Bisindolylmaleimides And Indolocarbazoles: Synthesis And Structure-Activity Relationship

Bisindolylmaleimides and indolocarbazoles have succeeded in attracting wide attention for their variety of chemical structures and, especially, for their interesting biological activities. This group of compounds shows excellent antitumor activity, targeting several tumor related biological molecules, such as protein kinase C, DNA topoisomerase, etc. Since 1980, modification and structure-activity relationship (SAR) studies on bisindolylmaleimides and indolocarbazoles have been widely carried out in the world. A number of molecular targeting antitumor drug candidates with efficiency and low toxicity have been obtained.A series of bisindolylmaleimides and indolocarbazoles with N-ethyl-N'-nitrile were designed and synthesized. With vitro antitumor activity test, the SAR of this class of compounds was fixed and four antitumor lead compounds with patent activity were acquired.Thirty-three new bisindolylmaleimides were synthesized by introducing alkyl and cyanoalkyl chains to the nitrogen atoms of indole residues, adding polar groups, such as amino, hydroxy, glycosyl, amino acid residues to the nitrogen atom of imide or modifying the aromatic rings with halogen atoms, etc. We also got 15 new indolocarbazoles via the cyclization of the corresponding bisindolylmaleimides, the addition of polar groups to the nucleus and the salt forming.The antitumor activities of the targeting compounds and crucial intermediates were in vitro evaluated both in cellular and molecular levels. SAR of these classes of bisindolylmaleimides and indolocarbazoles was summarized as: (1) proper length of the cyanoalkyl chains is for optimum activity; (2) compounds with single cyanoalkyl chain have better antitumor activity than the both cyanoalkyl chains derivatives; (3) the imide NH is essential for the activity and bisindolylmaleimides are more potential cytotoxicity than the corresponding indolocarbazoles, with both NH_ind replaced; (4) activity retained when the imide NH was substituted with single NH(_ind) replaced; (5) all the 6-halogen substituted bisindolylmaleimides reserved the cell proliferation inhibitory activity, with the exception of 6-fluorine derivatives.Through biological evaluation, four antitumor lead compounds with patent activity were obtained. Bisindolylmaleimides HD-ZWM-19 and HD-ZWM-94 were discovered as potent and selective inhibitors of protein kinase C. Another bisindolylmaleimide HD-ZWM-288 showed broad-spectrum inhibition activities against a panel of tumor cells with IC₅₀ values ranging from 0.46 to 1.95μM. Cell-cycle analysis showed that this class of halogenated compounds could arrest cells in the G₂/M phase and also could induce apoptosis at certain concentrations with dose dependence and time dependence. Indolocarbazole HD-ZWM-376 was also a broad- spectrum inhibitor against five tumor cells, with IC₅₀ values ranging from 0.6μM to 1.27μM. The Mechanism of antitumor activity of HD-ZWM-376 is in the further study.