Facile and efficient synthesis and biological evaluation of 4-anilinoquinazoline derivatives as EGFR inhibitors.
Series of 4-anilinoquinazoline derivatives were conveniently and efficiently synthesized and their antitumor activities were evaluated by MTT assay in three human cancer cell lines: H1975, HepG2 and SMMC-7721. New compounds 19a-19h were designed and synthesized to seek for powerful EGFR inhibitors and to explore whether methyl group at C-2 position of quinazoline ring has a positive effect on EGFR inhibition. All the compounds of 19a-19h were found potent against all three cell lines and five compounds (19c, 19d, and 19f-19h) were found more potent against H1975 than gefitinib. SAR studies revealed that methyl group at C-2 position of quinazoline ring could significantly improve the antitumor potency of 4-anilinoquinazolines. The same conclusion was also drawn according to the results of Western blotting analysis. Among all the tested compounds, 19g exhibited extremely potent against H1975 with an IC50 value of 0.11μM, remarkably lower than that of gefitinib (1.23μM). The results of western blotting analysis showed that compounds 19c and 19g could notably inhibit the expression of phosphorylated EGFR, especially 19g, almost inhibited completely.
Shaanxi Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Shaanxi Province Key Laboratory of New Drugs and Chinese Medicine Foundation Research, Shaanxi Rheumatism and Tumor Center of TCM Engineering Technology Research, Shaanxi University of Chinese Medicine, Xian Yang 712083, China.
Zheng
Z
Wang
Department of Burns and Cutaneous Surgery, Xijing Hospital, Xi'an 710032, China.
Xue
X
Wu
Shaanxi Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Shaanxi Province Key Laboratory of New Drugs and Chinese Medicine Foundation Research, Shaanxi Rheumatism and Tumor Center of TCM Engineering Technology Research, Shaanxi University of Chinese Medicine, Xian Yang 712083, China.
Li
L
Wang
Shaanxi Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Shaanxi Province Key Laboratory of New Drugs and Chinese Medicine Foundation Research, Shaanxi Rheumatism and Tumor Center of TCM Engineering Technology Research, Shaanxi University of Chinese Medicine, Xian Yang 712083, China.
Jiao
J
Zhang
Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Science, Northwest University, Xi'an 710069, China.
Jianli
J
Liu
Shaanxi Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Shaanxi Province Key Laboratory of New Drugs and Chinese Medicine Foundation Research, Shaanxi Rheumatism and Tumor Center of TCM Engineering Technology Research, Shaanxi University of Chinese Medicine, Xian Yang 712083, China.
Zhongxing
Z
Song
Shaanxi Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Shaanxi Province Key Laboratory of New Drugs and Chinese Medicine Foundation Research, Shaanxi Rheumatism and Tumor Center of TCM Engineering Technology Research, Shaanxi University of Chinese Medicine, Xian Yang 712083, China. Electronic address: zst6565@126.com.
Zhishu
Z
Tang
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D066246:ErbB Receptors
4-Anilinoquinazoline; MTT assay; Synthesis; Western blotting analysis