5-Aminosalicylic Acid Azo-Linked to Procainamide Acts as an Anticolitic Mutual Prodrug via Additive Inhibition of Nuclear Factor kappaB.
To improve the anticolitic efficacy of 5-aminosalicylic acid (5-ASA), a colon-specific mutual prodrug of 5-ASA was designed. 5-ASA was coupled to procainamide (PA), a local anesthetic, via an azo bond to prepare 5-(4-{[2-(diethylamino)ethyl]carbamoyl}phenylazo)salicylic acid (5-ASA-azo-PA). 5-ASA-azo-PA was cleaved to 5-ASA and PA up to about 76% at 10 h in the cecal contents while remaining stable in the small intestinal contents. Oral gavage of 5-ASA-azo-PA and sulfasalazine, a colon-specific prodrug currently used in clinic, to rats showed similar efficiency in delivery of 5-ASA to the large intestine, and PA was not detectable in the blood after 5-ASA-azo-PA administration. Oral gavage of 5-ASA-azo-PA alleviated 2,4,6-trinitrobenzenesulfonic acid-induced rat colitis. Moreover, combined intracolonic treatment with 5-ASA and PA elicited an additive ameliorative effect. Furthermore, combined treatment with 5-ASA and PA additively inhibited nuclear factor-kappaB (NFκB) activity in human colon carcinoma cells and inflamed colonic tissues. Finally, 5-ASA-azo-PA administered orally was able to reduce inflammatory mediators, NFκB target gene products, in the inflamed colon. 5-ASA-azo-PA may be a colon-specific mutual prodrug acting against colitis, and the mutual anticolitic effects occurred at least partly through the cooperative inhibition of NFκB activity.
College of Pharmacy, Pusan National University , Busan 609-735, Republic of Korea.
Wooseong
W
Kim
College of Pharmacy, Pusan National University , Busan 609-735, Republic of Korea.
Joon
J
Nam
College of Pharmacy, Pusan National University , Busan 609-735, Republic of Korea.
Sunyoung
S
Lee
College of Pharmacy, Pusan National University , Busan 609-735, Republic of Korea.
Seongkeun
S
Jeong
College of Pharmacy, Pusan National University , Busan 609-735, Republic of Korea.
Yunjin
Y
Jung
D000818:Animals; D001391:Azo Compounds / Q000737:chemistry / Q000494:pharmacology*; D003092:Colitis / Q000188:drug therapy*; D003106:Colon / Q000187:drug effects; D008297:Male; D019804:Mesalamine / Q000737:chemistry / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism*; D011342:Procainamide / Q000737:chemistry / Q000494:pharmacology*; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014302:Trinitrobenzenesulfonic Acid / Q000737:chemistry / Q000494:pharmacology
D001391:Azo Compounds; D016328:NF-kappa B; D011355:Prodrugs; D019804:Mesalamine; D014302:Trinitrobenzenesulfonic Acid; D011342:Procainamide
5-aminosalicylic acid; colitis; colon-specific prodrug; nuclear factor kappaB; procainamide