STRUCTURE-ACTIVITY-RELATIONSHIPS IN A SERIES OF SUBSTITUTED INDOLOCARBAZOLES - TOPOISOMERASE-I AND PROTEIN-KINASE-C INHIBITION AND ANTITUMORAL AND ANTIMICROBIAL PROPERTIES

A series of compounds structurally related to staurosporine, rebeccamy cin, and corresponding aglycones was synthesized, and their activities toward protein kinase C and topoisomerases I and II were tested toget her with their in vitro antitumor efficiency against murine B16 melano ma and P388 leukemia cells. Their antimicrobial activities were also e xamined against a Gram-negative bacterium (Escherichia coli), a yeast (Candida albicans), and three Grampositive bacteria (Bacillus cereus, Streptomyces chartreusis, and Streptomyces griseus). To avoid side eff ects expected with protein kinase C inhibitors, we introduced substitu tion on the maleimide nitrogen and/or a sugar moiety linked to one of the indole nitrogens to obtain specific inhibitors of topoisomerase I with minimal activities on protein kinase C. As expected, these struct ures were inefficient on topoisomerase II, and some of them exhibited a strong activity against topoisomerase I. Generally, dechlorinated co mpounds were found to be more active than chlorinated analogues agains t both purified topoisomerase I and protein kinase C. On the other han d, opposite results were obtained in the cell antiproliferative assays . These results suggest lack of cell membrane permeability in the abse nce of the chlorine residue or cleavage of carbon-chlorine bonds insid e the cell.