Page - (000227) - in Biomedical Chemistry: Current Trends and Developments

(Fig. 3.1.8, Gomes, 2003). Peptide derivatives of some drugs have been prepared and evaluated as prodrug candidates where prodrug activation processes involved DKP formation. One example are the peptide conjugates of the cytotoxic agent vinblastine, designed as potential prodrugs targeted at prostate cancer cells. In vitro and in vivo evaluation showed the best derivative was a conjugate bearing an octapeptide segment attached by an ester linkage to position 4 of vinblastine. This conjugate was found to undergo fast (t1/2 = 12 min) and specific cleavage of the Gln-Ser peptide bond by prostate enzymes, and additional data from metabolism studies supported that the final spontaneous vinblastine release was driven by DKP formation from a dipeptidyl intermediate (Brady, 2002). Figure 3.1.8: Prodrug intramolecular activation via DKP formation. The formation of DKPs was reported as a major degradation pathway for simple alkyl esters (Larsen, 2004) and dipeptide p-nitroanilides (Goolcharran, 1998). Dipeptides have been thus proposed as drug carriers to deliver the parent drug through enzyme-independent processes, namely via DKP formation. Dipeptides are also readily accessible carriers that can be easily modified to optimize the rate of release of the parent drug (Shan, 1997). Some authors have therefore considered that dipeptides might play a crucial role as carriers for