Synthesis and cytotoxic potency of novel tris(1-alkylindol-3-yl)methylium salts: Role of N-alkyl substituents

Bioorganic and Medicinal Chemistry. 2010. Vol. 18. No. 18. P. 6905–6913.

Lavrenov S. N., Luzikov Y. N., Bykov E. E., Reznikova M. I., Stepanova E. V., Glazunova V.A., Volodina Y. L., Tatarsky Jr. V. V., Shtil A. A., Preobrazhenskaya M. N.

Novel derivatives of tris(indol-3-yl)methane and tris(indol-3-yl)methylium salts with the alkyl substituents at the N-atoms of the indole rings were synthesized. An easy substitution of indole rings in trisindolylmethanes for other indoles under the action of acids is demonstrated, and the mechanism of substitution is discussed. To obtain trisindolylmethylium salts, the environmentally safe method of oxidation of trisindolylmethanes with air oxygen in acidic conditions was developed. Tris(1-alkylindol-3-yl)methanes and tris(1-alkylindol-3-yl)methylium salts represent three-bladed molecular propellers whose physico-chemical and biological properties strongly depend on the N-alkyl substituent. The cytotoxicity of novel compounds increased with the number of C atoms in the alkyl chains, with optimal number n = 3-5 whereas the derivatives with longer side chains were less cytotoxic. The most potent novel compounds killed human tumor cells at nanomolar-to-submicromolar concentrations, being one order of magnitude more potent than the prototype antibiotic turbomycin A [tris(indol-3-yl)methylium salt]. Apoptosis in HCT116 colon carcinoma cell line induced by tris(1-pentyl-1H-indol-3-yl)methylium methanesulfonate was detectable at concentrations tolerable by normal blood lymphocytes. Thus, N-alkyl substituted tris(1-alkylindol-3-yl)methylium salts emerge as perspective anticancer drug candidates. 

Keywords: Tumor cells, Cytotoxicity, turbomycin A, Apoptosis, Three-bladed molecular propellers