Synthesis and antitumor evaluation of novel 5-substituted-4-hydroxy-8-nitroquinazolines as EGFR signaling-targeted inhibitors.
The synthesis and biological activity of a series of novel 5-substituted-4-hydroxy-8-nitroquinazolines that may function as inhibitors of EGFR- and/or ErbB-2-related oncogenic signaling are described. These compounds were prepared by S(N)Ar reaction of 5-chloro-4-hydroxy-8-nitroquinazoline with alkyl or aryl amines, or alkyl alcohol as nucleophiles. Although the enzyme assay showed a weak inhibition effect against both EGFR and ErbB-2 tyrosine kinases, the cell-based antitumor activity turned out promising. Compounds having 5-anilino substituent exhibit high potency with 5-(4-methoxy)anilino-4-hydroxy-8-nitroquinazoline (1h) being the best dual EGFR/ErbB-2 inhibitors, which effectively inhibited the growth of both EGFR (MDA-MB-468, IC(50)<0.01microM) and ErbB-2 (SK-BR-3, IC(50)=13microM) overexpressing human tumor cell lines in vitro. More interestingly, the variation of the substituent(s) at the 3- and/or 4-position of the 5-anilino portion was found to modulate the selectivity and potency dramatically. However, compounds having an alkylamino or alkyloxy group at the 5-position of 4-hydroxy-8-nitroquinazolines are essentially inactive. These results are consistent with molecular modeling observations. This study was the first attempt to identify new structural types of dual EGFR/ErbB-2-related signaling inhibitors by incorporation of the anilino group at the 5-position of 4-hydroxy-8-nitroquinazolines' core structure, providing promising new templates for further development of potent inhibitors targeting both EGFR and ErbB-2 tyrosine kinases.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, CAS, 555 Zuchongzhi Road, Shanghai 201203, PR China.
Yi
Y
Jin
Hui-Yuan
HY
Li
Li-Ping
LP
Lin
Jinzhi
J
Tan
Jian
J
Ding
Xiaomin
X
Luo
Ya-Qiu
YQ
Long
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011799:Quinazolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D066246:ErbB Receptors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases