Phenylalanyl-aminocyclophosphamides as model prodrugs for proteolytic activation: synthesis, stability, and stereochemical requirements for enzymatic cleavage |
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Authors: | Jiang Yongying Hu Longqin |
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Institution: | Department of Pharmaceutical Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA. |
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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. |
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