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Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay
Published on: February 9, 2021
Design, synthesis and anticancer activity of β-carboline based pseudo-natural products by inhibiting AKT/mTOR
Lijie Lv1, Kunlin Song2, Yijie Xiao1
1Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention (Ministry of Education), Institute of Life Sciences & Department of Urology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China.
Abstract:
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and remains the leading cause of cancer deaths. Much progress has been made to treat NSCLC, however, only limited patients can benefit from current treatments. Thus, more efforts are needed to pursue novel molecular modalities for NSCLC treatment. It was demonstrated that pseudo-natural products (PNP) are a critical source for antitumor drug discovery. Herein, we describe a CH activation protocol for the expedient construction of a focused library utilizing the PNP rational design strategy. This protocol features a rhodium-catalyzed CH activation/ [4+2] annulation reaction between N-OAc-indole-2-carboxamide and alkynyl quinols, enabling facile access to diverse quinol substituted β-carboline derivatives (31 examples). The anticancer activities were assessed in vitro against NSCLC cell line A549, yielding a potent antiproliferative β-carboline derivative (8r) with an IC50 value of 0.8 ± 0.1 µM. Further investigation revealed that this compound could decrease the expression of Caspase 3, and increase the expression of autophagic protein Cyclin B1, thus markedly inducing autophagy and apoptosis. Mechanistic study suggested that 8r could be a potent anti-NSCLC agent through the AKT/mTOR signaling pathway in A549 cells. Moreover, the anticancer activities were also assessed against three other cancer cell lines, and 8r exhibits a broader inhibitory effect on cell proliferation in all cancer cell lines tested. These results indicated that carboline-based PNPs show great potential to induce cell autophagy and apoptosis, which serve as good leads for further drug discovery.
Insights
Researchers developed a new method to create pseudo-natural products for non-small cell lung cancer (NSCLC) treatment. A potent compound, 8r, effectively induced apoptosis and autophagy in NSCLC cells, showing promise for drug discovery.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Biology
Background:
- Non-small cell lung cancer (NSCLC) is a leading cause of cancer mortality with limited treatment options.
- Pseudo-natural products (PNPs) offer a promising avenue for novel antitumor drug discovery.
- Development of efficient synthetic strategies is crucial for exploring new therapeutic agents.
Purpose of the Study:
- To develop a novel CH activation protocol for synthesizing diverse β-carboline derivatives using a PNP rational design strategy.
- To evaluate the in vitro anticancer activity of the synthesized compounds against NSCLC.
- To investigate the mechanism of action of the most potent compound.
Main Methods:
- A rhodium-catalyzed CH activation and [4+2] annulation reaction was employed to construct a library of β-carboline derivatives.
- Anticancer activity was assessed against the A549 NSCLC cell line, determining IC50 values.
- Western blotting was used to analyze the expression of apoptosis-related proteins (Caspase 3) and autophagy markers (Cyclin B1).
- Mechanistic studies explored the involvement of the AKT/mTOR signaling pathway.
Main Results:
- A library of 31 quinol-substituted β-carboline derivatives was synthesized.
- Compound 8r demonstrated potent antiproliferative activity against A549 cells with an IC50 of 0.8 ± 0.1 µM.
- Compound 8r induced apoptosis and autophagy by decreasing Caspase 3 and increasing Cyclin B1 expression.
- Mechanistic studies indicated that 8r acts via the AKT/mTOR pathway in A549 cells.
- Compound 8r showed broad inhibitory effects across multiple cancer cell lines.
Conclusions:
- The developed CH activation protocol provides facile access to diverse β-carboline derivatives for drug discovery.
- Compound 8r is a potent anti-NSCLC agent that induces cell death through autophagy and apoptosis.
- Carboline-based PNPs represent a promising class of compounds for developing new NSCLC therapeutics.
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