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Tetrahydroquinoline/4,5-dihydroisoxazole hybrids with a remarkable effect over mitochondrial bioenergetic metabolism on melanoma cell line B16F10

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Abstract

Metastatic melanoma, unlike early-stage melanomas, requires significant interventions with a poor prognosis. In consequence, we evaluated the effect of three tetrahydroquinoline/4,5-dihydroisoxazole hybrids (CB35, CB46, and CB50) on cellular respiration in murine melanoma cells (B16F10). Additionally, the impact of these compounds against the main antioxidant enzymes and the electron transport on the mitochondrial respiratory chain also was determined. The effect on cellular respiration indicates that compound CB35 (10 µM) inhibits the electron transport through the mitochondrial respiratory chain after 24 h of treatment. This inhibition could be related to the transport of electrons to cytochrome c due to the decreasing activity in the NADH cytochrome c reductase at 1 µM in disrupted mitochondria. On the other hand, compounds CB46 and CB50 generate an uncoupling effect on oxidative phosphorylation by increasing oxygen consumption in the LEAK state (10 µM, 24 h), as well as the increase in state 4 in the mitochondrial bioenergetics. In all cases, molecular hybrids increase ATPase activity in coupled mitochondria, suggesting an uncoupled effect. All hybrids disrupt the redox system in B16F10, and the glycolytic pathway by inhibiting hexokinase and pyruvate kinase activities.

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Acknowledgements

This research study was supported by Vicerrectoría de Investigación y Extensión of Universidad Industrial de Santander, Colombia; COLCIENCIAS project code 110265842934. LCV wants to thank Colciencias for Scholarship fellowships 647 Doctorados nacionales.

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  1. These authors contributed equally: Luis C. Vesga, Ana Milena Pérez Silva

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  1. Grupo de Investigación en Bioquímica y Microbiología GIBIM, Escuela de Química, Universidad Industrial de Santander, A.A. 678, Bucaramanga, Colombia

    Luis C. Vesga, Cristian C. Bernal, Stelia Carolina Mendez-Sánchez & Arnold R. Romero Bohórquez

  2. Grupo de Investigación en Compuestos Orgánicos de Interés Medicinal CODEIM, Parque Tecnológico Guatiguará, Universidad Industrial de Santander, A.A. 678, Piedecuesta, Colombia

    Luis C. Vesga, Ana Milena Pérez Silva & Stelia Carolina Mendez-Sánchez

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Vesga, L.C., Silva, A.M.P., Bernal, C.C. et al. Tetrahydroquinoline/4,5-dihydroisoxazole hybrids with a remarkable effect over mitochondrial bioenergetic metabolism on melanoma cell line B16F10. Med Chem Res 30, 2127–2143 (2021). https://doi.org/10.1007/s00044-021-02796-5

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