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

Abstract

Background and Objective: Evidences point out promising anticancer activities of Dihydropyrimidinones (DHPM) and organoselenium compounds. The aim of this study was 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, HRT-18 and MCF-7) and normal cells (McCoy). HepG2 clonogenic assay allowed verifying antiproliferative effect. 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 CTDNA 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, PARP1, 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 CT-DNA molecule causing hypochromic effect. Docking simulations showed H-bonds and hydrophobic interactions, which kept the ligand partially inserted into 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 decreased cyclin A (46%) arresting cell cycle at G1 phase. Conclusions: Together all data obtained confirmed the hypothesis of disruptive interactions between Se-DHPM and DNA thereby highlighting its potential as a new anticancer drug.

IP-Se-06, a Selenylated Imidazo[1,2-a]pyridine, Modulates Intracellular Redox State and Causes Akt/mTOR/HIF-1α and MAPK Signaling Inhibition, Promoting Antiproliferative Effect and Apoptosis in Glioblastoma Cells

“…Subsequently, HIF-1 α plays an essential role during metastasis and angiogenesis in solid tumors [ 74 ]. Previous findings have shown that organoselenium compounds inhibit HIF-1 α , leading to strong anticancer effects on human cancer cell lines [ 23 ] [ 75 ].…”

“…Chen and collaborators [ 20 ] reported that the action mechanisms of chemically innovative organic compounds containing selenium in cancer therapy involve mitochondria-mediated pathway induced by ROS, activation of the AMPK pathway, and cell death by necrocytosis, autophagy, mitochondria, or death receptor-mediated pathways. Moreover, the toxicological and chemotherapeutic effects in which organoselenium compounds are involved also include inhibition of thioredoxin reductase [ 21 ], DNA damage, apoptosis, and cell cycle arrest [ 22 ] [ 23 ].…”

Dihydropyrimidinones as potent anticancer agents: Insight into the structure–activity relationship

“…Levels of proteins (CDK‐2, HIF‐1α, β‐actin, p53, BAX, PARP‐1, cyclin A, γH2AX, and pRB) were measured by immunoblotting. [ 57 ]…”

Polyunsaturated sulfur/selenium-containing products based on regio- and stereoselective nucleophilic addition and substitution reactions of 1,2-bis[(Z)-2-(vinylsulfanyl)ethenyl] diselane

“…Some organoselenium compounds, including diselenides, are considered as potential anti-cancer drugs. 25–33…”

“…[20][21][22][23][24] Some organoselenium compounds, including diselenides, are considered as potential anti-cancer drugs. [25][26][27][28][29][30][31][32][33] A range of selenium-containing compounds are known to exhibit antioxidant [34][35][36] and antidepressant properties. [37][38][39][40][41] Functionalized organoselenium compounds show antibacterial and antiviral activity.…”