Chemistry and pharmacology of imexon and related cyanoaziridines

W. A. Remers, Robert T Dorr

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Following the demonstration that addition of a 2-cyano group to aziridines prevented DNA alkylation and thus reduced toxicity, many novel 2-cyanoaziridines were synthesized and evaluated as immunomodulating and antitumor agents. They typically reacted with thiols such as cysteine, depleting them and allowing the accumulation of reactive oxygen species. Two of these compounds, azimexon and ciamexon, showed activity against tumors in clinical trials. Imexon was produced by cyclization of 2-cyanoaziridine-1-carboxamide in the presence of hydroxide ions. The two enantiomers were prepared by a process involving chiral chromatography. They were equipotent against cultured tumor cells. Imexon also reacts with thiols and it is especially potent against multiple myeloma in cell cultures. An efficient chemical synthesis and a lyophilization formulation of imexon as a water soluble, injectible drug, were developed. In Phase I and I/II clinical trials imexon showed hints of activity against a variety of tumors, but a randomized double-blind Phase II trial of imexon plus gemcitabine versus gemcitabine alone in pancreatic cancer showed no enhancement of activity above that of gemcitabine alone. This result was disappointing because in cell culture and mice the two compounds were synergistic. Based on a complete response in a Phase I trial, a new Phase II clinical trial of imexon is underway in non-Hodgkins lymphoma.

Original languageEnglish (US)
Pages (from-to)5745-5753
Number of pages9
JournalCurrent Medicinal Chemistry
Volume19
Issue number33
DOIs
StatePublished - 2012

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gemcitabine
Pharmacology
Tumors
Cell culture
Sulfhydryl Compounds
Cell Culture Techniques
Aziridines
Clinical Trials
Cultured Tumor Cells
Phase II Clinical Trials
Freeze Drying
Enantiomers
Cyclization
Alkylation
Chromatography
Multiple Myeloma
Pancreatic Neoplasms
Antineoplastic Agents
Non-Hodgkin's Lymphoma
Cysteine

Keywords

  • Antitumor
  • Clinical
  • Cyanoaziridine
  • Imexon
  • Immunomodulation
  • Pharmacology
  • Reactivity
  • Structure-activity
  • Synthesis
  • Toxicity

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Chemistry and pharmacology of imexon and related cyanoaziridines. / Remers, W. A.; Dorr, Robert T.

In: Current Medicinal Chemistry, Vol. 19, No. 33, 2012, p. 5745-5753.

Research output: Contribution to journalArticle

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