https://scholars.lib.ntu.edu.tw/handle/123456789/641374
標題: | Dual-targeting compounds possessing enhanced anticancer activity via microtubule disruption and histone deacetylase inhibition | 作者: | Tseng, Yu-Wei Yang, Tsung-Jung Hsu, Yuan-Ling Liu, Jyung-Hurng Tseng, Yin-Chen Hsu, Tse-Wei Lu, Yueh SZU-HUA PAN Cheng, Ting-Jen Rachel Fang, Jim-Min |
關鍵字: | Breast cancer; Histidine deacetylase; Hydroxamate; Katanin; Lung cancer; Microtubule; Purine-type conjugate | 公開日期: | 5-二月-2024 | 出版社: | Elsevier Masson s.r.l. | 卷: | 265 | 來源出版物: | European Journal of Medicinal Chemistry | 摘要: | 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. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/641374 | ISSN: | 02235234 | DOI: | 10.1016/j.ejmech.2023.116042 |
顯示於: | 基因體暨蛋白體醫學研究所 |
在 IR 系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。