Synthesis and Evaluation of Radiolabeled Phosphoramide Mustard with Selectivity for Hypoxic Cancer Cells

Wenting Zhang, Wei Fan, Zhengyuan Zhou, Jered C Garrison

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Tumor hypoxia has been widely explored over the years as a diagnostic and therapeutic marker. Herein, we synthesized an alkyne functionalized version of evofosfamide, a hypoxia-selective prodrug. The purpose of this effort was to investigate if this novel 2-nitroimidazole phosphoramide nitrogen mustard (2-NIPAM) retained hypoxia selectivity and could be utilized in radiopharmaceutical development to significantly increase retention of conjugated agents in hypoxic cells. 2-NIPAM demonstrated good hypoxia selectivity with a 62- and 225-fold increase in cytotoxicity toward PC-3 and DU145 human prostate cancer cell lines, respectively, under hypoxic conditions. Radiolabeling of 2-NIPAM with 125I was accomplished through a Cu(I)-mediated azide-alkyne cycloaddition reaction. The 125I-conjugate demonstrated 13.6 and 17.8% lower efflux rates for DU145 and PC-3 cells, correspondingly, under hypoxic conditions, suggesting that the increased retention is likely due to the known intracellular trapping mechanism. In conclusion, these studies demonstrate the potential of 2-NIPAM in serving as a trapping agent for radiopharmaceutical development.

Original languageEnglish (US)
Pages (from-to)1269-1274
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume8
Issue number12
DOIs
StatePublished - Dec 14 2017

Fingerprint

Mechlorethamine
Nitrogen
Cells
Alkynes
Radiopharmaceuticals
Neoplasms
Azides
Cycloaddition
Cycloaddition Reaction
Prodrugs
Cytotoxicity
Tumors
Prostatic Neoplasms
Cell Line
phosphoramide mustard
phosphoramide
azomycin
Hypoxia
Therapeutics

Keywords

  • 2-NIPAM
  • prodrug
  • prostate cancer
  • radioiodination

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

Cite this

Synthesis and Evaluation of Radiolabeled Phosphoramide Mustard with Selectivity for Hypoxic Cancer Cells. / Zhang, Wenting; Fan, Wei; Zhou, Zhengyuan; Garrison, Jered C.

In: ACS Medicinal Chemistry Letters, Vol. 8, No. 12, 14.12.2017, p. 1269-1274.

Research output: Contribution to journalArticle

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