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) bisal kylators and evaluated their antitumor activity. Among these derivatives, 1 1a (AT-760), in which the two seco 3-methoxycarbonyl-2-trifluoromethyl CPI (MCTFCPI) moieties are connected with a 3,3 '-(1,4-phenylene)bisacryloyl gr oup, was found to exhibit more potent cytotoxicity and antitumor activity a gainst HeLaS3 human uterine cervix carcinoma cells and Colon 26 adenocarcin oma cells, respectively, than 8 (bizelesin, U-77,779). It also appeared tha t compound 11a exhibits improved in vivo efficacy in the human colon CX-1 m odel when compared to either compound 8 or mitomycin C (MMC). Efficacious d oses for 11a were found to be 2-fold lower than those for 8.