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

Xiaofang Wang; Darren J. Creek; Charles E. Schiaffo; Yuxiang Dong; Jacques Chollet; Christian Scheurer; Sergio Wittlin; Susan A. Charman; Patrick H. Dussault; James K. Wood; Jonathan L. Vennerstrom

doi:10.1016/j.bmcl.2009.07.013

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

Xiaofang Wang, Darren J. Creek, Charles E. Schiaffo, Yuxiang Dong, Jacques Chollet, Christian Scheurer, Sergio Wittlin, Susan A. Charman, Patrick H. Dussault, James K. Wood, Jonathan L. Vennerstrom

Research output: Contribution to journal › Article › peer-review

30 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	4542-4545
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	19
Issue number	16
DOIs	https://doi.org/10.1016/j.bmcl.2009.07.013
State	Published - Aug 15 2009

Keywords

1,2,4-Trioxane
1,2,4-Trioxepane
1,2,4-Trioxolane
Antimalarial
Artemisinin
Peroxide

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

Access to Document

10.1016/j.bmcl.2009.07.013

Cite this

Wang, X., Creek, D. J., Schiaffo, C. E., Dong, Y., Chollet, J., Scheurer, C., Wittlin, S., Charman, S. A., Dussault, P. H., Wood, J. K., & Vennerstrom, J. L. (2009). 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 and Medicinal Chemistry Letters, 19(16), 4542-4545. https://doi.org/10.1016/j.bmcl.2009.07.013

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. / Wang, Xiaofang; Creek, Darren J.; Schiaffo, Charles E. et al.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 19, No. 16, 15.08.2009, p. 4542-4545.

Research output: Contribution to journal › Article › peer-review

Wang, X, Creek, DJ, Schiaffo, CE, Dong, Y, Chollet, J, Scheurer, C, Wittlin, S, Charman, SA, Dussault, PH, Wood, JK & Vennerstrom, JL 2009, '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 and Medicinal Chemistry Letters, vol. 19, no. 16, pp. 4542-4545. https://doi.org/10.1016/j.bmcl.2009.07.013

@article{cb2150225e394b25ba63cb284864c9cf,

title = "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",

abstract = "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.",

keywords = "1,2,4-Trioxane, 1,2,4-Trioxepane, 1,2,4-Trioxolane, Antimalarial, Artemisinin, Peroxide",

author = "Xiaofang Wang and Creek, {Darren J.} and Schiaffo, {Charles E.} and Yuxiang Dong and Jacques Chollet and Christian Scheurer and Sergio Wittlin and Charman, {Susan A.} and Dussault, {Patrick H.} and Wood, {James K.} and Vennerstrom, {Jonathan L.}",

year = "2009",

month = aug,

day = "15",

doi = "10.1016/j.bmcl.2009.07.013",

language = "English (US)",

volume = "19",

pages = "4542--4545",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Elsevier Ltd",

number = "16",

}

TY - JOUR

T1 - Spiroadamantyl 1,2,4-trioxolane, 1,2,4-trioxane, and 1,2,4-trioxepane pairs

T2 - Relationship between peroxide bond iron(II) reactivity, heme alkylation efficiency, and antimalarial activity

AU - Wang, Xiaofang

AU - Creek, Darren J.

AU - Schiaffo, Charles E.

AU - Dong, Yuxiang

AU - Chollet, Jacques

AU - Scheurer, Christian

AU - Wittlin, Sergio

AU - Charman, Susan A.

AU - Dussault, Patrick H.

AU - Wood, James K.

AU - Vennerstrom, Jonathan L.

PY - 2009/8/15

Y1 - 2009/8/15

N2 - 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.

AB - 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.

KW - 1,2,4-Trioxane

KW - 1,2,4-Trioxepane

KW - 1,2,4-Trioxolane

KW - Antimalarial

KW - Artemisinin

KW - Peroxide

UR - http://www.scopus.com/inward/record.url?scp=67651083553&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67651083553&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2009.07.013

DO - 10.1016/j.bmcl.2009.07.013

M3 - Article

C2 - 19616946

AN - SCOPUS:67651083553

SN - 0960-894X

VL - 19

SP - 4542

EP - 4545

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 16

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this