Discovery of 6-substituted 4-anilinoquinazolines with dioxygenated rings as novel EGFR tyrosine kinase inhibitors.
It had been reported that some dioxygenated rings fusing with the quinazoline scaffold could lead to new EGFR inhibitors. Based on this, several kinds of oxygenated alkane quinazoline derivatives were synthetized and evaluated as EGFR inhibitors. Their antiproliferative activities were tested against four cancer cell lines: A431, MCF-7, A549, and B16-F10. Most derivatives could counteract EGF-induced EGFR phosphorylation, and their potency was comparable to the reference compound Erlotinib. The size of the fused dioxygenated ring was crucial for the biological activity and the heptatomic ring derivative 19 showed potent in vitro inhibitory activity in the enzymatic assay as well as in the cellular assay.
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China.
Dong-Dong
DD
Li
Fei
F
Fang
Jing-Ran
JR
Li
Qian-Ru
QR
Du
Jian
J
Sun
Hai-Bin
HB
Gong
Hai-Liang
HL
Zhu
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; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010100:Oxygen / Q000737:chemistry*; 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; D010100:Oxygen