Sulfur mustard, [bis-(2-chloroethyl)sulfide] (SM), is a chemical warfare agent first synthesized in the early 19th century, however it remains a threat due to its possible use in a terrorist attack.  SM is a powerful vesicant which triggers an up-regulation of a host of hydrolytic, collagenolytic, esteratic, cholinergic, and inflammatory processes within an oxidative stressed domain on lungs, skin, and eyes.  No antidote or suitable therapeutic response for SM exposure exists.  We have synthesized and screened 15 multi-functional therapeutics in which component pharmacophores target up-regulated enzymes and are attached to a hydrolyzable core to provide �release� by skin enzymes. One agent, N-hydroxy-N-(4-hydroxy-3-methoxybenzyl)heptadecanamide, designed as an MMP-9, FAAH, and TRPV1 co-antagonist, showed 87% suppression of phorbol-ester induced inflammation in a mouse ear model. Other prodrugs which transported anti-oxidant and non-steroidal anti-inflammatory constructs joined by ester linkages showed promising, albeit lower, inflammation suppression.  Syntheses, in vitro, and in vivo screening results are displayed.

Synthesis and evaluation of novel antioxidant prodrugs for the topical treatment of sulfur-mustard induced skin inflammation

244th National Meeting (2012)

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