Virtual and experimental high throughput screening of substituted hydrazones on ß-Tubulin polymerization.

Microtubule targeting agents that disrupt the dynamic functioning of the mitotic spindle are some of the best chemotherapeutic agents. Interruption of microtubule dynamics through polymerization or depolymerization causes cell arrest leading to apoptosis. We report a novel class of aroylhydrazones with anticancer properties. Tubulin inhibition studies were performed using both computational and biological methods. Docking and pharmacophore mapping showed efficient binding between the ligands and the protein. Tubulin inhibition assay showed the aroylhydrazones to be inhibitors of tubulin polymerization. DFT studies explains the geometrical and electronic properties of the compounds. Furthermore, anticancer studies using lung and liver cancer cell lines gave low IC50 values with the methyl substituted hydrazone MH-2 being the most potent. (IC50 of 0.0896 and 0.1040 µM respectively). The methyl group is responsible for the effective binding to the protein. Thus, a new class of tubulin binding agents have been identified as potential agents in cancer therapy.

Syntheses, quantum mechanical modeling, biomolecular interaction and in vitro anticancer - Tubulin activity of thiosemicarbazones.

A new series of thiosemicarbazones were designed and synthesized. Their structures were confirmed by spectral characterization and single crystal XRD studies. Compounds MTSC-2 and ETSC-3 crystallized in the orthorhombic crystal system with space group Pbc21 andPca21respectively. Density functional theory computational studies were performed on MTSC-2 and ETSC-3 along with natural bond orbital analysis and Mulliken population analysis to study the structural and electronic properties of the thiosemicarbazones. The HOMOs of the two thiosemicarbazones are -5.2943 and -5.1133 eV respectively while the LUMOs are -1.6879 and -1.6398 eV respectively. The energy gap is 3.6064 and 3.4736 eV respectively. Molecular docking studies were performed to determine the binding mode of the thiosemicarbazones against ß-tubulin. The theoretical studies were further supplemented with tubulin polymerization inhibition assay. All the four thiosemicarbazones proved effective in inhibiting the polymerization of α- and ß-tubulin heterodimers into microtubules. The anticancer activity of these compounds showed their extreme potency against A549 and HepG2 cancer cell lines with IC50 values of 0.051 - 0.189 µm and 0.042 - 0.136 µm respectively. Compound PTSC-4 showed the highest activity both against tubulin and the two cancer cell lines. This was in correlation with the theoretical studies. Hence, these four compounds, specifically PTSC-4, can be considered to be potential leads in the development of non-metallic anticancer agents.