Florence Fabunmi MSc, CSSBB, CSPO

Topoisomerase IIα is an essential enzyme in cell division and replication which plays a vital role in the rapid proliferation of cancer cells. Previous studies have shown that α-(N)-heterocyclic thiosemicarbazone (TSC) metal complexes inhibit human topoisomerase IIα (TopoIIα) by stabilizing the DNA cleavage complexes mediated by TopoIIα. This research explores the mechanisms of action of three α-(N)-heterocyclic thiosemicarbazones using molecular docking and molecular dynamics simulations to… Show more

Topoisomerase IIα is an essential enzyme in cell division and replication which plays a vital role in the rapid proliferation of cancer cells. Previous studies have shown that α-(N)-heterocyclic thiosemicarbazone (TSC) metal complexes inhibit human topoisomerase IIα (TopoIIα) by stabilizing the DNA cleavage complexes mediated by TopoIIα. This research explores the mechanisms of action of three α-(N)-heterocyclic thiosemicarbazones using molecular docking and molecular dynamics simulations to investigate the interaction between thiosemicarbazone-copper (II) complexes and topoisomerase IIα. Molecular docking results suggest that the TSC complexes interact in a binding pocket adjacent to the ATP binding site of TopoIIα, mediated predominantly by electrostatic interactions. Several amino acid residues in the active site appear to contribute most to the binding interactions with TSC ligands, including Asp 94 … Show less

We propose a fast and accurate calculation method to compute the electronic couplings between molecular units in a thiophene-ring-based polymer chain mimicking a real organic semiconducting polymer, poly(3-hexylthiophene). Through a unit block diabatization scheme, the method employed minimal number of diabatic orbitals to compute the site energies and electronic couplings, which were validated by comparing with benchmark density functional theory calculations. In addition, by using the… Show more

We propose a fast and accurate calculation method to compute the electronic couplings between molecular units in a thiophene-ring-based polymer chain mimicking a real organic semiconducting polymer, poly(3-hexylthiophene). Through a unit block diabatization scheme, the method employed minimal number of diabatic orbitals to compute the site energies and electronic couplings, which were validated by comparing with benchmark density functional theory calculations. In addition, by using the obtained electronic couplings, a quantum dynamics simulation was carried out to propagate a hole initially localized in a thiophene-ring unit of the polymer chain. This work establishes a simple, efficient, and robust means for the simulation of electron or hole transfer processes in organic semiconducting materials, an important capability for study and understanding of the class of organic optoelectronic and photovoltaic materials. Show less

Our previous research has shown that α-(N)-heterocyclic thiosemicarbazone (TSC) metal complexes inhibit human topoisomerase IIα (TopoIIα), while the ligands without metals do not. To find out the structural elements of TSC that are important for inhibiting TopoIIα, we have synthesized two series of α-(N)-heterocyclic TSCs with various substrate ring segments, side chain substitutions, and metal ions, and we have examined their activities in TopoIIα-mediated plasmid DNA relaxation and cleavage… Show more

Our previous research has shown that α-(N)-heterocyclic thiosemicarbazone (TSC) metal complexes inhibit human topoisomerase IIα (TopoIIα), while the ligands without metals do not. To find out the structural elements of TSC that are important for inhibiting TopoIIα, we have synthesized two series of α-(N)-heterocyclic TSCs with various substrate ring segments, side chain substitutions, and metal ions, and we have examined their activities in TopoIIα-mediated plasmid DNA relaxation and cleavage assays. Our goal is to explore the structure-activity relationship of α-(N)-heterocyclic TSCs and their effect on TopoIIα. Our data suggest that, similar to Cu(II)-TSCs, Pd(II)-TSC complexes inhibit plasmid DNA relaxation mediated by TopoIIα. In TopoIIα-mediated plasmid DNA cleavage assays, the Cu(II)-TSC complexes induce higher levels of DNA cleavage than their Pd(II) counterparts. The Cu(II)-TSC complexes with methyl, ethyl, and tert-butyl substitutions are slightly more effective than those with benzyl and phenyl groups. The α-(N)-heterocyclic ring substrates of the TSCs, including benzoylpyridine, acetylpyridine, and acetylthiazole, do not exhibit a significant difference in TopoIIα-mediated DNA cleavage. Our data suggest that the metal ion of TSC complexes plays a predominant role in inhibition of TopoIIα, the side chain substitution of the terminal nitrogen plays a secondary role, while the substrate ring segment has the least effect. Our molecular modeling data support the biochemical data, which together provide a mechanism by which Cu(II)-TSC complexes stabilize TopoIIα-mediated cleavage complexes. Show less