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Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay
Published on: February 9, 2021
In silico, synthesis and anticancer evaluation of benzamide tryptamine derivatives as novel eEF2K inhibitors
Zedong Liu1, Aili Jiang1, Yaqi Wang1
1Li Dak Sum Yip Yio Chin Kenneth Li Marine Biopharmaceutical Research Center, Department of Marine Pharmacy, College of Food and Pharmaceutical Sciences, Ningbo University, Ningbo 315800, Zhejiang, China.
Abstract:
Eukaryotic elongation factor 2 kinase (eEF2K), a member of the atypical α-kinase family, is highly expressed in a variety of tumor tissues. Inhibition of eEF2K function can effectively kill cancer cells without affecting the function of normal cells. Therefore, eEF2K is a promising new target for cancer therapy. In this study, a series of benzamide tryptamine derivatives were designed and synthesized as novel eEF2K inhibitors. The druggability properties of the synthesized compounds were predicted in silico and performed well. The MTT assay indicated that most of these compounds displayed good antiproliferative activity against human leukemia CCRF-CEM and K562 cell lines. The structure-activity relationship (SAR) revealed that substituents with different electronic effects on the C5 position of indole ring or C2', C4' positions of benzene ring have a great influence on the anti-proliferative activity. Among them, 5j demonstrated the highest anti-proliferative activity with IC50 value of 1.63-3.54 μM. this compound displayed an effective eEF2K inhibition by down-regulated the level of phosphorylated eEF2 in CCRF-CEM cells. Additionally, the western blot analysis further revealed that 5j also significantly affected eEF2K-related signaling pathways. Anticancer mechanism studies have shown that 5j arrested the cell cycle in G0/G1 and induced CCRF-CEM cells apoptosis. Furthermore, 5j activated cleaved caspase-9, 8, 3 and cleaved PARP in a time-dependent manner, which suggesting that 5j induced cancer cells apoptosis through both intrinsic and extrinsic pathways. In summary, benzamide tryptamine derivative 5j represents a novel and promising lead structure for the development of eEF2K inhibitors in cancer therapy.
Insights
Researchers developed novel benzamide tryptamine derivatives as potential cancer therapies targeting eukaryotic elongation factor 2 kinase (eEF2K). Compound 5j showed significant anti-cancer activity by inhibiting eEF2K and inducing apoptosis in leukemia cells.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Oncology
Background:
- Eukaryotic elongation factor 2 kinase (eEF2K) is highly expressed in tumors and represents a promising cancer therapeutic target.
- Inhibiting eEF2K selectively eliminates cancer cells while sparing normal cells.
Purpose of the Study:
- To design and synthesize novel benzamide tryptamine derivatives as potent eEF2K inhibitors.
- To evaluate the antiproliferative activity and anticancer mechanisms of these derivatives against human leukemia cell lines.
Main Methods:
- In silico prediction of druggability.
- MTT assays for antiproliferative activity.
- Western blot analysis to assess eEF2K inhibition and related pathways.
- Cell cycle analysis and apoptosis assays.
Main Results:
- Synthesized benzamide tryptamine derivatives showed good antiproliferative activity against leukemia cell lines.
- Compound 5j exhibited the highest potency (IC50: 1.63–3.54 μM) and effectively inhibited eEF2K.
- 5j induced G0/G1 cell cycle arrest and apoptosis through both intrinsic and extrinsic pathways by activating caspases and PARP.
Conclusions:
- Benzamide tryptamine derivative 5j is a promising lead compound for developing novel eEF2K inhibitors for cancer therapy.
- The study elucidates the anticancer mechanism of 5j, highlighting its potential in targeting leukemia.
