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

Halogen-substituted iminosulfuranes are trans- dermal 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 RH, Cl, Br, and I, with l - � -dimyristoyl- sn -glycero-3-phos- phocholine (DMPC) has been studied using differential scan- ning calorimetry, isothermal titration calorimetry, nuclear Overhauser effect spectroscopy (NOESY), and NMR spectros- copy, 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 as- sociated with the transfer of 3 to the bilayer is much lower than that for the other compounds, indicating that 3 occu- pies or induces sites that afford it considerable local mo- tional 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 interac- tion of these agents with protein side chains. — Barrow, Jr., D. J., S. Chandrasekaran, H. H. Heerklotz, M. M. Henary, B. B. Michniak, P. M. Nguyen, Y. Song, J. C. Smith, and L. Strekowski. Mechanistic studies on percutaneous penetra- tion enhancement by N -(4-halobenzoyl)- S , S -dimethylimino- sulfuranes. J. Lipid Res. 2005. 46: 2192-2201. The stratum corneum (SC) layer of the skin provides both protection from foreign substances and a barrier against dehydration. The protective properties of the SC, how- ever, also inhibit most therapeutic agents from effectively