ChemInform Abstract: A Total Synthesis of the Antimalarial Natural Product (+)‐Qinghaosu (I) .

Liu, H.‐J.; Yeh, Wen-Lung; Chew, S. Y.

doi:10.1002/chin.199340292

Cited by 6 publications

(9 citation statements)

References 1 publication

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“…As indicated in Fig. 1, in a number of cases, the starting point for total synthesis is a monocyclic monoterpenoid which is elaborated to an equivalent of 7 (Avery et al, 1992;Liu et al, 1993;Ravindranathan et al, 1990;Schmid and Hofheinz, 1983;Yadav et al, 2003). Alternatively, synthesis proceeds first via dihydroartemisinate 3 and then 7 (Haynes and Vonwiller, 1990;Nowak and Lansbury, 1998;Roth and Acton, 1989;Xu et al, 1986).…”

Section: Chemical Synthesis Of Artemisinin (1)mentioning

confidence: 94%

“…Alternatively, synthesis proceeds first via dihydroartemisinate 3 and then 7 (Haynes and Vonwiller, 1990;Nowak and Lansbury, 1998;Roth and Acton, 1989;Xu et al, 1986). This is the case for total synthesis from 11 (Xu et al, 1986), (À)-b-pinene (Liu et al, 1993) and semi-synthesis from 2 (Roth and Acton, 1989) and from 6 (Nowak and Lansbury, 1998), for example. Recently, a family of processes for chemical synthesis of 1 from 4, again via dihydroartemisinate 3 has appeared in the patent literature (Reiling et al, 2006).…”

Section: Chemical Synthesis Of Artemisinin (1)mentioning

confidence: 96%

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Making artemisinin☆

2008

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Section: Chemical Synthesis Of Artemisinin (1)mentioning

confidence: 94%

Section: Chemical Synthesis Of Artemisinin (1)mentioning

confidence: 96%

Making artemisinin☆

2008

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“…The unusual endoperoxide group in artemisinin has been confirmed by a variety of means [ 219 , 220 , 221 , 222 , 223 , 224 , 225 , 226 ] and the absolute stereochemistry of artemisinin has been established by X-ray crystallography [ 227 ]. Many total [ 171 , 228 , 229 , 230 , 231 , 232 , 233 , 234 , 235 ] and partial syntheses [ 236 , 237 , 238 , 239 ] of artemisinin have been reported and the various synthetic strategies have been reviewed [ 144 ]. Artemisitene ( 497 ), the 11,13-dehydro analogue of artemisinin, is present in A. annua at much lower levels than artemisinin (typically concentrations in the order of 0.01%, as compared with 1%) [ 240 ], although artemisitene can be obtained readily by chemical transformations of artemisinin [ 165 , 213 , 241 , 242 ]; and a partial synthesis of artemisitene from artemisinic acid ( 473 ) has also been reported [ 243 ].…”

Section: The Phytochemistry Of Artemisia Annua mentioning

confidence: 99%

The Biosynthesis of Artemisinin (Qinghaosu) and the Phytochemistry of Artemisia annua L. (Qinghao)

2010

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The Chinese medicinal plant Artemisia annua L. (Qinghao) is the only known source of the sesquiterpene artemisinin (Qinghaosu), which 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 both sesquiterpenoids and flavonoids, as is the case for many other plants in the Asteraceae family. However, A. annua is distinguished from the other members of the family both by the very large number of natural products which have been characterised to date (almost six hundred in total, including around fifty amorphane and cadinane sesquiterpenes), and by the highly oxygenated nature of many of the terpenoidal secondary metabolites. In addition, this species also contains an unusually large number of terpene allylic hydroperoxides and endoperoxides. This observation forms the basis of a proposal that the biogenesis of many of the highly oxygenated terpene metabolites from A. annua – including artemisinin itself – may proceed by spontaneous oxidation reactions of terpene precursors, which involve these highly reactive allyllic hydroperoxides as intermediates. Although several studies of the biosynthesis of artemisinin have been reported in the literature from the 1980s and early 1990s, the collective results from these studies were rather confusing because they implied that an unfeasibly large number of different sesquiterpenes could all function as direct precursors to artemisinin (and some of the experiments also appeared to contradict one another). As a result, the complete biosynthetic pathway to artemisinin could not be stated conclusively at the time. Fortunately, studies which have been published in the last decade are now providing a clearer picture of the biosynthetic pathways in A. annua. By synthesising some of the sesquiterpene natural products which have been proposed as biogenetic precursors to artemisinin in such a way that they incorporate a stable isotopic label, and then feeding these precursors to intact A. annua plants, it has now been possible to demonstrate that dihydroartemisinic acid is a late-stage precursor to artemisinin and that the closely related secondary metabolite, artemisinic acid, is not (this approach differs from all the previous studies, which used radio-isotopically labelled precursors that were fed to a plant homogenate or a cell-free preparation). Quite remarkably, feeding experiments with labeled dihydroartemisinic acid and artemisinic acid have resulted in incorporation of label into roughly half of all the amorphane and cadinane sesquiterpenes which were already known from phytochemical studies of A. annua. These findings strongly support the hypothesis that many of the highly oxygenated sesquiterpenoids from this species arise by oxidation reactions involving allylic hydroperoxides, which seem to be such a defining feature of the chemistry of A. annua. In the particular case of a...

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“…Artemisinin (qinghaosu, ART), an endoperoxide sesquiterpene lactone extracted from the plant, is the main composition of artemisinin-based combination therapies (ACTs) which are the best anti-malarial drugs currently available (Mutabingwa 2005;Van Agtmael et al 1999). Its total synthesis has been achieved (Liu et al 1993), but is uneconomical and gives low yields due to complex chemical structure. Thus artemisinin extracted from plant currently is the only source of commercial artemisinin drug (Abdin et al 2003;deVries and Dien 1996;Klayman 1985;VanGeldre et al 1997).…”

Section: Introductionmentioning

confidence: 99%

Terpenoid metabolic profiling analysis of transgenic Artemisia annua L. by comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry

Wang

Lü

et al. 2009

Metabolomics

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Amorpha-4,11-diene synthase (ADS) is a very important enzyme which catalyzes the committed step of artemisinin biosynthesis. In this work, two lines of transgenic Artemisia annua L. which ADS was over-expressed (line A9) and suppressed (line Amsi), respectively, were utilized. And the transgenic line GUS with b-Glucuronidase gene was regarded as the control. Their terpenoid metabolic profiling was investigated by using GC 9 GC-TOFMS. The metabolic profiling method established included simple extraction, two-dimension separation and multivariate analysis. Partial least squares discriminant analysis (PLS-DA) was used to classify two transgenic lines and the control line. Eleven important compounds in classification were identified. Most of them were sesquiterpenoids including monoterpenoid, diterpenoid and four bioprecursors of artemsisnin. Compared with the control, artemisinin and bioprecursors in the line A9 increased as a result of over-expressing ADS. Borneol and phytol also increased in the line A9, but (E)-b-farnesene and germacrene D were reversely altered. The result indicated that over-expression of the ADS affected not only artemisinin biosynthesis, but also the whole metabolic network of terpenoid. Compared with the line A9, no opposite change of artemisinin and related derivatives was observed in the line Amsi, the ADS inhibition had no significant effect on artemisinin biosynthesis in the line Amsi.

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ChemInform Abstract: A Total Synthesis of the Antimalarial Natural Product (+)‐Qinghaosu (I) .

Cited by 6 publications

References 1 publication

Making artemisinin☆

Making artemisinin☆

The Biosynthesis of Artemisinin (Qinghaosu) and the Phytochemistry of Artemisia annua L. (Qinghao)

Terpenoid metabolic profiling analysis of transgenic Artemisia annua L. by comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry

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