Facile construction of fused benzimidazole-isoquinolinones that induce cell-cycle arrest and apoptosis in colorectal cancer cells

Liu Jun He, Dong Lin Yang, Shi Qiang Li, Ya Jun Zhang, Yan Tang, Jie Lei, Brendan Frett, Hui kuan Lin, Hong Yu Li, Zhong Zhu Chen, Zhi Gang Xu

Research output: Contribution to journalArticle

9 Citations (Scopus)

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 G2/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.

Original languageEnglish (US)
JournalBioorganic and Medicinal Chemistry
DOIs
StateAccepted/In press - Jan 1 2018
Externally publishedYes

Fingerprint

Cell Cycle Checkpoints
Colorectal Neoplasms
Cells
Apoptosis
Derivatives
Phosphatidylinositol 3-Kinases
Scaffolds
Tumors
CDC2 Protein Kinase
Cyclin B1
Phosphotransferases
G2 Phase Cell Cycle Checkpoints
Cell Line
Neoplasms
benzimidazole
Therapeutics
Growth

Keywords

  • Apoptosis
  • Benzimidazole
  • Cell-cycle arrest
  • Colorectal cancer
  • Isoquinolinones

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Facile construction of fused benzimidazole-isoquinolinones that induce cell-cycle arrest and apoptosis in colorectal cancer cells. / 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; Xu, Zhi Gang.

In: Bioorganic and Medicinal Chemistry, 01.01.2018.

Research output: Contribution to journalArticle

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 ; Xu, Zhi Gang. / Facile construction of fused benzimidazole-isoquinolinones that induce cell-cycle arrest and apoptosis in colorectal cancer cells. In: Bioorganic and Medicinal Chemistry. 2018.
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AU - Tang, Yan

AU - Lei, Jie

AU - Frett, Brendan

AU - Lin, Hui kuan

AU - Li, Hong Yu

AU - Chen, Zhong Zhu

AU - Xu, Zhi Gang

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