Synthesis and biological evaluation of novel macrocyclic bis-7-azaindolylmaleimides as potent and highly selective glycogen synthase kinase-3 beta (GSK-3 beta) inhibitors.
Palladium catalyzed cross-coupling reactions were used to synthesize two key intermediates 3 and 5 that resulted in the synthesis of novel series of macrocyclic bis-7-azaindolylmaleimides. Among the three series of macrocycles, the oxygen atom and thiophene containing linkers yielded molecules with higher inhibitory potency at GSK-3 beta (K(i)=0.011-0.079 microM) while the nitrogen atom containing linkers yielded molecules with lower potency (K(i)=0.150->1 microM). Compound 33 and 36 displayed 1-2 orders of magnitude selectivity at GSK-3 beta against CDK2, PKC beta II, Rsk3 and little or no inhibitions to the other 62 protein kinases. Compound 46 was at least 100-fold more selective towards GSK-3 beta than PKC beta II, and it had little or no activity against a panel of 65 protein kinases, almost behaved as a GSK-3 beta 'specific inhibitor'. All three compounds showed good potency in GS assay. Molecular docking studies were conducted in an attempt to rationalize the GSK-3 beta selectivity of azaindolylmaleimides. The high selectivity, inhibitory potency and cellular activities of these non-crown-ether typed molecules may provide them as a valuable pharmacological tools in elucidating the complex roles of GSK-3 beta in cell signaling pathways and the potential usage for the treatment of elevated level of GSK-3 beta involved diseases.
Shen
Lan
L
Drug Discovery Division, Johnson and Johnson Pharmaceutical Research and Development, L.L.C., 1000 Route 202, PO Box 300, Raritan, NJ 08869, USA.
Prouty
Catherine
C
Conway
Bruce R
BR
Westover
Lori
L
Xu
Jun Z
JZ
Look
Richard A
RA
Chen
Xin
X
Beavers
Mary Pat
MP
Roberts
Jerry
J
Murray
William V
WV
Demarest
Keith T
KT
Kuo
Gee-Hong
GH
D000595:Amino Acid Sequence; D002460:Cell Line; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008301:Maleimides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011494:Protein Kinases / Q000737:chemistry / Q000145:classification / Q000187:drug effects; D016415:Sequence Alignment; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D008301:Maleimides; D011494:Protein Kinases; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3