Prevention of acetic acid-induced colitis by desferrithiocin analogs in a rat model.
Iron contributes significantly to the formation of reactive oxygen species via the Fenton reaction. Therefore, we assessed whether a series of desferrithiocin analogs, both carboxylic acids and hydroxamates, could (1) either promote or diminish the iron-mediated oxidation of ascorbate, (2) quench a model radical species, 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS+), and (3) when applied topically, prevent acetic acid-induced colitis in rats. Surprisingly, most of the desferrithiocin analogs inhibited the Fenton reaction to an approximately equivalent degree; however, substantial differences were observed in the capacity of the analogs to scavenge the model radical cation. Four carboxylic acid desferrithiocin analogs and their respective N-methylhydroxamates were tested along with desferrioxamine and Rowasa, a currently accepted topical therapeutic agent for inflammatory bowel disease (IBD), in a rodent model of acetic acid-induced colitis. The colonic damage was quantitated by two independent measurements. Although neither radical scavenging nor prevention of Fenton chemistry was a definitive predictor of in vivo efficacy, the overall trend is that desferrithiocin analogs substituted with an N-methylhydroxamate in the place of the carboxylic acid are both better free radical scavengers and more active against acetic acid-induced colitis. These results represent an intriguing alternative avenue to the development of improved IBD therapeutic agents.
Bergeron
Raymond J
RJ
Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610-0485, USA.
Wiegand
Jan
J
Weimar
William R
WR
Nguyen
John Nhut
JN
Sninsky
Charles A
CA
D019342:Acetic Acid; D000818:Animals; D003092:Colitis / Q000473:pathology* / Q000517:prevention & control*; D004095:Dihydropyridines / Q000494:pharmacology*; D004195:Disease Models, Animal; D004347:Drug Interactions; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology; D008297:Male; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D012680:Sensitivity and Specificity; D013844:Thiazoles / Q000494:pharmacology*
D004095:Dihydropyridines; D013844:Thiazoles; D019342:Acetic Acid; C050223:desferrithiocin