Design, biological evaluation and 3D QSAR studies of novel dioxin-containing pyrazoline derivatives with thiourea skeleton as selective HER-2 inhibitors.
A series of novel dioxin-containing pyrazoline derivatives with thiourea skeleton have been designed, synthesized and evaluated for their EGFR/HER-2 inhibitory and anti-proliferation activities. A majority of them displayed selective HER-2 inhibitory activity against EGFR inhibitory activity. Compound C20 displayed the most potent activity against HER-2 and MDA-MB-453 human breast cancer cell line (IC50 = 0.03 μM and GI50 = 0.15 μM), being slightly more potent than the positive control Erlotinib (IC50 = 0.16 μM and GI50 = 1.56 μM) and comparable with Lapatinib (IC50 = 0.01 μM and GI50 = 0.03 μM). It is a more exciting result that C20 was over 900 times more potent against HER-2 than against EGFR while this value was 0.19 for Erlotinib and 1.00 for Lapatinib, indicating high selectivity. The results of docking simulation indicate that the dioxin moiety occupied the exit of the active pocket and pushed the carbothioamide deep into the active site. QSAR models have been built with activity data and binding conformations to begin our work in this paper as well as to provide a reliable tool for reasonable design of EGFR/HER-2 inhibitors in future.
Institute of Chemistry and BioMedical Sciences, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China.
Bing
B
Yang
Institute of Chemistry and BioMedical Sciences, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China.|State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, China.
Yu-Shun
YS
Yang
Institute of Chemistry and BioMedical Sciences, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China.|State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, China.
Na
N
Yang
Institute of Chemistry and BioMedical Sciences, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China.
Guigen
G
Li
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, China.
Hai-Liang
HL
Zhu
D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004147:Dioxins / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry; D015195:Drug Design; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage; D005260:Female; D006801:Humans; D000077341:Lapatinib; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry; D011720:Pyrazoles / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D011799:Quinazolines / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D013890:Thiourea / Q000737:chemistry
D004147:Dioxins; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D013890:Thiourea; C512478:EGFR protein, human; C508053:ERBB2 protein, human