Dextran and 5-aminosalicylic acid (5-ASA) conjugates:synthesis,characterisation and enzymic hydrolysis

摘要

Mesalamine (5-aminosalicylic acid) is the drug of choice for the treatment of Crohn's disease.A scheme for the synthesis of 5-aminosalicylic acid (5-ASA) conjugates of dextrans was developed with a focus on Crohn's disease applications.Dextrans were oxidised using sodium periodate (NaIO_4),where the aldehyde groups formed were coupled with the alpha-amino (-NH_2) group of 5-ASA.The resulting imine bonds were unstable in water and were consequently reduced to secondary amine groups.The effects of different aspects of the conjugation reaction were studied.These included the following:the molecular weight of the dextrans,the molar proportion of NaIO_4 to the dextrans (for periodate oxidation),the pH of the conjugation solutions,the ratio 5-ASA to oxidised polysaccharide and the relationship between the degree of conjugation and the amount of enzyme hydrolysis.Conjugates incubated in HC1 were stable in 0.5 and 1.0 M HC1,but they underwent degradation in 2.0 and 4.0 M HC1.Dextrans (MW 20,000) with various degrees of oxidation (12%,26%,46%,65%,90% and 93%) were also prepared.Each oxidised dextran sample was con-jugated with 5-ASA,and the product was quantified by high-performance liquid chromatography (HPLC).Dextrans with a max-imum degree of oxidation (93%) unsurprisingly gave maximum conjugation of 5-ASA (49.1 mg per 100 mg of product) but were resistant to dextranase hydrolysis.Less oxidised dextrans (12%) conjugated proportionally less 5-ASA (15.1 mg per 100 mg of prod-uct) but were successfully hydrolysed by dextranase,suggesting their potential applications for the treatment of Crohn's disease in the distal ileum and proximal colon.