Novel Dihydropyrimidinone-Derived Selenoesters as Potential Cytotoxic Agents to Human Hepatocellular Carcinoma: Molecular Docking and DNA Fragmentation

Autor(es)

Benassi, Jean C. ^[1] ; Barbosa, Flavio A. R. ^[2] ; Grinevicius, Valdelucia M. A. S. ^[1] ; Ourique, Fabiana ^[1] ; Coelho, Daniela ^[1] ; Felipe, Karina B. ^[3] ; Braga, Antonio L. ^[2] ; Filho, Danilo W. ^[4] ; Pedrosa, Rozangela C. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Fed Santa Catarina, Dept Biochem, Florianopolis, SC - Brazil

^[2] Univ Fed Santa Catarina, Dept Chem, Florianopolis, SC - Brazil

^[3] Univ Fed Parana, Dept Clin Anal, Curitiba, Parana - Brazil

^[4] Univ Fed Santa Catarina, Dept Ecol & Zool, Florianopolis, SC - Brazil

• Tipo de documento: Artigo Científico
• Fonte: ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY; v. 21, n. 6, p. 703-715, 2021.
• Citações Web of Science: 1

Resumo

Background and Objective: Evidence point out promising anticancer activities of Dihydropyrimidinones (DHPM) and organoselenium compounds. This study aimed to evaluate the cytotoxic and antiproliferative potential of DHPM-derived selenoesters (Se-DHPM), as well as their molecular mechanisms of action. Methods: Se-DHPM cytotoxicity was evaluated against cancer lines (HeLa, HepG2, and MCF-7) and normal cells (McCoy). HepG2 clonogenic assay allowed verifying antiproliferative effects. The propidium iodide/orange acridine fluorescence readings showed the type of cell death induced after treatments (72h). Molecular simulations with B-DNA and 49H showed docked positions (AutoDock Vina) and trajectories/energies (GROMACS). In vitro molecular interactions used CT-DNA and 49H applying UV-Vis absorbance and fluorescence. Comet assay evaluated DNA fragmentation of HepG2 cells. Flow cytometry analysis verified HepG2 cell cycle effects. Levels of proteins (beta-actin, p53, BAX, HIF-1 alpha, gamma H2AX, PARP-1, cyclin A, CDK-2, and pRB) were quantified by immunoblotting. Results: Among Se-DHPM, 49H was selectively cytotoxic to HepG2 cells, reduced cell proliferation, and increased BAX (80%), and p53 (66%) causing apoptosis. Molecular assays revealed 49H inserted in the CT-DNA molecule causing the hypochromic effect. Docking simulations showed H-bonds and hydrophobic interactions, which kept the ligand partially inserted into the DNA minor groove. 49H increased the DNA damage (1.5 fold) and gamma H2AX level (153%). Besides, treatments reduced PARP-1 (60%) and reduced pRB phosphorylation (21%) as well as decreased cyclin A (46%) arresting cell cycle at the G1 phase. Conclusion: Together all data obtained confirmed the hypothesis of disruptive interactions between Se-DHPM and DNA, thereby highlighting its potential as a new anticancer drug. (AU)

• Processo FAPESP: 14/50249-8 - Green chemistry: sustainable synthetic methods employing benign solvents, safer reagents, and bio-renewable feedstock
• Beneficiário: Arlene Gonçalves Corrêa
• Modalidade de apoio: Auxílio à Pesquisa - Programa Centros de Pesquisa em Engenharia