BISINDOLYLMALEIMIDES LINKED TO DNA MINOR-GROOVE BINDING LEXITROPSINS - SYNTHESIS, INHIBITORY ACTIVITY AGAINST TOPOISOMERASE-I, AND BIOLOGICAL EVALUATION

The synthesis, characterization, inhibitory activity against topoisome rase I, and biological evaluation of a series of oligopeptide-substitu ted bisindolylmaleimides 7-12 are described. Compounds 7-9, which cont ain a basic C-terminus function such as (dimethylamino)propyl and bind to DNA with C-50 values of 200, 160, and 135 mu M, respectively, exhi bited inhibition of topoisomerase I in a concentration dependent manne r. Also, the relative order of observed topoisomerase I inhibition is 9 > 8 > 7 at less than or equal to 100 mu M concentration, correspondi ng to the increase of the number of pyrrole units in the oligopeptide moiety. Compounds 10-12, which contain an electrostatically neutral mo iety, such as methyl ester, did not bind to DNA templates nor inhibit topoisomerase I. However, the cytotoxicity activities of these compoun ds were 1.5 times greater than those of compounds 7-9.