Seite - (000218) - in Biomedical Chemistry: Current Trends and Developments

amino acid containing a secondary amine at this position. The pKa of the α-amino group is typically in the range of 8.8 to 10.6 and the acidic α-carboxyl group has a pKa typically between 1.7 and 2.6. The dissociation constant of both the α-amino and α-carboxyl groups are affected by each other and the side chain. The α-amino group in its charged state is strongly electron withdrawing and makes the α-carboxyl group more acidic, thereby lowering its pKa as compared with the typical carboxylic acid pKa of approximately 4.5. At physiological pH, the predominant form of α-amino acids contains both a negative carboxylate and a positive ammonium group. This molecular state is known as a zwitterion and has minimum solubility at the isoelectric point (mid-point between 2 pKa). However, in most α-amino acid prodrugs either the carboxylic acid or amine group is linked to a parent drug, abolishing the zwitterionic form. Exceptions are α-amino acids that have an additional functional group in the side chain amenable to prodrug formation (e.g. -SH in Cys, -OH in Tyr, -NH2 in Lys, -COOH in Asp and Glu) which consequently can maintain a double charge. Water solubility of α-amino acids themselves is largely a function of the polar or nonpolar nature of the side chain. An increase in hydrocarbon content of the side chain (R group) from Gly to Val or Leu decreases water solubility. Consequently, amino acids with shorter hydrocarbon side chains resulted in higher aqueous solubility versus amino acids with longer hydrocarbon side chains for a series of α-amino acid amide prodrugs of dapsone (Fig. 3.1.5, Pochopin, 1995). Moreover, α-amino acids with uncharged but polar R groups are generally more soluble than the corresponding α-amino acids having nonpolar R groups. This trend is in line with the observations from several studies, where phenylalanine as a promoiety resulted in the least soluble prodrug in a series of amino acid prodrugs (Pochopin, 1995; Rautio, 1999). Among the α-amino acids with ionizable R groups, Lys renders relatively high water solubility over the wide pH range due to the ionized ε-amine regardless of prodrug type (e.g. ester or amide) (Pochopin, 1995; Nam, 2003).