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In Vivo and Mechanistic Studies on Antitumor Lead 7‑Methoxy-4-(2-methylquinazolin-4-yl)-3,4-dihydroquinoxalin-2(1H)‑one and Its Modification as a Novel Class of Tubulin-Binding Tumor-Vascular Disrupting Agents
journal contribution
posted on 2017-06-27, 14:54 authored by Mu-Tian Cui, Li Jiang, Masuo Goto, Pei-Ling Hsu, Linna Li, Qi Zhang, Lei Wei, Shou-Jun Yuan, Ernest Hamel, Susan L. Morris-Natschke, Kuo-Hsiung Lee, Lan Xie7-Methoxy-4-(2-methylquinazolin-4-yl)-3,4-dihydroquinoxalin-2(1H)-one (2), a promising anticancer lead previously
identified by us, inhibited tumor growth by 62% in mice at 1.0 mg/kg
without obvious signs of toxicity. Moreover, compound 2 exhibited extremely high antiproliferative activity in the NIH-NCI
60 human tumor cell line panel, with low to sub-nanomolar GI50 values (10–10 M level). It also showed a suitable
balance between aqueous solubility and lipophilicity, as well as moderate
metabolic stability in vivo. Mechanistic studies using Mayer’s
hematoxylin and eosin and immunohistochemistry protocols on xenograft
tumor tissues showed that 2 inhibited tumor cell proliferation,
induced apoptosis, and disrupted tumor vasculature. Moreover, evaluation
of new synthetic analogues (6a–6t) of 2 indicated that appropriate 2-substitution on
the quinazoline ring could enhance antitumor activity and improve
druglike properties. Compound 2 and its analogues with
a 4-(2-methylquinazolin-4-yl)-3,4-dihydroquinoxalin-2(1H)-one scaffold thus represent a novel class of tubulin-binding tumor-vascular
disrupting agents (tumor-VDAs) that target established blood vessels
in tumors.
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compound 2tumor cell line panelGIantiproliferative activitytumor cell proliferationantitumor activityNIH-NCI 60Mechanistic studiesxenograft tumor tissuesimmunohistochemistry protocolsCompound 2quinazoline ringtumor growthtubulin-binding tumor-vascularMechanistic StudiesNovel Class2- substitutionblood vesselsdruglike propertiesnovel classtumor vasculature
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