6-Substituted-4-(3-bromophenylamino)quinazolines as putative irreversible inhibitors of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor (HER-2) tyrosine kinases with enhanced antitumor activity.
A series of new 6-substituted-4-(3-bromophenylamino)quinazoline derivatives that may function as irreversible inhibitors of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor (HER-2) tyrosine kinases have been prepared. These inhibitors have, at the C-6 position, butynamide, crotonamide, and methacrylamide Michael acceptors bearing water-solublilizing substituents. These compounds were prepared by acylation of 6-amino-4-(3-bromophenylamino)quinazoline with unsaturated acid chlorides or mixed anhydrides. We show that attaching a basic functional group onto the Michael acceptor results in greater reactivity, due to intramolecular catalysis of the Michael addition and/or an inductive effect of the protonated basic group. This, along with improved water solubility, results in compounds with enhanced biological properties. We present molecular modeling and experimental evidence that these inhibitors interact covalently with the target enzymes. One compound, 16a, was shown to have excellent oral activity in a human epidermoid carcinoma (A431) xenograft model in nude mice.
Tsou
H R
HR
Wyeth-Ayerst Research, A Division of American Home Products, 401 N. Middletown Road, Pearl River, New York 10965-1215, USA. tsouh@war.wyeth.com
Mamuya
N
N
Johnson
B D
BD
Reich
M F
MF
Gruber
B C
BC
Ye
F
F
Nilakantan
R
R
Shen
R
R
Discafani
C
C
DeBlanc
R
R
Davis
R
R
Koehn
F E
FE
Greenberger
L M
LM
Wang
Y F
YF
Wissner
A
A
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D005470:Fluorometry; D005978:Glutathione / Q000737:chemistry; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D010766:Phosphorylation; D011233:Precipitin Tests; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D005978:Glutathione; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C433820:N-(4-((3-bromophenyl)amino)--6-quinazolinyl)-4-(dimethylamino)-2-butenamide