TY - JOUR
T1 - Design, synthesis and biological evaluation of novel 4-anilinoquinazoline derivatives as hypoxia-selective EGFR and VEGFR-2 dual inhibitors
AU - Wei, Huiqiang
AU - Duan, Yuqing
AU - Gou, Wenfeng
AU - Cui, Jie
AU - Ning, Hongxin
AU - Li, Deguan
AU - Qin, Yong
AU - Liu, Qiang
AU - Li, Yiliang
N1 - Funding Information:
This work was supported by the National Natural Science Foundation of China ( 31670859 ), CAMS Innovation Fund for Medical Sciences ( CIFMS 2016-I2M-3-022 and 2017-I2M-3-019 ) and Fundamental Research Funds for the Central Universities ( 3332018117 ).
Publisher Copyright:
© 2019 Elsevier Masson SAS
PY - 2019/11/1
Y1 - 2019/11/1
N2 - Tyrosine kinase inhibitors (TKIs) have achieved substantial clinical effects for cancer treatment while causing a number of adverse effects. Since hypoxia is an intrinsic difference between solid tumor and healthy tissues, one strategy to overcome the adverse effects of TKIs is to enhance the specificity of anti-tumor activity by selectively targeting hypoxic region of tumors. Herein, we designed and synthesized a series of novel 4-anilinoquinazoline derivatives by introducing 3-nitro-1,2,4-triazole group to the side chain of vandetanib with modification of aniline moiety. Lead compounds, 10a and 10g, exhibited potent inhibitory activity against EGFR and VEGFR-2 kinase. Moreover, these two compounds were shown to enhance anti-proliferative activities on A549 and H446 cells under hypoxic conditions compared to vandetanib and dramatically down-regulate VEGF gene expression. In vivo studies confirmed that 10a and 10g not only inhibited tumor growth in A549 xenografts of BALB/c-nu mice but also significantly reduce toxicity associated with weight loss compared to vandetanib. These results suggest that EGFR/VEGFR-2 dual inhibitors, 10a and 10g, emerged as potential hypoxia-selective anti-tumor drugs with less toxicity for inhibiting in vitro and in vivo models of non-small cell lung cancer cells.
AB - Tyrosine kinase inhibitors (TKIs) have achieved substantial clinical effects for cancer treatment while causing a number of adverse effects. Since hypoxia is an intrinsic difference between solid tumor and healthy tissues, one strategy to overcome the adverse effects of TKIs is to enhance the specificity of anti-tumor activity by selectively targeting hypoxic region of tumors. Herein, we designed and synthesized a series of novel 4-anilinoquinazoline derivatives by introducing 3-nitro-1,2,4-triazole group to the side chain of vandetanib with modification of aniline moiety. Lead compounds, 10a and 10g, exhibited potent inhibitory activity against EGFR and VEGFR-2 kinase. Moreover, these two compounds were shown to enhance anti-proliferative activities on A549 and H446 cells under hypoxic conditions compared to vandetanib and dramatically down-regulate VEGF gene expression. In vivo studies confirmed that 10a and 10g not only inhibited tumor growth in A549 xenografts of BALB/c-nu mice but also significantly reduce toxicity associated with weight loss compared to vandetanib. These results suggest that EGFR/VEGFR-2 dual inhibitors, 10a and 10g, emerged as potential hypoxia-selective anti-tumor drugs with less toxicity for inhibiting in vitro and in vivo models of non-small cell lung cancer cells.
KW - 3-Nitro-1,2,4-triazole
KW - EGFR
KW - Hypoxia
KW - Tyrosine kinase inhibitor
KW - VEGFR-2
KW - Vandetanib
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U2 - 10.1016/j.ejmech.2019.07.055
DO - 10.1016/j.ejmech.2019.07.055
M3 - Article
C2 - 31387063
AN - SCOPUS:85070064620
SN - 0223-5234
VL - 181
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
M1 - 111552
ER -