Artemisinin as a self-propagating radical initiator under aerobic conditions

Солодова, С. Л.; Денисов, Е. Т.; Denisova, T. G.

doi:10.1016/j.mencom.2008.01.010

Cited by 12 publications

(3 citation statements)

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“…A comparison of the oxygen addition with the monomolecular reactions of the artemisinin alkyl radicals as well as the reaction with L-cysteine showed that this reaction is the most rapid transformation channel for the majority of radicals [26,27]. Therefore, under aerobic conditions these are the following main reaction channels of radicals generated from peroxide bridge of artemisinin: The further transformations of the artemisinin peroxyl radicals were analyzed for the first time in the studies [24,25]. The formed peroxyl radical induces in 1 a cascade of intramolecular chain reactions with production of artemisinin with a line of hydroperoxide groups.…”

Section: Intramolecular Oxidation Of Artemisininmentioning

confidence: 99%

“…However, the synthesis and testing of its analogs on antimalarial activity showed that the whole structure of molecule 1 rather than its peroxide bridge only plays an important role [1,2]. Using the kinetic analysis of the reactions occurring after the cleavage of the peroxide bridge in compound 1 in the presence of oxygen, it was proved that the free radicals formed are involved in a cascade of consecutive transformations with participation of oxygen [21][22][23][24][25][26][27]. As a result, compound 1 is transformed into polyatomic hydroperoxide.…”

Section: Introductionmentioning

confidence: 99%

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Hydroxyl Radical as Key Intermediate in Curing Action of Artemisinin and its Analogs

Денисов¹

2014

Med chem

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A kinetic analysis of intramolecular oxidation reactions of 1 derivatives in combination with the published data on antimalarial activity makes it possible to formulate the following mechanism of action of the peroxide drugs, analogs of compound 1. Under the reaction of the Fe(II) chelates the compound containing the peroxide group is transformed into the alkoxyl radical. This radical isomerizes to the alkyl radical, which further undergoes intramolecular chain oxidation. This oxidation results in polyatomic hydroperoxides, which, in turn, generates radicals in the reaction with Fe(II). The next cascade of radical reactions generates very reactive hydroxyl radicals, whose sources are peroxyl radicals with hydroperoxide fragments and α-dihydroperoxides. The higher the yield of hydroxyl radicals nOH, the more efficient the drug. The dependence of the antimalarial activity of the ith drug IC50(1)M(i)/IC50(i)M(1) on the yield of radicals HO nOH is nonlinear (exponential). The compounds with nOH ≥ 3 are efficient.

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Section: Intramolecular Oxidation Of Artemisininmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hydroxyl Radical as Key Intermediate in Curing Action of Artemisinin and its Analogs

Денисов¹

2014

Med chem

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“…Isomerization of alkyl and alkoxy radicals plays an important role in this kind of free radical transformations. [10][11] The free radical chemistry of cyclization and decyclization of free radicals was successfully developed by Athel Beckwith. During the last 20 years, he investigated a great number of these reactions with free radicals of different structures.…”

Section: Introductionmentioning

confidence: 99%

An important role of intramolecular free radical reactions in antimalarial activity of artemisinin and its analogs

Денисов

2011

Org. Biomol. Chem.

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The kinetic schemes of intramolecular reactions of five analogs of artemisinin were built. The method of intersecting parabolas was used for the calculation of activation energies and rate constants of each elementary step of these schemes. The competition between monomolecular and bimolecular free radicals was taken into account. It was evidenced that the intramolecular oxidation of these compounds proceeds as a cascade of consecutive free radical reactions with the formation of hydroperoxide groups. The latter decompose via reactions with the Fe(II) complexes generating free radicals. Among the radicals formed, the hydroxyl radical was proved to play the key role. A correlation between the yield of hydroxyl radicals n(OH) and antimalarial activity of compounds (IC(50)) was observed. The dependence of index IC(50) on n(OH) is linear in the logarithmic coordinates: ln[IC(50)(Artemisinin)/IC(50)(Compound)] = -14.10 + 3.85 ×n(OH). The proposed scheme explains and demonstrates a strong dependence of the antimalarial effectiveness of a drug on the chemical structure.

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Reactions of alkoxy and peroxy radicals formed upon the decomposition of hydroxyperoxide groups in the artemisinin derivatives

Солодова

Денисов

2009

Russ Chem Bull

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The enthalpies of intramolecular reactions of alkoxy and peroxy radicals formed from polyatomic artemisinin hydroperoxides and of their bimolecular reactions with C-H, S-H, and O-H bonds of biological substrates were calculated. The activation energies and rate constants of these reactions were calculated using the intersecting parabolas method. The decomposition of artemisinin hydroperoxides can initiate the cascade of intramolecular oxida tion reactions involving radicals R • , RO • , HO • , HO 2 • , and RO 2 • . The main sequences of transformation of these radicals were established. The oxidative destruction of the artemisinin peroxy derivatives generates radicals RO 2 • , HO • , and HO 2 • in an amount of 4.5 radicals per peroxide derivative molecule on the average. The kinetic scheme of oxidative transformations of the hydroperoxide with four OOH groups and radicals formed from it was constructed using this radical as an example.Presently, artemisinin is considered the most efficient drug for malaria treatment. 1-6 Artemisinin is sesquiter penic lacton with the peroxide bridge. The peroxide frag ment is key in the medicinal effect of artemisinin. The medicinal effect is based on free radical generation via the reaction of the peroxide group with iron ions Fe II /Fe III , and the radicals formed escape into the bulk and react with enzymes of parasites deactivating them. 3-6 Several kinetic schemes that help to explain the medicinal effect of artemisinin were proposed. Un fortunately, all these schemes are qualitative, including a number of parallel steps, none of which can be preferred.In our previous studies 7,8 the problems of competition of intramolecular and bimolecular reactions of alkoxy and alkyl radicals generated from artemisinin were considered at the quantitative level. It was found 7,8 that the alkoxy radical formed upon the cleavage of the peroxide bridge react very rapidly in intramolecular reactions with hydro gen atom transfer and decyclization, transforming into the C centered radicals. Thus, the free valence is retained on artemisinin as its C centered radicals. Under aerobic con ditions, these radicals rapidly add oxygen and transform into peroxy radicals. The latter are involved in the in tramolecular reaction with hydrogen transfer and rapidly transform into alkyl radicals, which undergo further oxi dation. As a result, artemisinin is oxidized via the intramo lecular chain mechanism to form polyatomic hydroperox ides. This results in the situation where, under aerobic conditions, artemisinin can transform into the polyfunc tional initiator with several hydroperoxy groups. 9,10 Each of the hydroxyperoxide groups formed reacts with the Fe II /Fe III chelates and generates alkoxy radicals via the reactions 11-17 ROOH + Fe 2+ → RO • + FeOH 2+ , ROOH + Fe 3+ → FeO 2+ + H + + RO • ,The alkoxy radicals, in turn, undergo various intramolecu lar transformations. In the present study, we attempted to solve the problem of quantitative kinetic analysis of the further transformations of the radicals ...

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Artemisinin as a self-propagating radical initiator under aerobic conditions

Cited by 12 publications

References 11 publications

Hydroxyl Radical as Key Intermediate in Curing Action of Artemisinin and its Analogs

Hydroxyl Radical as Key Intermediate in Curing Action of Artemisinin and its Analogs

An important role of intramolecular free radical reactions in antimalarial activity of artemisinin and its analogs

Reactions of alkoxy and peroxy radicals formed upon the decomposition of hydroxyperoxide groups in the artemisinin derivatives

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