Dual-targeting compounds possessing enhanced anticancer activity via microtubule disruption and histone deacetylase inhibition
Journal
European Journal of Medicinal Chemistry
Journal Volume
265
Start Page
Article Number116042
Date Issued
2024-02-05
Author(s)
Tseng, Yu-Wei
Yang, Tsung-Jung
Hsu, Yuan-Ling
Liu, Jyung-Hurng
Tseng, Yin-Chen
Hsu, Tse-Wei
Lu, Yueh
Cheng, Ting-Jen Rachel
Fang, Jim-Min
Abstract
Dual-targeting anticancer agents 4-29 are designed by combining the structural features of purine-type microtubule-disrupting compounds and HDAC inhibitors. A library of the conjugate compounds connected by appropriate linkers was synthesized and found to possess HDACs inhibitory activity and render microtubule fragmentation by activating katanin, a microtubule-severing protein. Among various zinc-binding groups, hydroxamic acid shows the highest inhibitory activity of Class I HDACs, which was also reconfirmed by three-dimensional quantitative structure-activity relationship (3D-QSAR) pharmacophore prediction. The purine-hydroxamate conjugates exhibit enhanced cytotoxicity against MDA-MB231 breast cancer cells, H1975 lung cancer cells, and various clinical isolated non-small-cell lung cancer cells with different epidermal growth factor receptor (EGFR) status. Pyridyl substituents could be used to replace the C2 and N9 phenyl moieties in the purine-type scaffold, which can help to improve the solubility under physiological conditions, thus increasing cytotoxicity. In mice treated with the purine-hydroxamate conjugates, the tumor growth rate was significantly reduced without causing toxic effects. Our study demonstrates the potential of the dual-targeting purine-hydroxamate compounds for cancer monotherapy.
Subjects
Breast cancer; Histidine deacetylase; Hydroxamate; Katanin; Lung cancer; Microtubule; Purine-type conjugate
SDGs
Publisher
Elsevier Masson s.r.l.
Type
journal article