1. Facile construction of fused benzimidazole-isoquinolinones that induce cell-cycle arrest and apoptosis in colorectal cancer cells.
- Author
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He, Liu-Jun, Yang, Dong-Lin, Li, Shi-Qiang, Zhang, Ya-Jun, Tang, Yan, Lei, Jie, Frett, Brendan, Lin, Hui-kuan, Li, Hong-yu, Chen, Zhong-Zhu, and Xu, Zhi-Gang
- Subjects
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COLON cancer , *GASTROINTESTINAL tumors , *BENZIMIDAZOLE derivatives , *CELL cycle , *APOPTOSIS - Abstract
Colorectal cancer (CRC) is one of the most frequent, malignant gastrointestinal tumors, and strategies and effectiveness of current therapy are limited. A series of benzimidazole-isoquinolinone derivatives (BIDs) was synthesized and screened to identify novel scaffolds for CRC. Of the compounds evaluated, 7g exhibited the most promising anti-cancer properties. Employing two CRC cell lines, SW620 and HT29, 7g was found to suppress growth and proliferation of the cell lines at a concentration of ∼20 µM. Treatment followed an increase in G 2 /M cell cycle arrest, which was attributed to cyclin B1 and cyclin-dependent kinase 1 (CDK1) signaling deficiencies with simultaneous enhancement in p21 and p53 activity. In addition, mitochondrial-mediated apoptosis was induced in CRC cells. Interestingly, 7g decreased phosphorylated AKT, mTOR and 4E-BP1 levels, while promoting the expression/stability of PTEN. Since PTEN controls input into the PI3K/AKT/mTOR pathway, antiproliferative effects can be attributed to PTEN-mediated tumor suppression. Collectively, these results suggest that BIDs exert antitumor activity in CRC by impairing PI3K/AKT/mTOR signaling. Against a small kinase panel, 7g exhibited low affinity at 5 µM suggesting anticancer properties likely stem through a non-kinase mechanism. Because of the novelty of BIDs, the structure can serve as a lead scaffold to design new CRC therapies. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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