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Insights into the Isomerisation Mechanism of Warfarin
Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences. (BBCL)
Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences. (BBCL)ORCID iD: 0000-0002-7392-0591
Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences. (BBCL)
Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences. (BBCL)ORCID iD: 0000-0002-0407-6542
2010 (English)Conference paper, (Refereed)
Abstract [en]

Warfarin is one of the most commonly used drugs in anticoagulent therapy. Notwithstanding its wide use, achieving correct dosage is often a major challenge due to its narrow therapeutic window.[1] The bioavailability of warfarin is believed to be greatly influenced by the environment-dependent composition of the ensemble of isomers present. While the different structures of warfarin have been discussed in earlier publications,[2] details of the mechanism underlying the formation of the cyclic hemiacetal (Figure 1) had not yet been investigated.

Figure 1. Cyclization reaction of warfarin.

Figure 2. Transition state in presence of one water molecule.

 

We have now studied the reaction by means of density functional calculations. Comparison of results from calculations performed on the isolated warfarin molecule and in presence of water molecules (compare Figure 2) highlight the importance of intermolecular interactions in the key proton transfer step for the reaction to proceed. A viable model for the mechanism underlying the isomerisation shall be presented.

 

 

References

[1]             J. Ansell, J. Hirsh, L. Poller, H. Bussey, A. Jacobsen and E. Hylek, Chest, 126, 204S (2004).

[2]            B. C. G. Karlsson, A. M. Rosengren, P. O. Andersson and I. A. Nicholls, J. Phys. Chem. B, 111,10520 (2007).

Place, publisher, year, edition, pages
2010.
National Category
Organic Chemistry
Research subject
Natural Science, Organic Chemistry
Identifiers
URN: urn:nbn:se:lnu:diva-6711OAI: oai:DiVA.org:lnu-6711DiVA: diva2:329015
Conference
22:nd Organic Chemistry Days (Organikerdagarna), Uppsala
Available from: 2010-07-07 Created: 2010-07-07 Last updated: 2016-11-11Bibliographically approved

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Henschel, HenningKarlsson, Björn C. G.Rosengren, Annika M.Nicholls, Ian A.
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