2. Academic Validation
  3. Determining the necessity of phenyl ring π-character in warfarin

Determining the necessity of phenyl ring π-character in warfarin

  • Bioorg Med Chem Lett. 2019 Aug 1;29(15):1954-1956. doi: 10.1016/j.bmcl.2019.05.039.
Hui Xing 1,  Sevan D Houston 1,  Xuejie Chen 2,  Da-Yun Jin 2,  G Paul Savage 3,  Jian-Ke Tie 2,  Craig M Williams 4
Affiliations

Affiliations

  • 1 School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane 4072, Queensland, Australia.
  • 2 Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 3 CSIRO Manufacturing, Ian Wark Laboratory, Melbourne 3168, Victoria, Australia.
  • 4 School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane 4072, Queensland, Australia. Electronic address: c.williams3@uq.edu.au.
PMID: 31147103 DOI: 10.1016/j.bmcl.2019.05.039
Abstract

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 π-interactions and ring size in the activity of warfarin.

Keywords

Cyclohexane; Cyclooctane; VKOR; Warfarin; π-Interaction.

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