Synthesis and antitumor activity of duocarmycin derivatives: A-Ring pyrrole analogues of duocarmycin B2

Article abstract of DOI:10.1016/0968-0896(96)00132-0

A series of the eight-substituted A-ring pyrrole derivatives of duocarmycin B2 were synthesized, and evaluated for in vitro anticellular activity against HeLa S₃ cells and in vivo antitumor activity against murine sarcoma 180 in mice. In addition, the stability of the analogues in aqueous solution was examined. The 8-H and the 8-CN compounds which cannot structurally release the cyclopropane compound (DU-86), exhibited extremely diminished anticellular activity compared with duocarmycin A (1a) or DU-86. The ethers and the sulfonates which were not converted to DU-86 under usual conditions (35°C, pH 7), showed almost equal in vivo activities to that of 1a. However, their optimal doses were significantly higher than that for 1a. Most of the A-ring pyrrole analogues which can be chemically or enzymatically converted to DU-86, displayed remarkably superior in vivo antitumor activity to 1a. These results suggest that the A-ring pyrrole analogues need to chemically or enzymatically release DU-86 as an active metabolite to exhibit potent in vivo antitumor activity.