Novel Seco Cyclopropa[c]pyrrolo[3,2-e]indole Bisalkylators Bearing a 3,3‘-Arylenebisacryloyl Group as a Linker

We synthesized the novel seco cyclopropa[c]pyrrolo[3,2-e]indole (CPI) bisalkylators and evaluated their antitumor activity. Among these derivatives, 11a (AT-760), in which the two seco 3-methoxycarbonyl-2-trifluoromethyl CPI (MCTFCPI) moieties are connected with a 3,3‘-(1,4-phenylene)bisacryloyl group, was found to exhibit more potent cytotoxicity and antitumor activity against HeLaS3 human uterine cervix carcinoma cells and Colon 26 adenocarcinoma cells, respectively, than 8 (bizelesin, U-77,779). It also appeared that compound 11a exhibits improved in vivo efficacy in the human colon CX-1 model when compared to either compound 8 or mitomycin C (MMC). Efficacious doses for 11a were found to be 2-fold lower than those for 8.