Tetrahydropyrrolo[3,2-c]azepin-4-ones as a new class of cytotoxic compounds

Pyrroloazepinones 8a–j and 9a–j were designed by structural modification of lead compound 3. These compounds were tested on five tumor cell lines to determine the role of the azeto ring and the 2-methyl substituent in the cytotoxicity of compound 3. Our results show that compounds 8a–j (R1 = CH3) have dramatically reduced cytotoxicity, resulting from the loss of the azeto moiety of lead compound 3. By contrast, azepinones 9a–j (R1 = 4-nitrophenyl) inhibited the proliferation of almost all cancer cell lines tested even though they lack the azeto ring. Preliminary SAR studies with these compounds revealed the importance of halogens at the para- or meta-position of the 1-phenyl moiety. Additionally, derivatives 9a (R2 = H), 9e (R2 = 4-F), and 9g (R2 = 4-OMe) were selectively cytotoxic to U-251 cells. However, none of the pyrroloazepinones inhibited the enzymatic activity of CDK1/cyclin B, CDK5/p25, and GSK-3.

The synthesis of the title compounds was achieved using dimedone as starting material. The observed cytotoxic activity depends of substituent joined to C-2 (R1) of the pyrrole moietyFigure optionsDownload as PowerPoint slide