Design, Synthesis and Biological Evaluation of Quinoline-8-Sulfonamides as Inhibitors of the Tumor Cell-Specific M2 Isoform of Pyruvate Kinase: Preliminary Study

• Published in: Molecules (Basel, Switzerland) Vol. 28; no. 6; p. 2509
• Main Authors: Marciniec, Krzysztof, Rzepka, Zuzanna, Chrobak, Elwira, Boryczka, Stanisław, Latocha, Małgorzata, Wrześniok, Dorota, Beberok, Artur
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.03.2023; MDPI
• Subjects: Alkynes; Amino acids; Analgesics; Analysis; Apoptosis; Binding sites; Bosutinib; Cancer; Care and treatment; Cell growth; Cell Line, Tumor; Cell Proliferation; Cell viability; Contemporary literature; Cycloaddition; Cytotoxicity; Glycolysis; Health aspects; Humans; Hydrogen bonds; Kinases; Ligands; Lung cancer; Metabolism; Mode of action; Molecular docking; Molecular Docking Simulation; Molecular dynamics; Nitrogen; Nutrients; Phase distribution; Physiological aspects; PKM2 level; PKM2 modulators; Protein Isoforms; Proteins; Pyruvate kinase; Pyruvate Kinase - metabolism; Pyruvic acid; Quinoline; Quinolines - pharmacology; quinolinesulfonamide; Sulfonamides; Sulfonamides - pharmacology; Therapeutic targets; Tumors; Poland; PKM2 modulators; PKM2 level; cell viability; molecular docking; quinolinesulfonamide; molecular dynamics
• DOI: 10.3390/molecules28062509
• ISSN: 1420-3049

Cancer cells need to carefully regulate their metabolism to keep them growing and dividing under the influence of different nutrients and oxygen levels. Muscle isoform 2 of pyruvate kinase (PKM2) is a key glycolytic enzyme involved in the generation of ATP and is critical for cancer metabolism. PKM2 is expressed in many human tumors and is regulated by complex mechanisms that promote tumor growth and proliferation. Therefore, it is considered an attractive therapeutic target for modulating tumor metabolism. Various modulators regulate PKM2, shifting it between highly active and less active states. In the presented work, a series of 8-quinolinesulfonamide derivatives of PKM2 modulators were designed using molecular docking and molecular dynamics techniques. New compounds were synthesized using the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. Compound was identified in in silico studies as a potent modulator of muscle isoform 2 of pyruvate kinase. The results obtained from in vitro experiments confirmed the ability of compound to reduce the intracellular pyruvate level in A549 lung cancer cells with simultaneous impact on cancer cell viability and cell-cycle phase distribution. Moreover, compound exhibited more cytotoxicity on cancer cells than normal cells, pointing to high selectivity in the mode of action. These findings indicate that the introduction of another quinolinyl fragment to the modulator molecule may have a significant impact on pyruvate levels in cancer cells and provides further directions for future research to find novel analogs suitable for clinical applications in cancer treatment.