From imide to lactam metallo-pyridocarbazoles: distinct scaffolds for the design of selective protein kinase inhibitors.
Organometallic pyridocarbazole scaffolds are investigated as protein kinase inhibitors. Whereas our previous designs employed solely a maleimide pharmacophore for achieving the two crucial canonical hydrogen bonds to the hinge region of the ATP binding site, we have now extended our investigations to include the related lactam metallo-pyridocarbazoles. The synthetic access of the two regioisomeric lactam pyridocarbazoles is described, and the distinct biological properties of the two lactam scaffolds are revealed by employing a ruthenium half sandwich complex as a model system, resulting in organometallic lead structures for the inhibition of the protein kinases TrkA and CLK2. These new lactam metallo-pyridocarbazoles expand our existing molecular toolbox and assist toward the generation of metal complex scaffolds as lead structures for the design of selective inhibitors for numerous kinases of the human kinome.
Pagano
Nicholas
N
Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Strasse, 35032 Marburg, Germany.
Wong
Eric Y
EY
Breiding
Tom
T
Liu
Haidong
H
Wilbuer
Alexander
A
Bregman
Howard
H
Shen
Qi
Q
Diamond
Scott L
SL
Meggers
Eric
E
D002227:Carbazoles / Q000138:chemical synthesis / Q000737:chemistry*; D015195:Drug Design; D006801:Humans; D007094:Imides / Q000737:chemistry*; D007769:Lactams / Q000737:chemistry*; D008670:Metals; D009942:Organometallic Compounds / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry*; D020917:Receptor, trkA / Q000037:antagonists & inhibitors; D012428:Ruthenium / Q000737:chemistry
D002227:Carbazoles; D007094:Imides; D007769:Lactams; D008670:Metals; D009942:Organometallic Compounds; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D012428:Ruthenium; C066780:Clk dual-specificity kinases; D011505:Protein-Tyrosine Kinases; D020917:Receptor, trkA; D017346:Protein Serine-Threonine Kinases