Mechanistic studies on percutaneous penetration enhancement by N-(4-halobenzoyl)-S,S-dimethyliminosulfuranes

Abstract

Halogen-substituted iminosulfuranes are transdermal penetration enhancers (TPEs) 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 L-α-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) has been studied using differential scanning calorimetry, isothermal titration calorimetry, nuclear Overhauser effect spectroscopy (NOESY), and 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 melting temperature 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 reason 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, the partition coefficients, and NOESY cross-peak volume were observed. Molecular polarizabilities are not consistent with a TPE mode of action involving interaction of these agents with protein side chains. Copyright © 2005 by the American Society for Biochemistry and Molecular Biology, Inc.