Phosphate Prodrugs for Amines Utilizing a Fast Intramolecular Hydroxy Amide Lactonization

Abstract

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.

Cyclization-activated Prodrugs

“…This has been exploited by medicinal chemists, especially by Borchardt and co-workers, to develop two-step activation prodrugs [6]. Thus, these authors carried out covalent attachment of model drugs to the carboxyl group of the hydrocinnamic acid moiety while masking the o-hydroxyl substituent as a precursor structure sensitive to either reductases [76][77][78], esterases [79][80][81] or phosphatases [82]. Consequently, the o-hydroxyl group could be released in a first enzymatically-promoted transformation, after which fast lactonization would lead to drug release (Scheme 14).…”

“…Phosphatase-sensitive "trimethyl lock"-based twostep prodrugs of different amines and amino acids were also found to be good substrates for the human placental alkaline phosphatase (AP), although undistinguishable in terms of their activity for AP [82]. Scheme 14.…”

“…Scheme 14. Application of the "trimethyl lock" concept by Borchardt and co-workers for the design of two-step prodrugs (X=RCOO or PO 2 O; R 1 =H, OH) [6,[76][77][78][79][80][81][82]. In what concerns similar esterase-sensitive pro-prodrugs of anisidine as model amine, half-lives determined at 37 ºC in different media were as follows: 4030 min in phosphate buffer (pH 7.4), 11.9 min in the same buffer containing porcine liver esterase, 53.7 min in plasma and 475 min in plasma containing diisopropylfluorophosphate.…”

Design of Potent Aspartic Protease Inhibitors to Treat Various Diseases

“…To overcome this low water-solubility setback, one effective strategy is to convert the water-insoluble parent drugs into hydrophilic prodrugs by covalently attaching appropriate solubilizing moieties such as phosphates [34,35], sugars [36,37], and amino acids [38,39] that can enzymatically release the parent drugs. Phosphate-type water-soluble prodrugs of HIV-1 PR inhibitors were reported by Thaisrivongs and co-workers [32].…”

Synthesis of Bioreductive Esters from Fungal Compounds

“…Quinone delivery systems containing a trimethyl lock have been designed to release toxic moieties selectively and preferentially under reductive/hypoxic conditions [5][6][7][8][9] (Fig. 2).…”