Determining the necessity of phenyl ring π-character in warfarin

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:29

Article

Xing, Hui¹  Houston, Sevan D.¹  Chen, Xuejie²  Jin, Da-Yun²  Savage, G. Paul³  Tie, Jian-Ke²  Williams, Craig M.¹ 

[1] Univ Queensland, Sch Chem & Mol Biosci, Brisbane, Qld 4072, Australia

[2] Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA

[3] CSIRO Mfg, Ian Wark Lab, Melbourne, Vic 3168, Australia

关键词: Warfarin;    VKOR;    pi-Interaction;    Cyclohexane;    Cyclooctane;   

DOI  :  10.1016/j.bmcl.2019.05.039

来源: Elsevier

【 摘 要 】

Despite the difficulty in administering a safe dose regimen and reports of emerging resistance, warfarin (1) remains the most widely-used oral anticoagulant for the prevention and treatment of thrombosis in humans globally. Systematic substitution of the warfarin phenyl ring with either 1,3,5,7-cyclooctatetraene (COT) (2), cubane (3), cyclohexane (4) or cyclooctane (5) and subsequent evaluation against the target enzyme, vitamin K epoxide reductase (VKOR), facilitated interrogation of both steric and electronic properties of the phenyl pharmacophore. The tolerance of VKOR to further functional group modification (carboxylate 14, PTAD adduct 15) was also investigated. The results demonstrate the importance of both annulene conferred pi-interactions and ring size in the activity of warfarin.

【 授权许可】

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