Submitted on April 1, 2005
Revised on July 11, 2005
Accepted on July 19, 2005
Mechanistic studies on percutaneous penetration enhancement by N-(4-halobenzoyl)-S,S-dimethyliminosulfuranes
D. J. Barrow Jr, S. Chandrasekaran, H. H. Heerklotz, M. M. Henary, B. B. Michniak, P. M. Nguyen, Y. Song, J. C. Smith, and L. Strekowski
Chemistry Dept., Georgia State University, Atlanta, GA 30302-4098
Corresponding Author: chejcs{at}langate.gsu.edu
Halogen-substituted iminosulfuranes are transdermal penetration enhancers (TPE) in permeation studies using hairless mouse or human cadaver skin. The interaction of N-(4-R-benzoyl)-S,S-dimethyliminosulfuranes 1-4 where R = H, Cl, Br, and I, with DMPC has been studied using differential scanning calorimetry and isothermal titration calorimetry, NOESY NMR spectroscopy, and by calculation of the iminosulfurane polarizabilities, in order to elucidate the molecular basis of the TPE activity. The active compounds reduce the Tm of the gel to liquid crystal phase transition and induce multiple components in the transition excess heat capacity profile. The partitioning of the bromo derivative 3, the most active compound, into DMPC is unique in that 3 may be trapped in the bilayer affording an enhanced residence time and a rational for its high TPE activity. The entropy decrease associated with the transfer of 3 to the bilayer is much lower than that for the other compounds indicating that 3 occupies or induces sites that afford it considerable local motional freedom. Correlations between the iminosulfurane TPE activities and the partition coefficients and NOESY crosspeak volume were observed. Molecular polarizabilities are not consistent with a TPE mode of action involving interaction of these agents with protein side chains.
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