Prodrugs bonds

Prodrug bond linkage between a peptide and a drug... 

Acidic compounds with N—H bonds such as amides, carbamates, and hydan-toins, may be transformed to /V-rnannich bases to form oral prodrugs [2], These prodrugs are generally made by reacting an amide, carbamate, or hydantoin with formaldehyde and a primary or secondary aliphatic or aromatic amine (Fig. 4). The (V-mannich prodrugs tend to have better physicochemical properties than the parent compounds. The derivatives may have increased water solubility, dissolution rate, and/or lipophilicity. 

Fig. 2. Ligand substitution as a prodrug strategy for metallochem-otherapeutics (a) general scheme of prodrug activation by ligand substitution hydrolysis of a metal—halide bond is a typical activation pathway of metal-based anticancer drugs, as exemplified by the activation of cisplatin (b) and a ruthenium—arene complex (c).

Metabolic pathways rarely lead to breaking a carbon-carbon bond however, there are exceptions such as the conversion of the prodrug nabumetone to an active nonsteroidal anti-inflammatory agent as shown in Figure 4.84 (153). Although the mechanism of this conversion is unknown, if oxidation leads to two adjacent carbonyl groups it weakens the carbon-carbon bond and further oxidation leads the rupture of this bond. 

Beside the MMFO mediated (phase I) reactions there are a few other major reactions that are worthy of note. The two major ones involve ester hydrolysis and alcohol and aldehyde dehydrogenases. All mammalian species have an extensive ability to hydrolyze the ester bond. The products of the reactions then can go on to be further metabolized. In the pharmaceutical industry, this property has been utilized to synthesize prodrugs that is, chemicals that have desirable pharmaceutical properties (generally increased water solubility) that are not converted to their active moiety until hydrolyzed in the body. 

C. P. Landowski, X. Song, P. L. Lorenzi, J. M. Hilfinger, and G. L. Amidon. Flox-uridine amino acid ester prodrugs enhancing Caco-2 permeability and resistance to glycosidic bond metabolism. Pharm Res 22 1510-1518 (2005). 

The present chapter focuses on specific aspects of these challenges, namely peptide bond hydrolysis (chemical and enzymatic) and intramolecular reactions of cyclization-elimination (Fig. 6.4). This will be achieved by considering, in turn a) the enzymatic hydrolysis of prodrugs containing a peptide pro-moiety (Sect. 6.2), b) the chemical hydrolysis of peptides (Sect. 6.3), c) the enzymatic hydrolysis of peptides containing only common amino acids (Sect. 6.4), d) the hydrolysis of peptides containing nonproteinogenic amino acids (Sect. 6.5), and, finally, e) the hydrolysis of peptoids, pseudopeptides and peptidomimetics (Sect. 6.6). 

Another type of reaction was seen for dalvastatin (8.151), a prodrug that bears an unsaturated side chain. The hydrolysis of dalvastatin to the active acid competes with epimerization at C(6), the rate of the reaction being independent of pH above pH 2 [192], The mechanism is believed to be one of heterolytic cleavage of the C(6)-0 bond to generate a C-centered carbonium ion stabilized by the extended conjugated system characteristic of this compound. In the pH range 2 - 7, the rate of epimerization was found to be ca. 100 times faster than hydrolysis. Above pH 7, base catalysis accelerates hydrolysis, the rate of which increases ca. 100-fold between pH 7 and 9. These facts serve only to complicate the design of HMG-CoA reductase inhibitors and the interpretation of their pharmacokinetic behavior. 

Fig. 8.20. Two-step activation ofN-[(acyloxy)methyl] prodrugs, a) Cleavage of the ester bond, which may be enzymatic and/or nonenzymatic, is followed by decomposition of the N-(hy-droxymethyl) intermediate, b) For (V-(hydroxymethyl) derivatives of amides and imides, the decomposition is base-catalyzed, c) For N-(hydroxymethyl) derivatives of amines, the decomposition can be uncatalyzed or undergo acid or base catalysis (modified from [214]).

The 3-(2-hydroxy-4,6-dimethylphenyl)-3-methylbutanoic acid shown in Fig. 8.23, as well as another phenylpropanoic derivative presented below, have been used as pro-moieties to prepare a number of prodrugs of therapeutic peptides [169] [238], Of interest here is that the pro-moiety is linked to the peptide by both amide and ester bonds to form a cyclic, double prodrug, the two-step activation of which is schematized in Fig. 8.24. Briefly, enzymatic hydrolysis of the ester bond unmasks a nucleophile (in this case, a phenol) that carries out an intramolecular attack on the amide bond, resulting in cy-clization of the pro-moiety and elimination of the peptide. [Leu5]enkephalin was one of the therapeutic peptides used to validate the concept, as illustrated in Fig. 8.25 [241],... 

H. Bundgaard, G. J. Rasmussen, Prodrugs of Peptides. 11. Chemical and Enzymatic Hydrolysis Kinetics of N-Acyloxymethyl Derivatives of a Peptide-Like Bond , Pharm. Res. 1991, 8, 1238-1242. 

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