Ruthenium half-sandwich complexes as protein kinase inhibitors: derivatization of the pyridocarbazole pharmacophore ligand.
A general route to ruthenium pyridocarbazole half-sandwich complexes is presented and applied to the synthesis of sixteen new compounds, many of which have modulated protein kinase inhibition properties. For example, the incorporation of a fluorine into the pyridine moiety increases the binding affinity for glycogen synthase kinase 3 by almost one order of magnitude. These data are supplemented with cyclic voltammetry experiments and a protein co-crystallographic study.
Pagano
Nicholas
N
Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, PA 19104, USA. meggers@sas.upenn.edu
Maksimoska
Jasna
J
Bregman
Howard
H
Williams
Douglas S
DS
Webster
Richard D
RD
Xue
Feng
F
Meggers
Eric
E
D002227:Carbazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011494:Protein Kinases / Q000187:drug effects*; D012428:Ruthenium / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D002227:Carbazoles; D008024:Ligands; D009942:Organometallic Compounds; D047428:Protein Kinase Inhibitors; D012428:Ruthenium; D011494:Protein Kinases