Organometallic Pyridylnaphthalimide Complexes as Protein Kinase Inhibitors.

Authors: Blanck S, Cruchter T, Vultur A, Riedel R, Harms K, Herlyn M, Meggers E.
Publisher/Year: Organometallics. 2011 Jul 18;30(17):4598-4606.
Pub Med ID/Journal ID: PMID:21918590


A new metal-containing scaffold for the design of protein kinase inhibitors is introduced. Key feature is a 3-(2-pyridyl)-1,8-naphthalimide "pharmacophore chelate ligand" which is designed to form two hydrogen bonds with the hinge region of the ATP-binding site and is at the same time capable of serving as a stable bidentate ligand through C-H-activation at the 4-position of the electron-deficient naphthalene moiety. This C-H-activation leads to a reduced demand for coordinating heteroatoms and thus sets the basis for a very efficient three-step synthesis starting from 1,8-naphthalic anhydride. The versatility of this ligand is demonstrated with the discovery of a ruthenium complex that functions as a nanomolar inhibitor for myosin light-chain kinase (MYLK or MLCK).