Synthesis and Evaluation of the Cytotoxicities of Tetraindoles: Observation that the 5-Hydroxy Tetraindole (SK228) Induces G₂Arrest and Apoptosis in Human Breast Cancer Cells

Abstract

Current chemical and biological interest in indole-3-carbinol (I3C) and its metabolites has resulted in the discovery of new biologically active indoles. As part of a program aimed at the development of indole analogues, tetraindoles 1-15 were prepared and their antiproliferative effects on human breast cancer cells were evaluated. The results show that the 5-hydroxy-tetraindole 8 (SK228) has optimum antiproliferative activity against breast adenocarcinoma (MCF 7 and MDA-MB-231) cells and that this activity involves G(2)-phase arrest of the cell cycle with a distinctive increase in the expression of cyclin B1 and phospho-cdc2. Further observations suggest that 5-hydroxy-tetraindole 8 induces apoptosis through externalization of membrane phosphatidylserine, DNA fragmentation, and activation of caspase-3. Given the fact that I3C and its metabolites have been shown to improve therapeutic efficacy and to have a broad range of antitumor activities in human cancer cells, the current findings have important pharmacological relevance as they open a promising route to the development of a potential chemotherapeutic application of tetraindoles as agents for the treatment of breast cancer.

The Tetraindole SK228 Reverses the Epithelial-to-Mesenchymal Transition of Breast Cancer Cells by Up-Regulating Members of the miR-200 Family

“…For example, broccoli-derived compounds like the 3,3′-diindolylmethane (DIM), up-regulate the expression of members of the miR-200 family leading to reversal of the EMT process in pancreatic cancer cells [18]. In an earlier investigation, we showed that tetraindole (1,4-bis{di[1 H -indol-3-yl]methyl}benzene) and its 5-hydroxy tetraindole derivative, SK228, which contains a benzene core structure with four appended hydroxyindole groups, induce G2 arrest and apoptosis in human breast adenocarcinoma (MCF 7 and MDA-MB-231) cells through externalization of membrane phosphatidylserine, DNA fragmentation, and activation of caspase-3 [19]. In addition, it also has been shown that SK228 treatment causes a marked inhibition of the growth of an A549 tumor cell xenograft without producing adverse effects on liver and kidney function of treated mice [20].…”

Role of Indole Scaffolds as Pharmacophores in the Development of Anti-Lung Cancer Agents

“…Huang et al further identified a novel indole derivative, SK228 that can effectively inhibit lung cancer cell lines by ROS production and induce cell death by apoptosis. To evaluate the potency of SK228 against various human cancer cell lines, the authors treated the cells with varying concentrations of SK228 for 48 h. The resulting IC 50 values were found to be 3.4 and 0.3 µM for A549 and H1299 cells respectively [104,105]. Further investigation of the mechanism of action showed that SK228 enhanced mitochondrial ROS production and inflicted DNA damage on cancer cells, ultimately leading to intrinsic mitochondria-dependent mitosis.…”

“…SK228 was synthesized in a single step, as shown in Scheme 14 [105]. A mixture of terephthalaldehyde (80) and 5-hydroxy-indole (81) in the presence of iodine afforded the desired tetraindoles product (SK228).…”

“…Synthesis of SK228 adapted from the reference[105].Kim et al synthesized a novel indirubin-3'-oxime derivative AGM130 with excellent anti-tumor activity and inhibition of cancer growth in A549 cells (Figure 12). Further investigation of the activity on A549 cells demonstrated that AGM130 induced caspase-dependent apoptosis via the mitochondria-mediated intrinsic pathway[106].Liu et al reported a novel indolyl quinoline moiety 3-((7-ethyl-1H-indol-3-yl)-methyl)-2methyl-quinoline (EMMQ) that can arrest cell-growth in NSCLC (A549 and H460) cells(Figure 12).…”

Synthesis and Anticancer Activity Test of 2-Hydroxy-N-Phenylnicotinamide

“…With a little yield obtained from isolation, UK-3A compound has anticancer potent to develop [2]. At present various research groups worldwide are involved in search of more safe anti-inflammatory and anticancer agents [3][4][5][6]. Cancer is the second leading cause of death [7] worldwide after cardiovascular diseases, according to WHO.…”