Amalgamation of Synthetic Biology and Chemistry for High-Throughput Nonconventional Synthesis of the Antimalarial Drug Artemisinin

Singh, Dalbir; McPhee, Derek J.; Paddon, Christopher J.; Cherry, Joel R.; Maurya, Ghanshyam; Mahale, Ganesh; Patel, Yogesh T.; Kumar, Neeraj; Singh, Subhash; Sharma, Brajesh; Kushwaha, Lavkesh; Singh, Satinder; Kumar, Ashok

doi:10.1021/acs.oprd.6b00414

Cited by 25 publications

(19 citation statements)

References 38 publications

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“…Singh et al showed a novel method of artemisinin production from amorpha-4,11-diene that can easily be commercialized due to its favorable route of synthesis [ 67 ]. In this method, functionalization of the isopropenyl moiety of amorphadiene through endo -epoxyamorphadiene produced dihydroartemisinic acid [ 67 ]. This pure dihydroartemisinic acid is esterified, oxidized and its final cyclization resulted in artemisinin in high yields [ 67 ].…”

Section: Increased Production Of Artemisinin and Its Analoguesmentioning

confidence: 99%

“…In this method, functionalization of the isopropenyl moiety of amorphadiene through endo -epoxyamorphadiene produced dihydroartemisinic acid [ 67 ]. This pure dihydroartemisinic acid is esterified, oxidized and its final cyclization resulted in artemisinin in high yields [ 67 ]. Some scientists have discovered short routes for the biosynthesis of artemisinin.…”

Section: Increased Production Of Artemisinin and Its Analoguesmentioning

confidence: 99%

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Increasing the Strength and Production of Artemisinin and Its Derivatives

et al. 2018

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Artemisinin is a natural sesquiterpene lactone obtained from the Artemisia annua herb. It is widely used for the treatment of malaria. In this article, we have reviewed the role of artemisinin in controlling malaria, spread of resistance to artemisinin and the different methods used for its large scale production. The highest amount of artemisinin gene expression in tobacco leaf chloroplast leads to the production of 0.8 mg/g of the dry weight of the plant. This will revolutionize the treatment and control of malaria in third world countries. Furthermore, the generations of novel derivatives of artemisinin- and trioxane ring structure-inspired compounds are important for the treatment of malaria caused by resistant plasmodial species. Synthetic endoperoxide-like artefenomel and its derivatives are crucial for the control of malaria and such synthetic compounds should be further explored.

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Section: Increased Production Of Artemisinin and Its Analoguesmentioning

confidence: 99%

Section: Increased Production Of Artemisinin and Its Analoguesmentioning

confidence: 99%

Increasing the Strength and Production of Artemisinin and Its Derivatives

et al. 2018

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“…Subsequently, Paddon and Singh et al described a commercially feasible and practical method for synthesis of artemisinin from amorpha‐4,11‐diene (Scheme 16). [49] The key to this novel approach is an exceedingly effective functionalization of the isopropenyl group of amorphadiene via endo epoxy amorphadiene to give dihydroartemisinic acid, which on esterification followed by oxidation and cyclicization furnishes pure artemisinin in the yield approximating 60 %. The isopropenyl group of amorphadiene was converted into endoepoxy product with H 2 O 2 .…”

Section: Biosynthesis Strategy For Artemisinin Synthesismentioning

confidence: 99%

Strategy and Problems for Synthesis of Antimalaria Artemisinin (Qinghaosu)

et al. 2020

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Presence of multi‐stereo centre in the antimalaria artemisinin molecules makes difficult to chemist for diastereoselective synthesis. This diastereoselectivity is the main hurdle for low yield of product in the reported synthesis. Though, artemisinin‐based drugs are in the frontline treatment of malaria and effective medicine that kills malarial parasites. Due to insufficient production of artemisinin (qinghaosu), millions of people lost their lives in past years worldwide. The current review will summarize the strategy developed so far for synthesis of antimalaria artemisinin and problems encountered during the synthesis. The combined insight of different methods may allow finer approaches capable of delivering efficient synthetic approaches for developing artemisinin and their hybrid analogues for further drug discovery.

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“…Finally, very recently a route that differs in part from the previous approaches has been demonstrated. Chemists at IPCA have reported a novel large-scale synthesis of artemisinin from amorphadiene ( Singh et al, 2017 ). The key step in this route is the functionalization of amorphadiene using simple and cheap chemistry to directly afford ( R )-dihydroartemisinic acid (i.e., avoiding the need for a stereoselective reduction of artemisinic acid).…”

Section: Chemical Conversion Of Artemisinic Acid To Artemisininmentioning

confidence: 99%

Approaches and Recent Developments for the Commercial Production of Semi-synthetic Artemisinin

et al. 2018

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The antimalarial drug artemisinin is a natural product produced by the plant Artemisia annua. Extracts of A. annua have been used in Chinese herbal medicine for over two millennia. Following the re-discovery of A. annua extract as an effective antimalarial, and the isolation and structural elucidation of artemisinin as the active agent, it was recommended as the first-line treatment for uncomplicated malaria in combination with another effective antimalarial drug (Artemisinin Combination Therapy) by the World Health Organization (WHO) in 2002. Following the WHO recommendation, the availability and price of artemisinin fluctuated greatly, ranging from supply shortfalls in some years to oversupply in others. To alleviate these supply and price issues, a second source of artemisinin was sought, resulting in an effort to produce artemisinic acid, a late-stage chemical precursor of artemisinin, by yeast fermentation, followed by chemical conversion to artemisinin (i.e., semi-synthesis). Engineering to enable production of artemisinic acid in yeast relied on the discovery of A. annua genes encoding artemisinic acid biosynthetic enzymes, and synthetic biology to engineer yeast metabolism. The progress of this effort, which resulted in semi-synthetic artemisinin entering commercial production in 2013, is reviewed with an emphasis on recent publications and opportunities for further development. Aspects of both the biology of artemisinin production in A. annua, and yeast strain engineering are discussed, as are recent developments in the chemical conversion of artemisinic acid to artemisinin.

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Amalgamation of Synthetic Biology and Chemistry for High-Throughput Nonconventional Synthesis of the Antimalarial Drug Artemisinin

Cited by 25 publications

References 38 publications

Increasing the Strength and Production of Artemisinin and Its Derivatives

Increasing the Strength and Production of Artemisinin and Its Derivatives

Strategy and Problems for Synthesis of Antimalaria Artemisinin (Qinghaosu)

Approaches and Recent Developments for the Commercial Production of Semi-synthetic Artemisinin

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