Synthesis and antitumor activity of duocarmycin derivatives: Modification at C-8 position of A-ring pyrrole compounds bearing the simplified DNA-binding groups

A series of the 8-O-substituted A-ring pyrrole derivatives of duocarmycin b earing the simplified DNA-binding moieties such as cinnamoyl or heteroaryla cryloyl groups were synthesized, and evaluated for in vitro anticellular ac tivity against HeLa S-3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. In addition, the stability of the 8-O-substituted ana logues in aqueous solution and the conversion to their active form (cyclopr opane compound) from the 8-O-substituted analogues in mice or human serum w ere examined. The 8-O-substituted A-ring pyrrole derivatives bearing the si mplified DNA-binding moieties showed remarkably potent in vivo antitumor ac tivity and low peripheral blood toxicity compared with the 8-O-substituted A-ring pyrrole derivatives having the trimethoxyindole skeleton in segment- B (Seg-B), which were equal to 8-O-[(N-methylpiperazinyl)carbonyl] derivati ves of 4'-methoxycinnamates and 4'-methoxy-beta-heteroarylacrylates. Moreov er, among 8-O-substituted analogues, several compounds can be chemically or enzymatically converted to their active form in human serum. This result i ndicated that new 8-O-substituted derivatives were different prodrugs from KW-2189 and 8-O-substituted analogues being the same type of prodrug as KW- 21S9. (C) 2000 Elsevier Science Ltd. All rights reserved.