Benzimidazole-Coordinated Copper(II) Complexes as Effectual Chemotherapeutics against Malignancy

Cancer stands as the second-leading cause of global mortality,
persistently representing a peril to human well-being. The challenges
of drug insensitivity and resistance significantly impede advancements
in cancer treatment, emphasizing the critical importance of developing
innovative agents that specifically target malignant cells. Benzimidazole
derivatives are a preferred choice in cancer therapy, and a variety
of benzimidazole-based molecules have demonstrated incredible potential
for anticancer therapeutic objectives. Albeit such advancements, there
are certain pragmatic limitations, including low bioavailability,
which results in insufficient plasma concentration levels, side effects,
and toxicity that need to be addressed. In this quest to overcome
the existing hurdles, we elucidate the synthesis, structural characterization,
and substantial proliferative activity of two copper(II) complexes
bearing benzimidazole ligands. The ligands, 2-(thiophen-2-yl)-1-(thiophen-2-ylmethyl)-1H-benzo[d]imidazole (L) and 6-methyl-2-(thiophen-2-yl)-1-(thiophen-2-ylmethyl)-1H-benzo[d]imidazole (L′) were prepared
by the coupling of thiophene-2-carboxaldehyde with o-phenylenediamine and 3,4-diaminotoluene, respectively, in water
under an ambient condition. Both L and L′ react with Cu(NO3)2·3H2O in
methanol, producing the complexes, [Cu(L)2(NO3)2] (complex 1) and [Cu2(L′)2(μ-CH3O)2](NO3)2 (complex 2), respectively. Both complexes exhibited
solution-phase stability, as confirmed by mass spectral analysis.
X-ray structural analysis divulges the mononuclear and dinuclear nature
of complex 1 and complex 2, where Cu(II)
centers adopt a slightly distorted square planar geometry in both
complexes. Energy framework analysis suggests the higher stability
of complex 2 than complex 1, attributed
to the more robust character of the dinuclear copper complex. Molecular
docking studies for complex 1 and complex 2 against p53, BAX, BCL2, and PARP proteins suggest stable conformations
for both complexes. The cell viability and cytotoxicity of the synthetic
compounds were evaluated against mouse cancer cell lines, as well
as human breast cancer cell lines. Cell cycle, apoptosis, caspase,
and TUNEL assays have been carried out to unveil the cell proliferative
screening mechanism for the synthetic compounds. The intercalative
binding mode of the complexes for CT-DNA triggers the apoptosis of
the tumor cells. Hence, we postulate that these compounds have the
potential to broaden the arsenal of effective anticancer therapies.