A series of compounds structurally related to staurosporine, rebeccamycin, and corresponding aglycones was synthesized, and their activities toward protein kinase C and topoisomerases I and II were tested together with their in vitro antitumor efficiency against murine B16 melanoma and P388 leukemia cells. Their antimicrobial activities were also examined against a Gram-negative bacterium (Escherichia coli), a yeast (Candida albicans), and three Gram-positive bacteria (Bacillus cereus, Streptomyces chartreusis, and Streptomyces griseus). To avoid side effects expected with protein kinase C inhibitors, we introduced substitution 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 structures were inefficient on topoisomerase II, and some of them exhibited a strong activity against topoisomerase I. Generally, dechlorinated compounds were found to be more active than chlorinated analogues against both purified topoisomerase I and protein kinase C. On the other hand, opposite results were obtained in the cell antiproliferative assays. These results suggest lack of cell membrane permeability in the absence of the chlorine residue or cleavage of carbon-chlorine bonds inside the cell.

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Newcompounds, structurally related to the potent protein kinase C inhibitor staurosporine, and substituted on the imide nitrogen with a functional group bearing a labile hydrogen (hydroxymethyl, amino, hydroxy), were synthesized. Their in vitro inhibitory potencies towards protein kinase C and protein kinase A showed that TV-hydroxymethyl and N-hydroxy substitution, unlike alkyl substitution, can provide efficient protein kinase C inhibitors. The antimicrobial activities of these new compoundsagainst Streptomyces chartreusis and Streptomyces griseus, Bacillus cereus, Escherichia coli, Candida albicans and Botrytis cinerea were examined. They proved to be inactive against E. coli and two fungi. The results suggest that there is no link between in vitro inhibition of protein kinase C and inhibition of growth and sporulation of the two Streptomyces tested. Unlike indolocarbazole maleimides, bis-indole maleimides are active against the two Streptomyces species.