Phenylalanyl-aminocyclophosphamides as model prodrugs for proteolytic activation: Synthesis, stability, and stereochemical requirements for enzymatic cleavage

Yongying Jiang, Longqin Hu

Research output: Contribution to journalArticle

16 Citations (Scopus)

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 α-chymotrypsin with a half-life of 20 min, which is much shorter than the 8.9 h to >12 h 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.

Original languageEnglish (US)
Pages (from-to)517-521
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume17
Issue number2
DOIs
StatePublished - Jan 15 2007

Fingerprint

Prodrugs
Chemical activation
Proteolysis
Stereochemistry
Chymotrypsin
Phenylalanine
Isomers
Half-Life
Tumors
Buffers
Phosphates
Tissue
Peptides
Neoplasms
phosphoramide mustard

All Science Journal Classification (ASJC) codes

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

Keywords

  • 4-Aminocyclophosphamide
  • Anticancer prodrugs
  • Cyclophosphamide
  • Phosphoramide mustard
  • Proteolytic activation
  • Site-specific activation
  • gem-Diamines

Cite this

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title = "Phenylalanyl-aminocyclophosphamides as model prodrugs for proteolytic activation: Synthesis, stability, and stereochemical requirements for enzymatic cleavage",
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 α-chymotrypsin with a half-life of 20 min, which is much shorter than the 8.9 h to >12 h 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.",
keywords = "4-Aminocyclophosphamide, Anticancer prodrugs, Cyclophosphamide, Phosphoramide mustard, Proteolytic activation, Site-specific activation, gem-Diamines",
author = "Yongying Jiang and Longqin Hu",
year = "2007",
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language = "English (US)",
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TY - JOUR

T1 - Phenylalanyl-aminocyclophosphamides as model prodrugs for proteolytic activation

T2 - Synthesis, stability, and stereochemical requirements for enzymatic cleavage

AU - Jiang, Yongying

AU - Hu, Longqin

PY - 2007/1/15

Y1 - 2007/1/15

N2 - 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 α-chymotrypsin with a half-life of 20 min, which is much shorter than the 8.9 h to >12 h 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.

AB - 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 α-chymotrypsin with a half-life of 20 min, which is much shorter than the 8.9 h to >12 h 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.

KW - 4-Aminocyclophosphamide

KW - Anticancer prodrugs

KW - Cyclophosphamide

KW - Phosphoramide mustard

KW - Proteolytic activation

KW - Site-specific activation

KW - gem-Diamines

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