Spiroadamantyl 1,2,4-trioxolane, 1,2,4-trioxane, and 1,2,4-trioxepane pairs: Relationship between peroxide bond iron(II) reactivity, heme alkylation efficiency, and antimalarial activity

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:19

Article

Wang, Xiaofang¹  Creek, Darren J.²  Schiaffo, Charles E.³  Dong, Yuxiang¹  Chollet, Jacques⁴  Scheurer, Christian⁴  Wittlin, Sergio⁴  Charman, Susan A.²  Dussault, Patrick H.³  Wood, James K.⁵  Vennerstrom, Jonathan L.¹ 

[1] Univ Nebraska Med Ctr, Coll Pharm, Omaha, NE 68198 USA

[2] Monash Univ, Monash Inst Pharmaceut Sci, Ctr Drug Candidate Optimisat, Parkville, Vic 3052, Australia

[3] Univ Nebraska, Dept Chem, Lincoln, NE 68588 USA

[4] Swiss Trop Inst, CH-4002 Basel, Switzerland

[5] Univ Nebraska, Dept Chem, Omaha, NE 68182 USA

关键词: 1,2,4-Trioxolane;    1,2,4-Trioxane;    1,2,4-Trioxepane;    Peroxide;    Antimalarial;    Artemisinin;   

DOI  :  10.1016/j.bmcl.2009.07.013

来源: Elsevier

【 摘 要 】

These data suggest that iron(II) reactivity for a set of homologous spiroadamantyl 1,2,4-trioxolane, 1,2,4-trioxane, and 1,2,4-trioxepane peroxide heterocycles is a necessary, but insufficient, property of animalarial peroxides. Heme alkylation efficiency appears to give a more accurate prediction of antimalarial activity than FeSO4-mediated reaction rates, suggesting that antimalarial activity is not merely dependent on peroxide bond cleavage, but also on the ability of reactive intermediates to alkylate heme or other proximal targets. (C) 2009 Elsevier Ltd. All rights reserved.

【 授权许可】

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