Synthesis and in vitro evaluation of N-nicotinoylglycyl-2-(5-fluorouracil-1-yl)-d,l-glycine as a colon-specific prodrug of 5-fluorouracil

N-Nicotinoylglycyl-2-(5-fluorouracil-1-yl)-d,l-glycine (NGFG) was synthesized as a colon-specific prodrug of 5-fluorouracil (5-FU) expecting that hydrolysis of nicotinoyl and glycyl moieties by microbial enzymes in the colon will give 2-(5-fluorouracil-1-yl)-d,l-glycine, which releases 5-FU spontaneously. To in vitro-evaluate colon targetability of NGFG, apparent partition coefficient and chemical/biochemical stability of NGFG in the contents or/and tissue of the various segments of the gastrointestinal tract were determined. Low partition coefficient and stability of NGFG in the upper intestinal condition suggested its delivery to the colon in intact form after oral administration. Incubation with rat cecal contents produced 5-FU and its metabolite about 16%. Structural modification to enhance amide hydrolysis, the rate determining step in NGFG bioactivation, is suggested.