Molecular Design, Spectroscopic, DFT, Pharmacological, and Molecular Docking Studies of Novel Ruthenium(III)–Schiff Base Complex: An Inhibitor of Progression in HepG2 Cells

Abstract

A novel ruthenium(III)–pyrimidine Schiff base was synthesized and characterized using different analytical and spectroscopic techniques. Molecular geometries of the ligand and ruthenium complex were investigated using the DFT-B3LYP level of theory. The quantum global reactivity descriptors were also calculated. Various biological and molecular docking studies of the complex are reported to explore its potential application as a therapeutic drug. Cytotoxicity of the complex was screened against cancer colorectal (HCT116), breast (MCF-7 and T47D), and hepatocellular (HepG2) cell lines as well as a human normal cell line (HSF). The complex effectively inhibited the tested cancer cells with variable degree with higher activity towards HepG2 (IC50 values were 29 μM for HepG2, 38.5 μM for T47D, 39.7 μM for HCT, and 46.7 μM for MCF-7 cells). The complex induced apoptosis and cell cycle arrest in the S phase of HepG2 cells. The complex significantly induced the expression of H2AX and caspase 3 and caspase 7 gene and the protein level of caspase 3, as well as inhibited VEGF-A and mTOR/AKT, SND1, and NF-kB gene expression. The molecular docking studies supported the increased total apoptosis of treated HepG2 cells due to strong interaction of the complex with DNA. Additionally, the possible binding interaction of the complex with caspase 3 could be responsible for the elevated activity of caspase 3–treated cells. The score values for the two receptors were −3.25 and −3.91 kcal/mol.

Ru(II)-based complexes containing 2-thiouracil derivatives suppress liver cancer stem cells by targeting NF-κB and Akt/mTOR signaling

“…Mechanistically, complexes 1 and 2 target NF-κB and Akt/mTOR signaling in HepG2 cells. Interestingly, Noureldeen et al [ 37 ] demonstrated that a Ru(III)-pyrimidine Schiff base interferes with Akt/mTOR and NF-κB signaling in HepG2 cells. Moreover, cyclometalated Ru(II) β-carboline complexes inhibited ERK and Akt signaling in HeLa cervical cancer cells [ 38 ].…”

A novel ruthenium complex with 5-fluorouracil suppresses colorectal cancer stem cells by inhibiting Akt/mTOR signaling

“…Cyclometalated Ru(II)-isoquinoline complexes caused apoptosis in cisplatin-resistant lung cancer A549/DDP cells by modulating Akt/GSK-3β/Fyn signaling [ 22 ]. A ruthenium(III)-pyrimidine Schiff base complex induced apoptotic cell death in liver cancer HepG2 cells along with downregulation of the transcripts of the mTOR/Akt and NF-κB genes [ 23 ].…”

In vivo anticancer study of sodium 2‐[(4‐oxidobenzylidene)amino]‐6H‐1,3,4‐thiadiazine‐5‐olate against Ehrlich ascites carcinoma via targeting PI3K/mTOR pathway

“…The interactions between the test compound and the different proteins were explored with using molecular docking to learn how the test compound conjugates with the topoisomerase IIβ enzyme, β‐tubulin, aromatase enzyme, tumor suppressor p53, caspase‐ 3, mTOR, and PI3K. The tumor suppressor p53 (PDB: 2J1X) (Bauer et al., 2020), caspase‐3 (PDB: 3KJF) (Noureldeen et al., 2022), mTOR (3QAR) (Kawade et al., 2018; Qu et al., 2021), and PI3K (PDB: 4JPS) (Halder et al., 2022; Kawade et al., 2018) were all recovered from the RCSB Protein Data Bank (https://www.rcsb.org/). ChemDraw was utilized to create the test compound's 2D structure.…”