title: Phenylalanyl-aminocyclophosphamides as model prodrugs for proteolytic activation: synthesis, stability, and stereochemical requirements for enzymatic cleavage.
abstract: 4-Aminocyclophosphamide (4-NH2-CPA, 7) was proposed as a prodrug moiety of phosphoramide mustard. Four diastereomers of phenylalanine-conjugates of 4-NH2-CPA were synthesized and their stereochemistry was assigned based on chromatographic and spectroscopic data. All diastereomers were stable in phosphate buffer but only the cis-(4R)-isomer of 15 was efficiently cleaved by alpha-chymotrypsin with a half-life of 20 min, which is much shorter than the 8.9h to >12h half-lives found for the other diastereomers. LC-MS analysis of the proteolytic products of cis-(4R)-15 indicated that 4-NH2-CPA was released upon proteolysis and further disintegrated to phosphoramide mustard. These results suggest the feasibility of using peptide-conjugated cis-(4R)-4-NH2-CPA as potential prodrugs for proteolytic activation in tumor tissues.
authors.affiliation: Department of Pharmaceutical Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
authors.forename: Yongying
authors.initials: Y
authors.lastname: Jiang
authors.forename: Longqin
authors.initials: L
authors.lastname: Hu
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002918:Chymotrypsin / Q000378:metabolism; D015195:Drug Design; D004355:Drug Stability; D020536:Enzyme Activators / Q000138:chemical synthesis* / Q000494:pharmacology*; D006207:Half-Life; D008968:Molecular Conformation; D010447:Peptide Hydrolases / Q000378:metabolism*; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology*; D010752:Phosphoramide Mustards / Q000138:chemical synthesis* / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D020536:Enzyme Activators; D010752:Phosphoramide Mustards; D011355:Prodrugs; C030090:phosphoramide mustard; D010649:Phenylalanine; D010447:Peptide Hydrolases; D002918:Chymotrypsin; C117608:alpha-chymotrypsin