Synthesis and cytotoxic activity of new azepino[3′,4′:4,5]pyrrolo[2,1-a]isoquinolin-12-ones

Abstract A series of azepino[3′,4′:4,5]pyrrolo[2,1- a ]isoquinolin-12-ones ( 3a–f) , that were conformationally restricted analogs of lead compound 2, were designed as potential cytotoxic compounds and synthesized using a radical oxidative aromatic substitution reaction as the key step. Compounds 3a–f were tested on five tumor cell lines to determine the conformational requirements for biological activity of compound 2 . The results show that conformational restrictions on compound 2 , generating the derivatives 3a – f , do not appreciably reduce the cytotoxic activity of 2 , although compound 3d (R = Br) showed good activity against U-251 cells. Preliminary structure–activity relationship studies with these compounds revealed the importance of halogens bonded to the isoquinoline moiety. Additionally, derivatives 3f (R = NO 2 ) and 3b (R = F) were cytotoxic to PC-3 and K-562 cells. However, none of the azepino[3′,4′:4,5]pyrrolo[2,1- a ]isoquinolinones inhibited the enzymatic activity of CDK1/cyclin B, CDK5/p25, or GSK-3.