Synergistic Antiproliferative Activity of Newly Synthesized Benzimidazole-Based Silver(I) Complexes on MCF‑7 and T47D Cell Lines, CT-DNA Interactions Supported by Computational Studies

This article reports the synthesis, characterization,
and antitumor
properties of newly synthesized benzimidazole-based Ag(I)-(BNHCs)
complexes from their proligands. All of the compounds underwent comprehensive
characterization using techniques such as 1H, COSY, 13C NMR, IR spectroscopy, electrospray ionization (ESI)-mass,
elemental, and single-crystal X-ray diffraction (XRD) analysis. Density
functional theory (DFT) studies were carried out to observe the electronic
effects of bound ligands to modulate the selectivity and reactivity
of silver complexes. Time-dependent DFT (TD-DFT) studies assessed
the optical properties of synthesized complexes and were further highlighted
by orbital contributions with oscillator strengths. All compounds
were tested against breast cancer MCF-7 and T47D cell lines. The synergistic
effects of benzimidazole-incorporated aryl constituent structuring
silver complexes were also observed. Nearly all silver complexes have
been found to be promising anticancer agents with the added benefit
of low cytotoxic effects toward normal cells. Intriguingly, [AgL4(Cl)] exhibited
the best cytotoxic activity among our screened complexes as IC50 values for both MCF-7 and T47D were 9 ± 1.04 and 11
± 1.41, respectively. The apoptosis mode of cell death was confirmed
by phosphatidylserine exposure and annexin V/PI staining imaging method.
CT-DNA interactions of the most active silver complex ([AgL4(Cl)]) and its proligand (HL4(Cl)) were carried
out to support the mode of compound-DNA interaction. Strong DNA binding
affinities (Kb) with compounds through
electrostatic and intercalation modes induced structural changes in
DNA. Moreover, molecular docking studies were carried out to comprehend
the possible interactions of compounds with various receptors such
as EGFR (epidermal growth factor receptor), VEGFR2 (vascular endothelial
growth factor receptors), FGFR (fibroblast growth factor receptor),
and SRC (proto-oncogene tyrosine kinase protein) of tyrosine kinase
family serves as crucial receptors in breast cancer.