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
Posted on 2017-06-27 - 14:54
7-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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Cui, Mu-Tian; Jiang, Li; Goto, Masuo; Hsu, Pei-Ling; Li, Linna; Zhang, Qi; et al. (2017). 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. ACS Publications. Collection. https://doi.org/10.1021/acs.jmedchem.7b00273
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AUTHORS (12)
MC
Mu-Tian Cui
LJ
Li Jiang
MG
Masuo Goto
PH
Pei-Ling Hsu
LL
Linna Li
QZ
Qi Zhang
LW
Lei Wei
SY
Shou-Jun Yuan
EH
Ernest Hamel
SM
Susan L. Morris-Natschke
KL
Kuo-Hsiung Lee
LX
Lan Xie
KEYWORDS
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