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

Author(s): Jean C. Benassi, Flavio A.R. Barbosa, Valdelúcia M.A.S. Grinevicius, Fabiana Ourique, Daniela Coelho, Karina B. Felipe, Antônio L. Braga, Danilo W. Filho, Rozangela C. Pedrosa*

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 21 , Issue 6 , 2021


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Abstract:

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 (β-actin, p53, BAX, HIF-1α, γH2AX, 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 γH2AX 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.

Keywords: HepG2, dihydropyrimidinones, organoselenium, molecular docking, DNA damage, cell, apoptosis.

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Article Details

VOLUME: 21
ISSUE: 6
Year: 2021
Published on: 28 July, 2020
Page: [703 - 715]
Pages: 13
DOI: 10.2174/1871520620666200728124640
Price: $65

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