Chemical Basis for the Biological Activity of Imexon and Related Cyanoaziridines

Abstract

Chemical aspects of mode of action of imexon and related cyanoaziridines were studied. These compounds do not alkylate DNA nor react with the epsilon-amino groups of l-lysine, despite the presence of an aziridine ring. They do react readily with biologically important sulfhydryl compounds to give products derived from either aziridine ring opening, interaction with the cyano group of cyanoaziridines, or opening of the iminopyrrolidone ring of imexon. The products from reactions of imexon and related cyanoaziridines with thiols are not as potent as their parent compounds against tumor cells. These results are consistent with biological studies that show that the mechanism of cytotoxicity involves thiol depletion followed by oxidative stress leading to apoptosis.

Redox-Directed Cancer Therapeutics: Molecular Mechanisms and Opportunities

“…In leukemia, myeloma, and pancreatic cancer cell lines in vitro, this very small thiol-reactive organic electrophile (molecular weight ¼ 111.1 Da) induces apoptotic cell death by causing oxidative stress and mitochondrial changes involving spontaneous formation of thiol-adducts with cellular glutathione and protein-bound cysteine residues depleting glutathione in the absence of nuclear genotoxic stress (92,93). The SAR of thiol reactivity of imexon and related electrophilic cyanoaziridines has been elucidated in detail (165), and accumulative data suggest that intracellular thiol conjugation and subsequent depletion may be a crucial factor determining Imexon pharmacodynamic effects on cancer cells. Interestingly, thiol depletion from erythrocytes may serve as a potential clinical biomarker of imexon drug action.…”

A phase I trial of imexon, a pro-oxidant, in combination with docetaxel for the treatment of patients with advanced breast, non-small cell lung and prostate cancer

“…Imexon (Amplimexon®, AmpliMed Corp. Tucson AZ) is an aziridine-derived iminopyrrolidone that has demonstrated direct cytotoxicity by binding sulfhydryls, such as glutathione, increasing reactive oxygen species and reducing mitochondrial membrane potential [1][2][3][4]. The resultant mitochondrial swelling is associated with release of cytochrome C, activation of caspases and induction of apoptosis [5].…”

Compatibility and stability of Imexon in infusion devices and its in vitro biocompatibility

“…Stability after reconstitution Inherent to the reactivity of the aziridine ring present in the molecule, which has been shown to be crucial to its cytotoxic activity [5], Imexon was shown to degrade to several degradation products lacking this ring structure upon accelerated stress testing (Fig. 2) [6].…”