Dual-targeting compounds possessing enhanced anticancer activity via microtubule disruption and histone deacetylase inhibition

被引：6

作者：

Tseng, Yu-Wei ^{[1
]}

Yang, Tsung-Jung ^{[1
]}

Hsu, Yuan-Ling ^{[2
]}

Liu, Jyung-Hurng ^{[3
]}

Tseng, Yin-Chen ^{[4
]}

Hsu, Tse-Wei ^{[1
]}

Lu, Yueh ^{[1
]}

Pan, Szu-Hua ^{[2
,5
,6
,7
]}

Cheng, Ting-Jen Rachel ^{[4
]}

Fang, Jim-Min ^{[1
,4
]}

机构：

[1] Natl Taiwan Univ, Dept Chem, Taipei 106, Taiwan

[2] Natl Taiwan Univ, Grad Inst Med Genom & Prote, Coll Med, Taipei 100, Taiwan

[3] Natl Chung Hsing Univ, Grad Inst Genom & Bioinformat, Coll Life Sci, Taichung 40227, Taiwan

[4] Acad Sinica, Genom Res Ctr, Taipei 115, Taiwan

[5] Natl Taiwan Univ, Doctoral Degree Program Translat Med, Taipei 100, Taiwan

[6] Natl Taiwan Univ, Genome & Syst Biol Degree Program, Taipei 100, Taiwan

[7] Acad Sinica, Taipei 100, Taiwan

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2024年 / 265卷

关键词：

Purine-type conjugate; Hydroxamate; Katanin; Microtubule; Histidine deacetylase; Lung cancer; Breast cancer; HDAC INHIBITOR; CANCER; AGENTS; THERAPEUTICS; APOPTOSIS; DOCKING; DESIGN; FIELD;

D O I：

10.1016/j.ejmech.2023.116042

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

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 threedimensional 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.

引用

页数：24

共 58 条

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