Synthesis and stereochemical preference of peptide 4-aminocyclophosphamide conjugates as potential prodrugs of phosphoramide mustard for activation by prostate-specific antigen (PSA).
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-NH(2)-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 12min. LC/MS analysis of the incubation solution of this isomer with PSA suggests that 4-NH(2)-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-NH(2)-CPA and demonstrated the potential of these conjugates as potential PSA-activated prodrugs targeting prostate cancer.
Department of Pharmaceutical Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
Yongying
Y
Jiang
Robert S
RS
Dipaola
Longqin
L
Hu
D002853:Chromatography, Liquid / Q000379:methods; D003520:Cyclophosphamide / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D008956:Models, Chemical; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology; D011355:Prodrugs / Q000737:chemistry*; D017430:Prostate-Specific Antigen / Q000737:chemistry*; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D020033:Protein Isoforms; D013237:Stereoisomerism; D013997:Time Factors
D010455:Peptides; D011355:Prodrugs; D020033:Protein Isoforms; D003520:Cyclophosphamide; D017430:Prostate-Specific Antigen