used as pharmaceuticals to treat an array of human diseases, such as cancer (Taxol), malaria (artemisinin), and HIV (coumarins). In contrast to the huge market demand, isoprenoids are present only in low abundance in their host organisms. Thus, isolation of the required isoprenoids consumes a large quantity of natural resources. Furthermore, owing to their structural complexity, total chemical synthesis is often not commercially feasible. For these reasons, metabolic engineering may provide an alternative to produce these valuable isoprenoids [88,89]. 

The IPP monomer serves as the universal building block for the production of all isoprenoids, including artemisinine, carotenoids, and Taxol. Thus, an engineered strain with high potential for generating IPP provides a platform for production of a variety of complex isoprenoids. The presence of two IPP synthesis pathways allows two approaches for engineering such strains. One is to introduce a heterozygous pathway and the other is to alter or modify the native pathway. Both approaches have been accomplished in E. coli. 

The entire biosynthesis pathway of artemisinin has not been elucidated yet. The first committed step is conversion of FPP to amorphadiene via the cyclization catalyzed by ADS [102] followed by further oxidations of amorphadiene to artemisinic acid. Artemisinic acid can be used as a precursor for semi-synthesis of artemisinin and related chemicals [88]. 

Mercke, P., Bengtsson, M., Bouwmeester, H.J. etal. (2000) Molecular cloning, expression, and characterization of amorpha-4,11 -diene synthase, a key enzyme of artemisinin biosynthesis in Artemisia annua L. Archives of Biochemistry and Biophysics, 381, 173-180. 

Artemisinin E. amstelodami Cultures were incubated at 500 mg L 1 Residual artemisinin after 5p-Hydroxyartemisinin 7p- [52]... 

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