Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
1363985 | Bioorganic & Medicinal Chemistry Letters | 2009 | 4 Pages |
In an effort to develop proteolytically activated prodrugs of phosphoramide mustard by prostate-specific antigen (PSA), a series of tetrapeptide (Cbz-Ser-Ser-Phe-Tyr)-conjugated 4-aminocyclophosphamide (4-NH2-CPA) isomers were synthesized and evaluated as substrates of PSA. The cleavage of the conjugates by PSA were found to be stereoselective as only the two isomers with 4R-configuration were efficiently cleaved by PSA. The cis-(2R,4R)-isomer was the best substrate of PSA with a half-life of 12 min. LC/MS analysis of the incubation solution of this isomer with PSA suggests that 4-NH2-CPA is released upon proteolysis and quickly degrades to cytotoxic phosphoramide mustard. These results clarified the stereochemical requirements of PSA on the peptide conjugates of 4-NH2-CPA and demonstrated the potential of these conjugates as potential PSA-activated prodrugs targeting prostate cancer.
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