Synthesis and protein-tyrosine kinase inhibitory activities of flavonoid analogues.
Treatment of o-hydroxyacetophenones 2a-e with excess lithium bis(trimethylsilyl)amide followed by dialkyl carbonates gave alkyl 3-(2-hydroxyaryl)-3-oxopropanoates 3a-e. The latter substances were transformed through the reaction of their magnesium chelates with benzoyl chlorides into a series of 3-(alkoxycarbonyl)-2-arylflavones, which were subsequently elaborated into a variety of flavonoids. These compounds were tested for their abilities to inhibit the in vitro protein-tyrosine kinase activity of p56lck, an enzyme which is thought to play a key role in mediating signal transduction from the CD4 receptor during lymphocyte activation. All of the active compounds had either an amino or a hydroxyl substituent at the 4'-position of the 2-aryl ring. The most active substance prepared in this study is compound 17c, which is approximately 1 order of magnitude more potent than the natural product quercetin (1). Compound 17c was a competitive inhibitor of p56lck with respect to ATP and was highly selective for the inhibition of protein-tyrosine over protein-serine/threonine kinases.
Cushman
M
M
Department of Medicinal Chemistry and Pharmacognosy, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907.
Nagarathnam
D
D
Burg
D L
DL
Geahlen
R L
RL
D055598:Chemical Phenomena; D002621:Chemistry; D005419:Flavonoids / Q000138:chemical synthesis* / Q000494:pharmacology; D019833:Genistein / Q000031:analogs & derivatives; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D005419:Flavonoids; C067397:4'-amino-6-hydroxyflavone; D019833:Genistein; D011505:Protein-Tyrosine Kinases