Synthesis and evaluation of N-acyl-2-(5-fluorouracil-1-yl)-D,L-glycine as a colon-specific prodrug of 5-fluorouracil

✍ Scribed by Jeoung Soo Lee; Yun Jin Jung; Young Mi Kim

• Book ID: 102399005
• Publisher: John Wiley and Sons
• Year: 2001
• Tongue: English
• Weight: 158 KB
• Volume: 90
• Category: Article
• ISSN: 0022-3549
• DOI: 10.1002/jps.1128

✦ Synopsis

N-Nicotinyl-2-(5-¯uorouracil-1-yl)-D,L-glycine (NFG) and N-isonicotinyl-2-(5-¯uorouracil-1-yl)-D,L-glycine (INFG) were synthesized as colon-speci®c prodrugs of 5-¯uorouracil (5-FU). As N-aromatic acyl amides of glycine, they are expected to be stable in the upper intestine and delivered to the colon as an intact form if they are nonabsorbable. Microbial hydrolysis of amide bond in the colon will give 2-(5-¯uorouracil)-D,L-glycine, which releases 5-FU by spontaneous decomposition. NFG and INFG were soluble in water and stable in pH 1.2 and 7.4 buffer solutions. The apparent partition coef®cient of NFG or INFG in 1-octanol/pH 7.4 phosphate buffer solution at 378 was 0.025 or 0.024, respectively. On incubation with cecal contents of rats, conversion of NFG or INFG proceeded only 9 or 5% in 8 h, respectively, producing 5-FU and a metabolite. The metabolite formation was inhibited in the presence of diazouracil, a dihydrouracil dehydrogenase inhibitor. The HPLC retention time of the metabolite from the incubation of 5-FU, NFG, or INFG with cecal contents was identical to dihydro-5-¯uorouracil (dihydro-5FU). When N-nicotinyl-2-hydroxy-D,L-glycine methyl ester (NHGM) was incubated with the cecal contents, the extent of amide bond hydrolysis was 85% in 24 h. The result suggested that steric hindrance imposed by 5-FU at 2-position of glycine retarded the hydrolysis of the amide bond in NFG or INFG and suppressed the prodrug conversion.