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A novel tetrahydroisoquinoline (THIQ) analogue induces mitochondria-dependent apoptosis

Xia Sun1, Min Liu2, Luyao Gao1

  • 1Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, 250012, China.

European Journal of Medicinal Chemistry
|March 25, 2018
PubMed

Insights

Novel tetrahydroisoquinoline (THIQ) analogues were synthesized to combat non-small cell lung cancer (NSCLC). Analogue 5c effectively inhibited A549 lung cancer cell proliferation by inducing apoptosis and activating key cellular pathways.

Area of Science:

  • Medicinal Chemistry
  • Cancer Biology
  • Pharmacology

Background:

  • Non-small cell lung cancer (NSCLC) remains a major global health concern with limited therapeutic options.
  • Existing treatments for NSCLC often face challenges with efficacy and rapid development of drug resistance.
  • Previous research indicated anti-proliferative activity of a C1-phenylethynyl tetrahydroisoquinoline (THIQ) analogue in prostate cancer cells, but with lower potency against lung cancer cells.

Purpose of the Study:

  • To develop novel THIQ analogues with improved anti-cancer potency against A549 lung cancer cells.
  • To investigate the anti-proliferative effects and underlying mechanisms of these new analogues.
  • To explore the utility of oxidative C-H functionalization in enhancing drug efficacy.

Main Methods:

  • Synthesis of novel THIQ analogues (5a-d) utilizing an oxidative C-H functionalization strategy.
  • Evaluation of anti-cancer activity against A549 lung cancer cells, including IC50 determination.
  • Assessment of cell cycle progression (G0/G1 arrest) and apoptosis induction.
  • Analysis of cellular events such as reactive oxygen species (ROS) generation, mitochondrial membrane potential, glutathione levels, intracellular calcium, and Caspase-3 activation.
  • Investigation of DNA damage and p53 pathway activation.

Main Results:

  • Analogue 5c demonstrated significant dose-dependent inhibition of A549 cell proliferation with an IC50 of 14.61 ± 1.03 μM.
  • Analogue 5c induced cell cycle arrest at the G0/G1 phase and promoted apoptosis.
  • Treatment with analogue 5c led to increased ROS, disrupted mitochondrial membrane potential, reduced glutathione, elevated intracellular calcium, and activated Caspase-3.
  • Analogue 5c caused DNA double-strand breaks and activated the p53 pathway in A549 cells.

Conclusions:

  • The oxidative C-H functionalization strategy successfully generated analogue 5c with enhanced anti-cancer efficacy.
  • Analogue 5c exerts its anti-cancer effect by inducing mitochondria-dependent apoptosis in A549 lung cancer cells.
  • The findings suggest that analogue 5c is a promising candidate for further development as an NSCLC therapeutic agent.
Keywords:
ApoptosisLung cancerMitochondriaROSTHIQ analogue 5c

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