SYNTHESIS AND PHYSICAL STUDIES OF AZAMITOSENE AND IMINOAZAMITOSENE REDUCTIVE ALKYLATING-AGENTS - IMINOQUINONE HYDROLYTIC STABILITY, SYN/ANTI-ISOMERIZATION, AND ELECTROCHEMISTRY

The synthesis of 2,3-dihydro-1H-pyrrolo[l,2-a] benzimidazole-5,8-diones (azamitosenes) was carried out in conjunction with the design of potential DNA cross-linkers activated by reduction (reductive alkylation). These quinones resemble mitosene antitumor agents, but are based on the benzimidazole nucleus rather than the indole nucleus. Preliminary results indicate the azamitosenes are potent antitumor agents. Iminoquinone derivatives of azamitosenes (iminoazamitosenes) were synthesized as reductive alkylating agents exhibiting low oxygen toxicity. The iminoazamitosenes are hydrolytically stable in neutral buffers and undergo buffer-catalyzed syn/anti isomerization at the imino center. Electrochemical and oxygen reactivity studies in aqueous buffers indicate the change from quinone to iminoquinone is accompanied by an increase in reduction potential and a decrease in oxygen reactivity of the corresponding reduced species. It is concluded that iminoazamitosenes, and perhaps other iminoquinones, would exhibit low oxygen toxicity during cellular reductive alkylation. © 1990, American Chemical Society. All rights reserved.