J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.M500123-JLR200 on August 1, 2005

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Journal of Lipid Research, Vol. 46, 2192-2201, October 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

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

D. J. Barrow, Jr.*, S. Chandrasekaran*, H. H. Heerklotz{dagger}, M. M. Henary*, B. B. Michniak§, P. M. Nguyen*, Y. Song§, J. C. Smith1,* and L. Strekowski*

* Department of Chemistry, Georgia State University, Atlanta, GA
{dagger} Department of Biophysical Chemistry, Biozentrum, University of Basel, Basel, Switzerland
§ Department of Pharmacology and Physiology, University of Medicine and Dentistry, New Jersey–New Jersey Medical School, Newark, NJ

Published, JLR Papers in Press, August 1, 2005. DOI 10.1194/jlr.M500123-JLR200

1 To whom correspondence should be addressed. e-mail: chejcs{at}langate.gsu.edu

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-{alpha}-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 crosspeak volume were observed. Molecular polarizabilities are not consistent with a TPE mode of action involving interaction of these agents with protein side chains.

Abbreviations: CUP, cooperative unit parameter; DMPC, L-{alpha}-dimyristoyl-sn-glycero-3-phosphocholine; DSC, differential scanning calorimetry; ER, enhancement ratio; FID, free induction decay; ITC, isothermal titration calorimetry; NOESY, nuclear Overhauser effect spectroscopy; SC, stratum corneum; Tm, melting temperature; TPE, transdermal penetration enhancer

Supplementary key words transdermal penetration enhancer • vesicle • bilayer • nuclear magnetic resonance • calorimetry • polarizability


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