Synthesis and stereochemical preference of peptide 4-aminocyclophosphamide conjugates as potential prodrugs of phosphoramide mustard for activation by prostate-specific antigen (PSA)

Yongying Jiang, Robert S. DiPaola, Longqin Hu

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)2587-2590
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume19
Issue number9
DOIs
StatePublished - May 1 2009

Bibliographical note

Funding Information:
We gratefully acknowledge the financial support of grant SNJ-CCR 700-009 from the State of New Jersey Commission on Cancer Research and grant RSG-03-004-01-CDD from the American Cancer Society. This work was also partially supported by a pilot grant from the Gallo Prostate Cancer Center of the Cancer Institute of New Jersey that was supported by grant DAMD17-01-1-0755 from the Department of Defense.

Keywords

  • Cyclophosphamide
  • Prodrug
  • Prostate-specific antigen
  • Proteolytic

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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