Several new prodrug systems for amines, alcohols, and peptides are reviewed. The design of these new prodrug systems takes advantage of several facile intramolecular cyclization reactions, that permit separate manipulation of the release kinetics independent of the structural features of the drug moiety. Such systems can be used for the preparation of esterase-, phosphatase-, and redox-sensitive prodrugs of amines and alcohols and esterase-sensitive cyclic prodrugs of peptides and peptide mimetics.

A novel phosphate prodrug system for amines, amino acids, peptides, and peptide mimetics, which utilizes a fast hydroxy amide lactonization of a 3-(2‘-hydroxy-4‘,6‘-dimethylphenyl)-3,3-dimethylpropionic amide system, was developed. Prodrugs of five model amine/amino acids, including p-anisidine, GlyOMe, PheOMe, LysOMe, and Asp-α-OMe, were synthesized. The syntheses of these model phosphate prodrugs were accomplished by coupling the amine or the protected amino acids with 3-[2‘-(dibenzylphosphono)oxy-4‘,6‘-dimethylphenyl]-3,3-dimethylpropionic acid using coupling agents such as bis(2-oxo-3-oxazolidinyl)phosphinic chloride and 1-(3-dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride, followed by hydrogenolysis. These phosphate prodrugs were evaluated as substrates for the human placental alkaline phosphatase (AP). The structural features of the amine/amino acids attached to the carboxylic acid group of the promoiety were not found to significantly affect the substrate activity for AP, as evidenced by the small variations observed in the Michaelis−Menten parameters (K m and V max) of the phosphate prodrugs. Results obtained from this study suggest that such a phosphate prodrug system may be applied to a variety of structurally diverse amine-containing drugs.

No abstract

The chemical stability studies of amides of 3-(3',6'-dioxo-2',4'-dimethyl-1',4'-cyclohexadienyl)-3,3-dimethylpropionic acid (Qa) [Qop(a-j)] were conducted in order to determine the utility of this redox-sensitive system as a potential prodrug promoiety or redox-sensitive protecting group in organic synthesis. This study showed that quinone propionic amides of aniline derivatives [Qop(a-d)] underwent rapid degradation in mildly acidic conditions (pH 4.5-6.0) to yield degradation products resulting from the intramolecular 1,2- or 1,4- conjugate addition of the amide nitrogen to the quinone ring. This conjugate addition was found to be specific base-catalyzed and independent of the para substituent on the aromatic ring of the amine. The predominant route of degradation yielded a five-membered ring spirolactam. By altering the nature of the amine component of the amide, these degradation reactions were prevented. Amides of Qa other than those of the aniline type [Qop(e-j)] were found to be substantially more stable and were thus proposed as the more suitable candidates for this potential redox-sensitive prodrug system and redox-sensitive protecting group for amines and alcohols in organic synthesis.

No abstract