A Concise Synthesis of (+)-Artemisinin

Zhu, Chunyin; Cook, Silas P.

doi:10.1021/ja3061479

Cited by 135 publications

(88 citation statements)

References 28 publications

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“…A general ‘blueprint’ of a potential route to produce 10 from inexpensive building blocks was recently developed by the Cook laboratory at Indiana University (IN, USA) [21]. Based on knowledge gleaned from the semi-synthetic conversion of 11 to 10 , the Cook group realized that three stereocenters (in green) of the stereochemically complex artemisinin core could be immediately cleared to achiral or racemic precursor carbons (Figure 3).…”

Section: Stereochemistry-based Strategies: the Power Of Substrate Relaymentioning

confidence: 99%

Synthesis of Medicinally Relevant Terpenes: Reducing the Cost and Time of Drug Discovery

Jansen

Shenvi

2014

Future Med. Chem.

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Terpenoids constitute a significant fraction of molecules produced by living organisms that have found use in medicine and other industries. Problems associated with their procurement and adaptation for human use can be solved using chemical synthesis, which is an increasingly economical option in the modern era of chemistry. This article documents, by way of individual case studies, strategies for reducing the time and cost of terpene synthesis for drug discovery. A major trend evident in recent syntheses is that complex terpenes are increasingly realistic starting points for both medicinal chemistry campaigns and large-scale syntheses, at least in the context of the academic laboratory, and this trend will likely penetrate the commercial sector in the near future.

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Section: Stereochemistry-based Strategies: the Power Of Substrate Relaymentioning

confidence: 99%

Synthesis of Medicinally Relevant Terpenes: Reducing the Cost and Time of Drug Discovery

Jansen

Shenvi

2014

Future Med. Chem.

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“…The drug also has shown promise against a wide variety of human (Efferth, 2009) and livestock diseases (Ferreira et al, 2011); many are common to the developing world. Although new sources of the drug are emerging from chemical synthesis (Zhu and Cook, 2012) and engineered microbes (Paddon et al, 2013), artemisinin is currently only commercially available from A. annua with insufficient supply to treat malaria, let alone other artemisinin-susceptible diseases. To obviate emergence of drug resistance, ACT co-drugs are also needed, which usually increases cost (O’Connell et al, 2011).…”

Section: 0 Introductionmentioning

confidence: 99%

Pharmacokinetics of artemisinin delivered by oral consumption of Artemisia annua dried leaves in healthy vs. Plasmodium chabaudi-infected mice

Weathers

Elfawal

Towler

et al. 2014

Journal of Ethnopharmacology

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Ethnopharmacological Relevance The Chinese have used Artemisia annua as a tea infusion to treat fever for > 2,000 yrs. The active component is artemisinin. Previously we showed that when compared to mice fed an equal amount of pure artemisinin, a single oral dose of dried leaves of Artemisia annua (pACT) delivered to Plasmodium chabaudi-infected mice reduced parasitemia at least fivefold. Dried leaves also delivered >40 times more artemisinin in the blood with no toxicity. The pharmacokinetics (PK) of artemisinin delivered from dried plant material has not been adequately studied. Material and Methods Healthy and P. chabaudi-infected mice were oral gavaged with pACT to deliver a 100 mg kg−1 body weight dose of artemisinin. Concentrations of serum artemisinin and one of its liver metabolites, deoxyartemisinin, were measured over two hours by GCMS. Results The first order elimination rate constant for artemisinin in pACT-treated healthy mice was estimated to be 0.80 hr−1 with an elimination half-life (T½) of 51.6 min. The first order absorption rate constant was estimated at 1.39 hr−1. Cmax and Tmax were 4.33 mg L−1 and 60 min, respectively. The area under the curve (AUC) was 299.5 mg·min L−1. In contrast, the AUC for pACT-treated infected mice was significantly greater at 435.6 mg·min L−1. Metabolism of artemisinin to deoxyartemisinin was suppressed in infected mice over the period of observation. Serum levels of artemisinin in the infected mice continued to rise over the 120 min of the study period, and as a result, the elimination T½ was not determined; the Cmax and Tmax were estimated at ≥ 6.64 mg L−1 and ≥ 120 min, respectively. Groups of healthy mice were also fed either artemisinin or artemisinin mixed in mouse chow. When compared at 60 min, artemisinin was undetectable in the serum of mice fed 100 mg AN kg−1 body weight. When plant material was present either as mouse chow or A. annua pACT, artemisinin levels in the serum rose to 2.44 and 4.32 mg L−1, respectively, indicating that the presence of the plant matrix, even that of mouse chow, had a positive impact on the appearance of artemisinin in the blood. Conclusions These results showed that artemisinin and one of its drug metabolites were processed differently in healthy and infected mice. The results have implications for possible therapeutic use of pACT in treating malaria and other artemisinin-susceptible diseases.

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“…Yet, these synthetic endeavors are not reflected in the broad industrial manufacture of natural products. There is at least one total synthesis for each of the plant-derived natural products approved for therapeutic use in the last thirty years, presented in Table 1, with exemplary syntheses of (+)-artemisinin (Zhu and Cook, 2012), (+)-arglabin (Kalidindi et al, 2007), (−)-cannabidiol (Petrzilka et al, 1969), capsaicin (Kaga et al, 1989), (−)-colchicine (Lee et al, 1998), dronabinol ((−)-Δ 9 -trans-tetrahydrocannabinol (THC); (Trost and Dogra, 2007)), (+)-ingenol (as described in greater detail in the next paragraphs, ingenol is chemically converted to ingenol mebutate for therapeutic supply; (Liang et al, 2012)), masoprocol (meso-nordihydroguaiaretic acid; (Gezginci and Timmermann, 2001)), omacetaxine mepesuccinate ((−)-homoharringtonine; (Eckelbarger et al, 2008)), (−)-paclitaxel (Nicolaou et al, 1994), and (−)-solamargine (Wei et al, 2011a). Also found in this list is (−)-galanthamine, which is particularly notable because it is a rather complex plant-derived compound for which an entirely chemical industrial-scale production process exists (as described in detail in the next paragraphs).…”

Section: Organic Synthesismentioning

confidence: 99%

Discovery and resupply of pharmacologically active plant-derived natural products: A review

2015

Draw Science

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Medicinal plants have historically proven their value as a source of molecules with therapeutic potential, and nowadays still represent an important pool for the identification of novel drug leads. In the past decades, pharmaceutical industry focused mainly on libraries of synthetic compounds as drug discovery source. They are comparably easy to produce and resupply, and demonstrate good compatibility with established high throughput screening (HTS) platforms. However, at the same time there has been a declining trend in the number of new drugs reaching the market, raising renewed scientific interest in drug discovery from natural sources, despite of its known challenges. In this survey, a brief outline of historical development is provided together with a comprehensive overview of used approaches and recent developments relevant to plant-derived natural product drug discovery. Associated challenges and major strengths of natural product- Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts based drug discovery are critically discussed. A snapshot of the advanced plant-derived natural products that are currently in actively recruiting clinical trials is also presented. Importantly, the transition of a natural compound from a "screening hit" through a "drug lead" to a "marketed drug" is associated with increasingly challenging demands for compound amount, which often cannot be met by re-isolation from the respective plant sources. In this regard, existing alternatives for resupply are also discussed, including different biotechnology approaches and total organic synthesis.While the intrinsic complexity of natural product-based drug discovery necessitates highly integrated interdisciplinary approaches, the reviewed scientific developments, recent technological advances, and research trends clearly indicate that natural products will be among the most important sources of new drugs also in the future.

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A Concise Synthesis of (+)-Artemisinin

Cited by 135 publications

References 28 publications

Synthesis of Medicinally Relevant Terpenes: Reducing the Cost and Time of Drug Discovery

Synthesis of Medicinally Relevant Terpenes: Reducing the Cost and Time of Drug Discovery

Pharmacokinetics of artemisinin delivered by oral consumption of Artemisia annua dried leaves in healthy vs. Plasmodium chabaudi-infected mice

Discovery and resupply of pharmacologically active plant-derived natural products: A review

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