Coumarin-1,2,3-Triazole Conjugates as Molecular Scaffolds for the Selective Induction of ROS-Driven Apoptosis in Cancer Cells in the Development of Pyruvate Kinase M2 Inhibitors

  • ACS Omega. 2025 Dec 9;10(50):61899-61914. doi: 10.1021/acsomega.5c08635.
Gabriel Ouverney  1 ,  Amanda de Andrade Borges  2 ,  Acácio Souza da Silva  2 ,  Caroline Reis Santiago Paschoal  3  4 ,  Paula Alvarez Abreu  3 ,  Analice Gonçalves Rodrigues da Cruz  2 ,  Mateus de Freitas Brito  2 ,  Lucas Silva Abreu  2 ,  Vitor Francisco Ferreira  5 ,  Fernando de Carvalho da Silva  2 ,  Bruno Kaufmann Robbs  6 ,  Luana da Silva Magalhães Forezi  2
Affiliations
  • 1. Graduate Program in Morphological Sciences, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Fundão, Rio de Janeiro, RJ 21941-902, Brazil.
  • 2. Department of Organic Chemistry, Institute of Chemistry, Fluminense Federal University, Valonguinho Campus, Niterói, RJ 24020-150, Brazil.
  • 3. Institute of Biodiversity and Sustainability (NUPEM), Federal University of Rio de Janeiro, Macaé, RJ 27965-045, Brazil.
  • 4. Graduate Program in Pharmaceutical Sciences, School of Pharmacy, Ilha Do Fundão, Rio de Janeiro, RJ 21941-599, Brazil.
  • 5. Department of Pharmaceutical Technology, School of Pharmacy, Fluminense Federal University, Niterói, RJ 24020-141, Brazil.
  • 6. Department of Basic Science, Nova Friburgo University Campus, Fluminense Federal University, Nova Friburgo, RJ 28625-650, Brazil.
PMID: 41476541 DOI: 10.1021/acsomega.5c08635
Abstract

The increasing incidence of Cancer and the emergence of drug resistance underscore the urgent need for new therapeutic options. This study aimed to synthesize and evaluate new coumarin-triazole hybrids for their cytotoxic selectivity and safety profile, providing insights into their potential as Anticancer scaffolds. Twelve novel coumarin-based compounds were obtained in good yields (40-80%) and evaluated through in vitro, in silico, and in vivo assays. Among them, compound 7f displayed the highest antiproliferative potency and selectivity, with selectivity indices (SI) of 4.61 for B16F-10, 3.38 for HCT116, and 2.98 for 4T1, and an average SI of 2.18 across SCC-4, SCC-9, and SCC-25 cell lines. Mechanistic assays indicated that the cytotoxic effect of 7f is associated with oxidative stress-induced Apoptosis, as evidenced by elevated ROS levels and activation of caspases 3/7. In vivo toxicity assessment in C57BL/6 mice revealed no significant changes in body weight, food intake, or macroscopic organ alterations at doses of up to 400 mg/kg, indicating a favorable safety profile. Additionally, in vitro biochemical evaluation and molecular docking suggested that 7f interacts with Pyruvate Kinase M2 (PKM2) and inhibits its glycolytic activity in a dose-dependent manner. Overall, the findings identify compound 7f as a selective and low-toxicity coumarin hybrid that exerts cytotoxic effects through ROS-mediated Apoptosis, representing a promising lead structure for future optimization in Anticancer drug development.

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