Synthesis and biological evaluation of novel tetranuclear cyclopalladated complex bearing thiosemicarbazone scaffold ligand: Interactions with double-strand DNA, coronavirus, and molecular modeling studies

Threading intercalators are a novel class of materials that carry two substituents
along the diagonal positions of an aromatic ring. When bound to DNA, these
substituents project out in DNA grooves. Tetranuclear complexes appear to be
promising threading intercalators for developing therapeutics against cancer and
viral infections that require high nucleic acid binding affinity. The objective of
this work was to prepare the thiosemicarbazone scaffold ligand [4-ClC6H4
CHN=NC(S)NHPh] and tetranuclear cyclopalladated complex [Pd(4-ClC6H4
CHN=NC(S)NHPh)4] and to characterize the compounds by elemental analysis,
1D and 2D NMR, HRMS, and IR spectroscopy. The calf thymus DNA (CT-DNA)
binding properties of the compounds were investigated in vitro under simulated
physiological conditions using UV–vis spectroscopy, emission spectral titration,
methylene blue competitive binding, circular dichroism, DNA thermal denaturation,
DNA binding, and coronavirus interactions using molecular simulation.
The compounds showed cytotoxic effect against both human breast (MCF-7)
and colorectal (HCT116) cancer cells in a dose-dependent manner. We demonstrated
that the compounds are promising for DNA threading intercalation
binders with large DNA binding constants on the order of 107 M�1 magnitude.