Synthesis, Characterization, DNA/HSA Interaction, and Cytotoxic Activity of a Copper(II) Thiolate Schiff Base Complex and Its Corresponding Water-Soluble Stable Sulfinato–O Complex Containing Imidazole as a Co-ligand

A Cu(II) thiolato
complex [CuL(imz)]
(1) (H2L = o-HOC6H4C(H)NC6H4SH-o) and
the corresponding water-soluble stable sulfinato–O complex
[CuL′(imz)] (2) (H2L′ = o-HOC6H4C(H)NC6H4S(O)OH) were synthesized and characterized
using physicochemical techniques. Compound 2 is found
to be a dimer in the solid state as characterized using single-crystal
X-ray crystallography. XPS studies clearly showed the differences
in the sulfur oxidation states in 1 and 2. Both compounds are found to be monomers in solution as revealed
from their four-line X-band electron paramagnetic resonance spectra
in CH3CN at room temperature (RT). 1–2 were tested to assess their ability to exhibit DNA binding and cleavage
activity. Spectroscopic studies and viscosity experiments suggest
that 1–2 bind to CT-DNA through the intercalation
mode having moderate binding affinity (Kb ∼ 104 M–1). This is further
supported by molecular docking studies of complex 2 with
CT-DNA. Both complexes display significant oxidative cleavage of pUC19
DNA. Complex 2 also showed hydrolytic DNA cleavage. The
interaction of 1–2 with HSA revealed that they
have strong ability to quench the intrinsic fluorescence of HSA by
a static quenching mechanism (kq ∼
1013 M–1 s–1). This
is further complemented by Förster resonance energy transfer
studies that revealed binding distances of r = 2.85
and 2.75 nm for 1 and 2, respectively, indicating
high potential for energy transfer from HSA to complex. 1–2 were capable of inducing conformational changes of HSA at secondary
and tertiary levels as observed from synchronous and three-dimensional
fluorescence spectroscopy. Molecular docking studies with 2 indicate that it forms strong hydrogen bonds with Gln221 and Arg222
located near the entrance of site-I of HSA. 1–2 showed potential toxicity in human cervical cancer HeLa cells, lung
cancer A549 cells, and cisplatin-resistant breast cancer MDA-MB-231
cells and appeared to be most potent against HeLa cells (IC50 = 2.04 μM for 1 and 1.86 μM for 2). In HeLa cells, 1–2 mediated cell cycle arrest
in S and G2/M phases, which progressed into apoptosis. Apoptotic features
seen from Hoechst and AO/PI staining, damaged cytoskeleton actin viewed
from phalloidin staining, and increased caspase-3 activity upon treatment
with 1–2 collectively suggested that they induced
apoptosis in HeLa cells via caspase activation. This is further supported
by western blot analysis of the protein sample extracted from HeLa
cells treated with 2.