Metabolism and hydrophilicity of the polarised ‘Janus face’ all-cis tetrafluorocyclohexyl ring, a candidate motif for drug discovery
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The metabolism and polarity of the all-cis tetra-fluorocyclohexane motif is explored in the context of its potential as a motif for inclusion in drug discovery programmes. Biotransformations of phenyl all-cis tetra-, tri- and di- fluoro cyclohexanes with the human metabolism model organism Cunninghamella elegans illustrates various hydroxylated products, but limited to benzylic hydroxylation for the phenyl all-cis tetrafluorocyclohexyl ring system. Evaluation of the lipophilicities (Log P) indicate a significant and progressive increase in polarity with increasing fluorination on the cyclohexane ring system. Molecular dynamics simulations indicate that water associates much more closely with the hydrogen face of these Janus face cyclohexyl rings than the fluorine face owing to enhanced hydrogen bonding interactions with the polarised hydrogens and water.
Rodil , A , Bosisio , S , Salah Ayoup , M , Quinn , L , Cordes , D B , Slawin , A M Z , Murphy , C , Michel , J & O'Hagan , D 2018 , ' Metabolism and hydrophilicity of the polarised ‘Janus face’ all- cis tetrafluorocyclohexyl ring, a candidate motif for drug discovery ' Chemical Science , vol 9 , no. 11 , pp. 3023-3028 . DOI: 10.1039/C8SC00299A
Copyright 2018 the Authors. This is an Open Access Article licensed under a Creative Commons Attribution 3.0 Unported Licence
DescriptionThis work was supported by the Initial Training Network, FLUOR21, funded by the FP7 Marie Curie Actions of the European Commission (FP7-PEOPLE-2013-ITN-607787). JM is supported by a University Research Fellowship from the Royal Society. The research leading to these results has received funding from the European Research Council under the EU 7th Framework Programme (FP7/2007-2013)/ERC No 336289.
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