- Chemical and electro-chemical reduction of qinghaosu (artemisinin)
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1,2,4-Trioxane is the essential segment of the new antimalarial agent qinghaosu 1, and hence its reduction is an important plausible process related to the bio-activity mode. An overview of its reduction and a careful examination of some reducing systems are presented herewith. Electrochemical reduction is a two-electron reduction, which is confirmed by the isolation of product deoxyqinghaosu. However, in the presence of a catalytic amount of FeII/III electrochemical reduction yields mainly the single-electron-reduction products, which are identified with the products from reduction of qinghaosu with one equivalent ferrous sulfate or a catalytical amount of FeII/III and excess of other reducing agents, such as ascorbic acid, or cysteine. These results mean that qinghaosu is reduced by ferrous ion and the resulting ferric ion is then reduced on the electrode to regenerate ferrous ion. In addition, qinghaosu could be reduced to deoxyqinghao by iodide, but not by bromide, and also could be reduced by the ascorbic acid-CuSO4 system to give free-radical reaction products. The Royal Society of Chemistry 2000.
- Wu, Wen-Min,Wu, Yu-Lin
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- Ferrous ion induced cleavage of the peroxy bond in qinghaosu and its derivatives and the DNA damage associated with this process
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In the presence of iron(II) the peroxy bridge of the drug qinghaosu and its derivatives are cleaved to give two major rearrangement products; DNA damage due to this free radical process is observed and may be responsible for the antimalarial activity of these compounds.
- Wu, Wen-Min,Yao, Zhu-Jun,Wu, Yu-Lin,Jiang, Kun,Wang, Yan-Fang,Chen, Hai-Bao,Shan, Feng,Li, Ying
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- A novel ketone derivative of artemisinin biotransformed by Streptomyces griseus ATCC 13273
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A novel ketone derivative of artemisinin, artemisitone-9, was produced by the biotransformation of cultured Streptomyces griseus ATCC 13273. The structure of the ketone product was fully elucidated by various spectroscopic techniques, and the mechanism of generating such novel metabolite is also discussed.
- Liu, Ji-Hua,Chen, You-Gen,Yu, Bo-Yang,Chen, Yi-Jun
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- A possible antimalarial action mode of qinghaosu (artemisinin) series compounds. Alkylation of reduced glutathione by C-centered primary radicals produced from antimalarial compound qinghaosu and 12-(2,4-dimethoxyphenyl)-12-deoxoqinghaosu
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Antimalarial compound qinghaosu (1) and its phenyl derivative 2 were reacted with reduced glutathione (GSH) and Fe(II/III) to give, besides other known degradation products, an interesting adduct from a primary C-centered free radical and GSH. Because GSH plays a very important role in the cell cycle, this finding may eventually lead to a new understanding of its mode of action.
- Wang,Wu
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- Microbial transformations of artemisinin by Cunninghamella echinulata and Aspergillus niger
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Microbial transformations of artemisinin 1 by Cunninghamella echinulata (AS 3.3400) and Aspergillus niger (AS 3.795) were carried out. Two products, 10β-hydroxyartemisinin 2 and 3α-hydroxydeoxyartemisinin 3, were obtained. Their structures were identified on the basis of chemical and spectroscopic data. 10β-Hydroxyartemisinin is a new compound.
- Zhan, Jixun,Guo, Hongzhu,Dai, Jungui,Zhang, Yuanxing,Guo, Dean
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- Hairy root mediated functional derivatization of artemisinin and their bioactivity analysis
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Biotransformation of artemisinin (1) with the selected hairy root clones of three medicinally important plants, i.e., Atropa belladonna, Hyoscyamus muticus and Ocimum basilicum, yielded two biotransformed products, which were identified as 3-α-hydroxy-1-deoxyartemisinin (2) and 4-hydroxy-9,10-dimethyloctahydrofuro-(3,2-i)-isochromen-11(4H)-one (3). Their structures were elucidated through spectroscopic analysis (NMR/MS) and X-ray crystallography. The relative transformation efficiencies of the tested hairy root clones differed concerning individual bioconversion reactions. Consequently, the HR clones of H. muticus and A. belladonna accomplished the highest conversion of (1) to (2) and (3) respectively, while that of O. basilicum imparted an intermediate response. In-silico and in-vitro bioactivity analysis of the derivatives revealed promising anti-plasmodial activity profile in tandem with notable TNF level lowering potential of compound (2), indicating thereby its prospective therapeutic merit in ameliorating the severity of malarial infection.
- Pandey, Pallavi,Singh, Sailendra,Tewari, Nimisha,Srinivas,Shukla, Aparna,Gupta, Namita,Vasudev, Prema G.,Khan, Feroz,Pal, Anirban,Bhakuni, Rajendra Singh,Tandon, Sudeep,Kumar, Jonnala Kotesh,Banerjee, Suchitra
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- New insights into the degradation of qinghaosu (Artemisinin) mediated by non-heme-iron chelates, and their relevance to the antimalarial mechanism
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Probing the degradation of qinghaosu (1) induced by cysteine-iron chelates by varying the acidity of the reaction medium led to interesting insights into the cleavage of 1, which help to elucidate the antimalarial action of the 1,2,4-trioxanes.
- Wu, Yikang,Yue, Zheng-Yu,Liu, He-Hua
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- Transition-metal-catalyzed group transfer reactions for selective C-H bond functionalization of artemisinin
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Three types of novel artemisinin derivatives have been synthesized through transition-metal-catalyzed intramolecular carbenoid and nitrenoid C-H bond insertion reactions. With rhodium complexes as catalysts, lactone 11 was synthesized via carbene insertion reaction at the C16 position in 90% yield; oxazolidinone 13 was synthesized via nitrene insertion reaction at the C10 position in 87% yield based on 77% conversion; and sulfamidate 14 was synthesized via nitrene insertion reaction at the C8 position in 87% yield.
- Liu, Yungen,Xiao, Wenbo,Wong, Man-Kin,Che, Chi-Ming
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p. 4107 - 4110
(2008/03/13)
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- Cleavage of qinghaosu (artemisinin) induced by non-iron transition-metal ions in the presence of excess cysteine
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In the presence of an excess of cysteine, a catalytic amount of a non-iron transition-metal ion (Co2+, Cu2+, Ni2+, Ti 4+, and Mn2+) may also induce cleavage of qinghaosu (artemisinin; 1) to give those end products previously reported for Fe 2+-mediated degradation.
- Wu, Yikang,Liu, He-Hua
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p. 3074 - 3080
(2007/10/03)
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- Fourier transform infrared investigation of non-heme Fe(III) and Fe(II) decomposition of artemisinin and of a simplified trioxane alcohol
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Fourier transform infrared spectra are reported for the Fe(III)- and Fe(II)-mediated activation of the antimalarial agents artemisinin I and its simplified synthetic analogue, trioxane alcohol 2. By monitoring the frequencies of the newly established marker lines in the FTIR spectra, the products of the Fe(II) and Fe(III) reactions have been characterized. In both reactions, artemisinin is activated giving a product mixture of a ring-contracted tetrahydrofuran acetatal 3, C4-hydroxy deoxyartemisinin 4, and deoxyartemisinin 5. These data illustrate that the oxidation state of the iron places no restrictions on the endoperoxide reduction mechanism. The FTIR difference (light - dark) spectra indicate that the endoperoxide moiety of artemisinin is photolabile and that the resulted products have the same vibrational characteristics as those observed in the reactions with Fe(II) and Fe(III). The use of 18O-18O enriched endoperoxide in 2 has allowed us to identify two oxygen sensitive modes in the reactions with Fe(II). The reduction of the peroxide bond by Fe(II) in trioxane alcohol 2 follows both the C - C cleavage and 1,5-H shift pathways and produces a ring-contracted tetrahydrofuran acetal 6 which is converted to tetrahydrofuran aldehyde 7 and C4-hydroxy deoxytrioxane alcohol 8, respectively. The cleavage of the O - O bond in 1 and 2 by iron and the ability to correlate vibrational properties of the reaction products with structural properties of the isolated products suggest that infrared spectroscopy is an appropriate tool to study the mode of action of antimalarial endoperoxides.
- Kapetanaki,Varotsis
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p. 3150 - 3156
(2007/10/03)
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- Interaction of qinghaosu (artemisinin) with cysteine sulfhydryl mediated by traces of non-heme iron
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The antimalarial action of 1,2,4-trioxanes such as qinghaosu (QHS) may take place through the mechanism shown schematically: In the presence of cysteine traces of non-heme iron (FeSO4) may cleave the peroxy bond of QHS rapidly, and the transien
- Wu, Yikang,Yue, Zheng-Yu,Wu, Yu-Lin
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p. 2580 - 2582
(2007/10/03)
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- Unified mechanistic framework for the Fe(II)-induced cleavage of Qinghaosu and derivatives/analogues. The first spin-trapping evidence for the previously postulated secondary C-4 radical
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Qinghaosu and derivatives were easily reduced by ferrous sulfate in aqueous acetonitrile to give results different from those reported for other reducing systems. The unstable epoxide 7, a compound that was postulated earlier as a species responsible for
- Wu, Wen-Min,Wu, Yikang,Wu, Yu-Lin,Yao, Zhu-Jun,Zhou, Cheng-Ming,Li, Ying,Shan, Feng
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p. 3316 - 3325
(2007/10/03)
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- The behaviour of qinghaosu (artemisinin) in the presence of heme iron(II) and (III)
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With hemin [chlorprotoporphyrin IX iron(III)] or hemin/cysteine in aqueous MeCN, oxygen loss from the peroxide bridge of qinghaosu takes place to give a precursor to desoxoqinghaosu, a known malaria-inactive metabolite, in low yield. Ring-opened forms of
- Haynes, Richard K.,Vonwiller, Simone C.
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p. 253 - 256
(2007/10/02)
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- The behaviour of qinghaosu (artemisinin) in the presence of non-heme iron(II) and (III)
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In aprotic solvents with FeCl3, FeCl3/N-acetyl cysteine or FeCl2, qinghaosu (artemisinin) undergoes rearrangement to give the tetrahydrofuran acetate, 4-hydroxydesoxoqinghaosu or the enol lactone as the major product on th
- Haynes, Richard K.,Vonwiller, Simone C.
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p. 257 - 260
(2007/10/02)
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- Total synthesis of (-)-qinghaosu IV (artemisinin D, arteannuin D)
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Starting from (-)-β-pinene (3), a total synthesis of (-)-qinghaosu IV (1) has been accomplished.
- Liu, Hsing-Jang,Yeh, Wen-Lung
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p. 493 - 497
(2007/10/03)
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