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.