Details

Autor(en) / Beteiligte

• Li, Wenlong
• Yin, Ying
• Shuai, Wen
• Xu, Feijie
• Yao, Hong
• Liu, Jie
• Cheng, Keguang
• Xu, Jinyi
• Zhu, Zheying
• Xu, Shengtao

Titel

Discovery of novel quinazolines as potential anti-tubulin agents occupying three zones of colchicine domain

Ist Teil von

• Bioorganic chemistry, 2019-03, Vol.83, p.380-390

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2019

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• [Display omitted] •A series of quinazolines have been designed to occupy three zones of colchicine domain.•19c showed the most potent in vitro anti-proliferative activity.•19c was identified as a tubulin polymerization inhibitor with potent vascular disrupting activity.•19c was validated to occupy three zones of colchicine domain on in silico studies.•19c exhibited potent tumor growth inhibition in H22 liver cancer xenograft mouse model. A series of novel quinazolines as tubulin inhibitors occupying three zones of colchicine domain have been designed and synthesized inspired by the recently disclosed crystal structure of verubulin analogue 6 with tubulin. Among the newly synthesized compounds, 19c showed noteworthy potency against K562, HepG2, KB, HCT-8 and MDB-MB-231 cancer cells. In vitro microtubule polymerization assays identified 19c as a potent tubulin assembly inhibitor, the binding mode of which with tubulin was confirmed by molecular modeling studies to occupy three zones of tubulin domain. Furthermore, 19c disrupted the intracellular microtubule network, caused G2/M phase arrest, induced cell apoptosis and depolarized mitochondria of K562 cells. 19c also reduced the cell migration and disrupted the capillary-like tube formation of human umbilical vein endothelial cells (HUVECs). Importantly, 19c significantly and dose dependently inhibited tumor growth in H22 liver cancer xenograft mouse model. All these results suggested that 19c deserves further research as a novel and potential anti-tubulin agent for the treatment of cancers.