Том 25, № 3 (2025)
- Жылы: 2025
- Мақалалар: 4
- URL: https://kld-journal.fedlab.ru/1871-5206/issue/view/14216
Oncology
Advancements in Pyrazine Derivatives as Anticancer Agents: A Comprehensive Review (2010-2024)
Аннотация
Cancer, an intricate and formidable disease, continues to challenge Medical Science with its diverse manifestations and relentless progression. In the pursuit of novel therapeutic strategies, organic heterocyclic compounds have emerged as promising candidates due to their versatile chemical structures and intricate interactions with biological systems. Among these, pyrazine derivatives are characterized by a six-membered aromatic ring containing four carbon and two nitrogen atoms situated in a 1,4-orientation. These compounds garnered significant attention for their potential as anticancer agents. This comprehensive review provides a detailed analysis of the advancements made during this timeframe, encompassing the chemical diversity of pyrazine derivatives, their mechanisms of action at the cellular level, and structure-activity relationships, spanning the years 2010 to 2024. By examining their therapeutic potential, challenges, and future prospects, this review offers valuable insights into the evolving landscape of pyrazine derivatives as potent tools in the fight against cancer.
151-163
Pioneering the Battle Against Breast Cancer: The Promise of New Bcl-2 Family
Аннотация
Currently, breast cancer is the most common cancer type, accounting for 1 in every 4 cancer cases. Leading both in mortality and incidence, breast cancer causes 1 in 4 cancer deaths. To decrease the burden of breast cancer, novel therapeutic agents which target the key hallmarks of cancer, are being explored. The Bcl-2 family of proteins has a crucial role in governing cell death, making them an attractive target for cancer therapy. As cancer chemotherapies lead to oncogenic stress, cancer cells upregulate the Bcl-2 family to overcome apoptosis, leading to failure of treatment. To fix this issue, Bcl-2 family inhibitors, which can cause cell death, have been introduced as novel therapeutic agents. Members of this group have shown promising results in in-vitro studies, and some are currently in clinical trials. In this review, we will investigate Bcl-2 family inhibitors, which are already in trials as monotherapy or combination therapy for breast cancer, and we will also highlight the result of in vitro studies of novel Bcl-2 family inhibitors on breast cancer cells. The findings of these studies have yielded encouraging outcomes regarding the identification of novel Bcl-2 family inhibitors. These compounds hold significant potential as efficacious agents for employment in both monotherapy and combination therapy settings.
164-178
In silico-driven identification of Pranlukast as a Stabilizer of PD-L1 Homodimers
Аннотация
Introduction:Programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) are critical immune checkpoints in cancer biology. Multiple small-molecule drugs have been developed as inhibitors of the PD-1/PD-L1 axis. Those drugs promote the formation of PD-L1 homodimers, causing their stabilization, internalization, and subsequent degradation. Drug repurposing is a strategy that expedites the clinical translation by identifying new effects of drugs with clinical use. Herein, we aimed to repurpose drugs as inductors of PD-L1 homodimerization and, therefore, as potential inhibitors of PD-L1.
Methods:We generated a hybrid pharmacophore model by analyzing the structures of reported ligands that induce PD-L1 homodimerization and their target-binding mode. Pharmacophore-matching compounds were selected from a chemical library of Food and Drug Administration (FDA)-approved drugs. Their binding modes to PDL1 homodimers were assessed by molecular docking and the stability of the complexes and the corresponding binding energies were evaluated by molecular dynamics (MD) simulations. Finally, the activity of one drug as promoter of PD-L1 homodimerization was assessed in protein crosslinking assays.
Results:We identified 12 pharmacophore-matching compounds, but only 4 reproduced the binding mode of the reference inhibitors. Further characterization by MD showed that pranlukast, an antagonist of leukotriene receptors that is used to treat asthma, generated stable and energy-favorable interactions with PD-L1 homodimers and induced homodimerization of recombinant PD-L1.
Conclusion:Our results suggest that pranlukast inhibits the PD-1/PD-L1 axis, meriting its repurposing as an antitumor drug.
179-193
Anticancer Properties Against Select Cancer Cell Lines and Metabolomics Analysis of Tender Coconut Water
Аннотация
Background:Tender Coconut Water (TCW) is a nutrient-rich dietary supplement that contains bioactive secondary metabolites and phytohormones with anti-oxidative and anti-inflammatory properties. Studies on TCW’s anti-cancer properties are limited and the mechanism of its anti-cancer effects have not been defined.
Objective:In the present study, we investigate TCW for its anti-cancer properties and, using untargeted metabolomics, we identify components form TCW with potential anti-cancer activity.
Methodology:Cell viability assay, BrdU incorporation assay, soft-agar assay, flow-cytometery, and Western blotting were used to analyze TCW’s anticancer properties and to identify mechanism of action. Liquid chromatography- Tandem Mass Spectroscopy (LC-MS/MS) was used to identify TCW components.
Results:TCW decreased the viability and anchorage-independent growth of HepG2 hepatocellular carcinoma (HCC) cells and caused S-phase cell cycle arrest. TCW inhibited AKT and ERK phosphorylation leading to reduced ZEB1 protein, increased E-cadherin, and reduced N-cadherin protein expression in HepG2 cells, thus reversing the ‘epithelial-to-mesenchymal’ (EMT) transition. TCW also decreased the viability of Hep3B hepatoma, HCT-15 colon, MCF-7 and T47D luminal A breast cancer (BC) and MDA-MB-231 and MDA-MB-468 triplenegative BC cells. Importantly, TCW did not inhibit the viability of MCF-10A normal breast epithelial cells. Untargeted metabolomics analysis of TCW identified 271 metabolites, primarily lipids and lipid-like molecules, phenylpropanoids and polyketides, and organic oxygen compounds. We demonstrate that three components from TCW: 3-hydroxy-1-(4-hydroxyphenyl)propan-1-one, iondole-3-carbox aldehyde and caffeic acid inhibit the growth of cancer cells.
Conclusion:TCW and its components exhibit anti-cancer effects. TCW inhibits the viability of HepG2 hepatocellular carcinoma cells by reversing the EMT process through inhibition of AKT and ERK signalling.
207-221