Details

Autor(en) / Beteiligte

• Nicolaou, Michalis G
• Yuan, Chong-Sheng
• Borchardt, Ronald T

Titel

Phosphate Prodrugs for Amines Utilizing a Fast Intramolecular Hydroxy Amide Lactonization

Ist Teil von

• Journal of organic chemistry, 1996-11, Vol.61 (24), p.8636-8641

Ort / Verlag

American Chemical Society

Erscheinungsjahr

1996

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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.