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

doi:10.1016/j.bmcl.2009.03.009

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 journal › Article › peer-review

18 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 language	English
Pages (from-to)	2587-2590
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	19
Issue number	9
DOIs	https://doi.org/10.1016/j.bmcl.2009.03.009
State	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bmcl.2009.03.009

Cite this

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

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.",

keywords = "Cyclophosphamide, Prodrug, Prostate-specific antigen, Proteolytic",

author = "Yongying Jiang and DiPaola, {Robert S.} and Longqin Hu",

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.",

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doi = "10.1016/j.bmcl.2009.03.009",

language = "English",

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Synthesis and stereochemical preference of peptide 4-aminocyclophosphamide conjugates as potential prodrugs of phosphoramide mustard for activation by prostate-specific antigen (PSA). / Jiang, Yongying; DiPaola, Robert S.; Hu, Longqin.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 19, No. 9, 01.05.2009, p. 2587-2590.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Synthesis and stereochemical preference of peptide 4-aminocyclophosphamide conjugates as potential prodrugs of phosphoramide mustard for activation by prostate-specific antigen (PSA)

AU - Jiang, Yongying

AU - DiPaola, Robert S.

AU - Hu, Longqin

N1 - 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.

PY - 2009/5/1

Y1 - 2009/5/1

N2 - 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.

AB - 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.

KW - Cyclophosphamide

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KW - Prostate-specific antigen

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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