4-Anilinoquinazolines with Lavendustin A subunit as inhibitors of epidermal growth factor receptor tyrosine kinase: syntheses, chemical and pharmacological properties.
4-Anilinoquinazoline derivatives are widely investigated due to their potent epidermal growth factor receptor (EGFR) tyrosine kinase inhibitory activity. Two 4-anilinoquinazolines with Lavendustin A subunit (10a,b) were synthesized and examined for their EGFR tyrosine kinase inhibitory activity as well as their antiproliferative properties on variant human cancer cell lines. Both compounds maintained their EGFR tyrosine kinase inhibitory activity at the 10-7 M level and led to significant growth inhibition in certain leukemia, non-small cell lung cancer (NSCLC), ovarian cancer, renal cancer and breast cancer cell lines with GI50 values at the 10-6 M level. There could not be observed any notable difference between 10a and 10b regarding to their antiproliferative activity. Interestingly, we observed the high tendency of 10a and 10b to include certain solvents, e.g. water, DMF, DMSO, which may be due to the remarkable number of hydrogen accepting/donating groups in 10a and b. An X-ray analysis of 10a including water and DMF illustrates a possible hydrogen bond pattern and could serve as information for preferred receptor (e.g. EGFR tyrosine kinase) binding sites. Finally, we aimed for irreversible EGFR tyrosine kinase inhibitors. The p-quinone derivatives 11a and 11b, which contain a Michael acceptor position according to the irreversible inhibitor CI-1033, could be derived from the p-hydroquinone derivatives 10a or 10b, respectively, by oxidation. However, due to their instability 11a and 11b could not be obtained in a pure form.
Albuschat
Rica
R
Institute of Pharmacy, Free University of Berlin, Königin-Luise-Strasse 2+4, 14195 Berlin, Germany.
Löwe
Werner
W
Weber
Manuela
M
Luger
Peter
P
Jendrossek
Verena
V
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004334:Drug Administration Schedule; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D006873:Hydroquinones / Q000138:chemical synthesis / Q000494:pharmacology; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D010636:Phenols / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
C496323:2-((4-(3-bromophenylamino)quinazolin-6-ylamino)methyl)benzene-1,4-diol; C496324:2-((4-(3-chloro-4-fluorophenylamino)quinazolin-6-ylamino)methyl)benzene-1,4-diol; D000970:Antineoplastic Agents; D006873:Hydroquinones; D010636:Phenols; D011799:Quinazolines; C062898:lavendustin A; D066246:ErbB Receptors