Page - (000228) - in Biomedical Chemistry: Current Trends and Developments

hydroxyl-containing drugs. This hypothesis was developed in a systematic study of the reactivity of paracetamol dipeptide esters, as this phenolic drug represents an excellent leaving group in the course of intramolecular dipeptide ester aminolysis (Santos, 2005) and is known to originate hepatotoxic metabolites (Bertoloni, 2006). Dipeptide esters of paracetamol were found to be quantitatively hydrolysed to the parent drug and corresponding DKPs at physiological pH and temperature. Additional evidence that the rate of paracetamol release depended on the structure of the dipeptide carrier also supported an intramolecular pathway. Paracetamol esterification with dipeptides also led to significant decrease or even elimination of the drug’s hepatotoxic effects on mice, reinforcing the great potential of dipeptide carriers in prodrug design (Santos, 2005). From what has been described, it is clear that a major drawback of dipeptide-based prodrugs is their susceptibility to non-specific peptidases. However, this problem can be easily solved by incorporating at least one non-natural amino acid. For instance, enzymatically stable dipeptides (e.g. containing α-aminoisobutyric acid or Sar) have been successfully employed in prodrugs of cytarabine (Wipf, 1996) and cyclosporine A (CsA) (Hamel, 2004). Dipeptide esters of CsA showed high thermodynamic stability, differential conversion rates under physiological conditions and strongly increased water solubility, offering a novel route for the design of CsA prodrugs (Hamel, 2004). Unnatural amino acids were also used to construct prodrugs of 5- fluorodeoxyuridine (FdU) to improve prodrug stability against protease/esterase action. Interestingly, these compounds were designed to be resistant to certain enzymes but to be susceptible to others. In fact, the antibacterial prodrugs of FdU developed by Wei and Pei are first activated in vivo by peptide deformylase, after which spontaneous intramolecular aminolysis of the resulting dipeptide carrier forms a DKP, with simultaneous release of FdU (Wei, 2000). 3.1.2.3. L-type Amino Acid Transporter Although the classical approach to improve membrane permeability of polar drugs uses lipophilic derivatives to increase passive membrane penetration, the targeted prodrug approach uses transporters designed