Protective effects of some azo derivatives of 5-aminosalicylic acid and their PEGylated prodrugs on acetic acid-induced rat colitis

Abstract

The protective and anti-inflammatory effects of azo and azo-linked polymeric prodrugs of 5-aminosalicylic acid (5-ASA) on acetic acid induced colitis in rats were investigated. Three azo prodrugs; 4,4?-dihydroxy- azobenzene-3-carboxilic acid (azo compound I), 4-hydroxy-azobenzene-3,4?- dicarboxilic acid (azo compound II), 4,4?-dihydroxy-3?-formyl- azobenzene-3-carboxylic acid (azo compound III) and their polyethylene glycol (PEG 6000) derivatives were synthesized. Rats were pretreated orally (1 hour prior to induction of colitis) with sulfasalazin (300 mg/kg), azo compounds I, II, III and polyethylene glycol conjugates of azo compounds II and III in doses which had the same amount of 5-ASA as sulfasalazin contains. The colonic damage was examined 24 hours later and characterized by gross microscopic injury and colonic edema. Among prodrugs only azo compound III (215 mg/kg) produced a significant (p<0.01) protective effect against colonic injury comparable with sulfasalazin. Doubling the dose (430 mg/kg) showed more anti-colitis effects. Polyethylene glycol conjugate of azo compounds II and III also showed reduction in the extent of the cell death and tissue disorganization similar to sulfasalazin. While neither sulfasalazin, nor azo compound II and its PEG polymer produced anti-edema effects, both azo compound III and its PEG polymer decreased colon edema significantly (p<0.05). Histological examinations also indicated a marked reduction in tissue injury and inhibition in neutrophil infiltration in rats treated with azo compound III and PEG conjugates of azo compounds II and III. Results of this investigation provide experimental evidence supporting new cytoprotective, antiinflammatory and anti-edema properties of the azo derivatives of 5-ASA and their PEGylated prodrugs.