Sunday, 29 July 2012

Imidazole lipophilicity revisited

It's almost three months since I arrived in Brasil to spend year in São Carlos at Universidade de São Paulo. One of the advantages of being back in academia is that access to literature is a lot better and I managed to dig up some cyclohexane/water partition coefficients for a couple of the compounds that featured last year's Lipophilicity Teaser. While octanol/water doesn't appear to 'see' the hydrogen bond donor that is unmasked by moving the methyl group, the cyclohexane/water partitioning system certainly does. Readers with an interest in Physical-Organic Chemistry might like to think about how tautomerism might affect partition coefficients. There are also a couple of lipophilicity-based items (logP versus logD for ADMET discussion and poll on correlation of pharmacological promiscuity) that are current in the FBDD LinkedIn group so why not drop by and join the fun there.


Literature cited

Abraham, Chadha, Whiting & Mitchell, Hydrogen bonding. 32. An analysis of water-octanol and water-alkane partitioning and the Δlog P parameter of Seiler. J. Pharm. Sci. 1994, 83, 1085-1100. DOI

Radzicka & Wolfenden, Comparing the polarities of the amino acids: side-chain distribution coefficients between the vapor phase, cyclohexane, 1-octanol, and neutral aqueous solution. Biochem. 1988, 27, 1664-1670. DOI


Dan Erlanson said...

This is interesting - think there is any kind of host-guest interaction between the cyclohexane and the N-methyl imidazole?

Also, although the experiment would be a pain, has anyone tried doing LogD type analyses with actual lipids instead of simple hydrocarbons?

Pete said...
This comment has been removed by the author.
Pete said...

I don't believe that there is a host-guest interaction between N-methylimidazole and the cyclohexane. This is not to say that the free energy for transferring the compound from gas phase to water is zero. Also alkane/water partition coefficients are relatively insensitive to the alkane. I think that cyclohexane/water logP values tend to be a 0.1 to 0.2 units higher than those for other alkanes, although I've never actually done the analysis myself. If this is indeed the case, it may be related as much to standard state definition (e.g. mole fraction versus molar) as it is to what I'll call (while waving my arms) 'molecular shape effects'.

Measurements of binding to membranes and membrane models have been made although I can't lay my hands on anything relevant right now. I'm not aware of any measurements where the researchers attempted to reproduce the non-polar core of the membrane in a (solvent) partitioning experiment. In a real membrane the (free) energy will in general be a function of position and binding to the membrane is not equivalent to transport through it.

I believe that alkanes are better models than octanol for the non-polar core of the membrane but that is not the only (or the main) reason for my interest in alkane/water logP. When we attempt to predict affinity, we need to be able to model transfer of molecular surface from contact with water to contact with non-polar surface. If one uses (as do more than one software package) octanol/water logP to derive the parameters one will underestimate the costs of forcing contact between polar and non-polar surface.