2. Academic Validation
  3. Design, synthesis and biological evaluation of novel 1,3,4,9-tetrahydropyrano[3,4-b]indoles as potential treatment of triple negative breast cancer by suppressing PI3K/AKT/mTOR pathway

Design, synthesis and biological evaluation of novel 1,3,4,9-tetrahydropyrano[3,4-b]indoles as potential treatment of triple negative breast cancer by suppressing PI3K/AKT/mTOR pathway

  • Bioorg Med Chem. 2021 Dec 31;55:116594. doi: 10.1016/j.bmc.2021.116594.
Jing Qin 1,  Xia Sun 2,  Yingang Ma 3,  Yahong Cheng 2,  Qiushuang Ma 2,  Weiqiang Jing 4,  Sifeng Qu 5,  Lei Liu 6
Affiliations

Affiliations

  • 1 School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Shandong Key Laboratory of Water Pollution Control and Resource Reuse, School of Environmental Science and Engineering, Shandong University, Qingdao, Shandong 266237, China; School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China.
  • 2 Department of Pharmacology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
  • 3 School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China.
  • 4 Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
  • 5 School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China. Electronic address: [email protected].
  • 6 School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China. Electronic address: [email protected].
PMID: 34990979 DOI: 10.1016/j.bmc.2021.116594
Abstract

Triple-negative breast Cancer (TNBC) represents a subset of breast Cancer characterized by high aggressiveness and poor prognosis. Currently, there is no curative therapeutic regimen for TNBC patients. In this study, molecular hybridization strategy is adopted by combining benzopyran and indole pharmacophores together, and a library of structurally simple 1,3,4,9-tetrahydropyrano[3,4-b]indoles was rapidly constructed. The structure-activity relationship studies indicated that compound 23 exhibited the most potent effect against the MDA-MB-231 cells with IC50 value of 2.29 μM. Mechanistic studies revealed that compound 23 inhibited cell proliferation via arresting cell cycle at G0/G1 phase. It induced cell Apoptosis by disruption of mitochondrial membrane potential (MMP), accumulation of Reactive Oxygen Species (ROS), reduction of glutathione (GSH), elevation of intracellular calcium ion (Ca2+) and activation of Caspase cascade. Furthermore, compound 23 significantly inhibited the regulators of PI3K/Akt/mTOR pathway in MDA-MB-231 cells, suggesting that PI3K/Akt/mTOR pathway was involved in the 23-mediated Apoptosis. To our knowledge, this is the first example of the anti-cancer activity study of indole-fused pyrans through suppressing PI3K/Akt/mTOR pathway. Overall, the current study suggested that compound 23 would serve as a promising lead compound for TNBC treatment.

Keywords

1,3,4,9-Tetrahydropyrano[3,4-b] indoles; Apoptosis; Molecular hybridization; PI3K/AKT/mTOR pathway; Triple negative breast cancer.

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