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

Wu, Weiming; Wu, Yikang; Wu, Yunying; Yao, Zhu‐Jun; Zhou, Cheng-Ming; Liu, Ying; Shan, Feng

doi:10.1021/ja973080o

Cited by 190 publications

(204 citation statements)

References 15 publications

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“…The mechanism of action of artemisinin derivatives is thought to involve the interac-tion between the drugs and hemin within the digestive vacuole of the parasite. [45][46][47][48] The iron-dependent decomposition of artemisinin generates free oxygen radicals that destroy the parasites. The 4-aminoquinolines and aminoalcohols also concentrate within the digestive vacuole but their precise mode of action has not been elucidated.…”

Section: Discussionmentioning

confidence: 99%

In vitro activity of dihydroartemisinin against clinical isolates of Plasmodium falciparum in Yaounde, Cameroon.

Ringwald¹,

Bickii²,

Basco³

1999

The American Journal of Tropical Medicine and Hygiene

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Abstract. The in vitro activities of dihydroartemisinin (the biologically active metabolite of artemisinin derivatives), chloroquine, monodesethylamodiaquine (the biologically active metabolite of amodiaquine), quinine, mefloquine, halofantrine, and pyrimethamine were assessed in 65 African isolates of Plasmodium falciparum from Yaoundé, Cameroon using an isotopic microtest. The 50% inhibitory concentration (IC 50 ) values for dihydroartemisinin were within a narrow range from 0.25 to 4.56 nM, with a geometric mean of 1.11 nM (95% confidence interval ϭ 0.96-1.28 nM). Dihydroartemisinin was equally active (P Ͼ 0.05) against the chloroquine-sensitive isolates (geometric mean IC 50 ϭ 1.25 nM, 95% confidence interval ϭ 0.99-1.57 nM) and the chloroquine-resistant isolates (geometric mean IC 50 ϭ 0.979 nM, 95% confidence interval ϭ 0.816-1.18 nM). A significant positive correlation was observed between the responses to dihydroartemisinin and mefloquine (r ϭ 0.662) or halofantrine (r ϭ 0.284), suggesting in vitro crossresistance. There was no correlation between the responses to dihydroartemisinin and other antimalarial drugs.Artemisinin (qinghaosu) has been used for centuries in traditional Chinese medicine for antimalarial treatment. 1 In 1972, Chinese scientists isolated the active principle from the plant Artemisia annua. 2 Artemisinin is a sesquiterpene lactone characterized by the presence of an endoperoxide that is associated with a potent antimalarial activity. Because artemisinin is chemically unstable and poorly soluble in water or oil, the carbonyl group at C-10 of the parent compound was reduced to obtain dihydroartemisinin. Several derivatives have been developed by adding an ether, ester, or other substituents to the hydroxyl group of dihydroartemisinin. These semi-synthetic derivatives include the water-soluble derivatives, sodium artesunate and artelinic acid, and the oilsoluble derivatives, artemether and arteether. With the exception of arteether and artelinic acid, these compounds are used to treat malarial infections in endemic countries, mainly in Southeast Asia and, to a lesser extent, in Africa and South America.Artemisinin derivatives are available in different formulations for oral, parenteral, and rectal administration. Clinical studies have shown that artemisinin derivatives are highly potent, rapidly acting, and well-tolerated blood schizontocides, resulting in shorter parasite clearance times than other antimalarial drugs. 3,4 Artemisinin derivatives are highly effective against Plasmodium falciparum isolates that are resistant to other drugs. These derivatives are indicated for the emergency treatment of severe and complicated falciparum malaria by parenteral administration and for the oral treatment of uncomplicated multidrug-resistant malaria. 5 So far, resistance to artemisinin derivatives has not been reported in clinical studies. However, because of the high recrudescence rate when used as monotherapy, many current therapeutic regimens used in Southeast Asia include a combination of o...

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Section: Discussionmentioning

confidence: 99%

In vitro activity of dihydroartemisinin against clinical isolates of Plasmodium falciparum in Yaounde, Cameroon.

Ringwald¹,

Bickii²,

Basco³

1999

The American Journal of Tropical Medicine and Hygiene

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“…For exploring the mode of action, reaction of QHS and Fe 2+ was carefully studied by Chinese chemists [22,23] . The major products tetrahydrofuran 3 and 3-hydroxy deoxyqinghaosu 4 were proposed to be derived from primary C-centered free radical 1 and secondary C-centered free radical 2, respectively, as shown in Scheme 2.…”

mentioning

confidence: 99%

“…The major products tetrahydrofuran 3 and 3-hydroxy deoxyqinghaosu 4 were proposed to be derived from primary C-centered free radical 1 and secondary C-centered free radical 2, respectively, as shown in Scheme 2. In addition, the electron spin resonance (ESR) signals of the C-centered free radicals were detected [23,24] .…”

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confidence: 99%

Qinghaosu (artemisinin): Chemistry and pharmacology

2012

Acta Pharmacol Sin

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Qinghaosu and its derivatives are widely used in the world as a new generation of antimalarial drug. Up to now, some important progresses of Qinghaosu research have been made, including synthesis of new Qinghaosu derivatives and analogs, investigation on their bioactivities and mode of actions. The present review briefly describes these efforts made by researchers in China, particularly in this Institute.Keywords: Qinghaosu; artemisinin; structure modification; antimalarial activity; anticancer activity; immunosuppressive activity; mode of action Acta Pharmacologica Sinica (2012) 33: 1141-1146; doi: 10.1038/aps.2012.104; published online 27 Aug 2012On 23rd May 1967, China established National Steering Group on antimalarial drug research, more than 60 institutes and 500 researchers joined in this project. After screening of over 5000 traditional Chinese medicines, Qinghaosu (QHS), an antimalarial principle, was isolated from Artemisia annua L in 1972 [1,2] . At the end of 1975, its unique chemical structure was elucidated, as a sesquiterpene lactone bearing a peroxy group, quite different from that of all known antimalarial drugs [3] .Early pharmacological and clinic studies showed QHS have rapid onset of action, low toxicity and high effect on both drug-resistant and drug-sensitive malaria. However, its shortcomings (poor solubility in water or oil; high rate of parasite recrudescence) needed to be overcome. In 1976, our Institute was charged with this important mission, and a research in relationship between chemical structure and activity immediately started.First of all, the function of peroxy group for antimalarial activity was examined. The negative result of deoxyqinghaosu (Scheme 1) against P berghei in mice demonstrated that the peroxy group was essential. Soon afterwards, it was found that some other simple peroxides including monoterpene ascaridol had no antimalarial activity. These experimental results proved peroxy group to be an essential but not a sufficient factor. At that time, we noted the molecule contained a rare segment -O-C-O-C-O-C=O, and realized that whole molecular skeleton might play an important role for antimalarial activity.When dihydroartemisinin (DHA) was found to be more active than QHS, but was still with poor solubility and lower stability (as a lactol) than QHS, we decided to prepare its derivatives. In 1976-1977, over 50 derivatives of DHA were synthesized (Scheme 1) and evaluated [4,5] .The first 25 compounds (in oil solution) were tested in mice infected chloroquine-resistant P berghei though intramuscular injection [6] . Most of these derivatives showed higher activity than QHS (SD 50 6.20 mg/kg) and DHA (SD 50 3.65 mg/kg). In the ether series, SM 224 (R=CH 3 , SD 50 1.02 mg/kg) is more

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“…12,13 Recently, Gu et al 14 in a DFT study showed that the rate constant for the classical 1,5-H shift is 30 K, respectively, and they reported that the C-centered radical is 5.2 kcal/mol more stable than the O-centered radical. Since there is experimental evidence both for the formation of a secondary 4-C radical and of an unstable epoxide by Wu et al 15 and for the formation of a primary4-C radical, 16 their structures were used in Scheme 1. The epoxide was characterized by its IR spectrum giving rise to ν(OH) and ν (C=O) at 3500 and 1728 cm -1 , respectively.…”

Section: Resultsmentioning

confidence: 99%

Antimalarial endoperoxides: synthesis and implications for the mode of action

Koutsoupakis¹,

Gialou²,

Pavlidou³

et al. 2003

Arkivoc

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2 has been applied in probing the bonds of the endoperoxide moiety and the bonds of the rings owing to the presence of the O-O, the C-O, the O-O-C as well as the C=O modes in the spectrum. The endoperoxide moiety is especially useful in this regard because the homolytic cleavage of the O-O bond can be characterized and hence can be used to assess the vibrational properties of the O-and C-centered radicals and subsequently that of the C-C bond cleavage. The cleavage of the O-O bond, 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.

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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

Cited by 190 publications

References 15 publications

In vitro activity of dihydroartemisinin against clinical isolates of Plasmodium falciparum in Yaounde, Cameroon.

In vitro activity of dihydroartemisinin against clinical isolates of Plasmodium falciparum in Yaounde, Cameroon.

Qinghaosu (artemisinin): Chemistry and pharmacology

Antimalarial endoperoxides: synthesis and implications for the mode of action

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