Chemistry and Pharmacology of Imexon and Related Cyanoaziridines

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.

Synthesis and Antiproliferative Activity of Phosphorus Substituted 4-Cyanooxazolines, 2-Aminocyanooxazolines, 2-Iminocyanooxazolidines and 2-Aminocyanothiazolines by Rearrangement of Cyanoaziridines

“…However, in contrast to the initial findings, these cyanoaziridines showed no alkylating activity in vitro or in vivo [ 4 ]. These results suggest that the cyano group reduces the reactivity required for the alkylation of DNA bases and that they may selectively react with sulfur moieties in biological thiols such as cysteine, depleting the stores of cysteine and glutathione and subsequently allowing the accumulation of cellular reactive oxygen species (ROS) [ 6 , 7 , 8 ]. Preclinical studies have evaluated the antitumor activity and the mechanism of action of cyanoaziridine AMP423 ( Ib , Figure 1 ) [ 6 ].…”