Synthesis, conformational analysis, and antimalarial activity of tricyclic analogs of artemisinin

Avery, Mitchell A.; Gao, Fenglan; Chong, Wesley K. M.; Hendrickson, Thomas F.; Inman, Wayne D.; Crews, Phillip

doi:10.1016/s0040-4020(01)80810-3

Cited by 57 publications

(26 citation statements)

References 24 publications

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“…The preparation of the title compound, (À)-(I), by hydroboration of (À)-isopulegol, (II), was ®rst reported by Schulte-Elte & Ohloff (1967). In the meantime, (À)-(I) has found broad application as an optically active starting material in the synthesis of natural products, especially of the antimalarial drug artemisinin and a number of its analogues (Imakura et al, 1988;Constantino et al, 1996;Avery et al, 1990Avery et al, , 1994Hui et al, 1997). Although the stereochemistry of (À)-(I) appears to be well established in the literature by NMR data and by the con®guration of derivatives synthesized from it, the crystal structure of the important relay compound itself is still lacking.…”

Section: Commentmentioning

confidence: 99%

(−)-(1R,2S,2′R,5R)-2-(1-Hydroxyprop-2-yl)-5-methylcyclohexanol

et al. 2000

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Section: Commentmentioning

confidence: 99%

(−)-(1R,2S,2′R,5R)-2-(1-Hydroxyprop-2-yl)-5-methylcyclohexanol

et al. 2000

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“…Thiyl radicals are formed in bimolecular reactions of RO • or RO 2 • radicals with thio-groups of L-cystein in polypeptides. They have low activity and recombine with resulting scission of polypeptides [32][33][34][35][36][37]. Scheme 1: The mechanism of 1 oxidation; the values of enthalpies (ΔH, kJ/mol), activation energies (E, kJ/mol) and rate constants (k(310 K) s −1 ) were calculated by the method of intersecting parabolas: [32][33][34].…”

Section: The Important Role Of Hydroxyl Radicalsmentioning

confidence: 99%

“…Comparison of the antimalarial activity of compound 1 and its analogs (2−13)[35][36][37] with the number of hydroxyl radicals n OH , which are formed due to their intramolecular oxidation[28][29][30][31]. (i)IC 50 (1)/M(1)IC 50 (i) = 1 + 0.27(n OH (i) − 3.17)…”

mentioning

confidence: 99%

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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“…Upon ozonolysis of 583a, the TBS-protected intermediate 584a was isolated in 57% yield and subsequently cyclized with acetone to give the cis-fused 1,2,4-trioxane 585a (73%) 492 . The more labile TMS-protected alcohols 584b and 584c deriving from 583b and 583c were converted to trioxanes 585b-d in the same vessel (Scheme 165) 493,494 . A direct route to artemisinin (6) and analogues thereof 586 was based on the employment of compounds of type 583 in which R 2 represents a suitable carbonyl-carrying side chain is described in Scheme 166.…”

Section: A Peroxyacetalization Of Carbonyl Functions With β-Hydropermentioning

confidence: 99%