Organometallic Pyridylnaphthalimide Complexes as Protein Kinase Inhibitors

Abstract

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).

Bioactive cyclometalated phthalimides: design, synthesis and kinase inhibition

“…A crystal structure of complex 8a is displayed in Figure 5 and demonstrates the expected almost perfectly octahedral coordination around the ruthenium, as compared to a strongly distorted octahedral coordination sphere around the ruthenium center in the related pyridylnaphthalimide complex (Figure 1). 14 …”

“…13 To address these limitations we recently introduced a new class of cyclometalated metal complexes with the ligand 3-(pyridin-2-yl)-1,8-naphthalimide and we demonstrated their suitability for the development of nanomolar protein kinase inhibitors. 14,15 It turned out that a drawback of this scaffold is manifested by the steric interference between the ligand sphere of the metal complexes and the 5-position of the naphthalene moiety (highlighted in Figure 1), resulting in a distortion of the octahedral coordination geometry and thus rendering structure-based inhibitor design somewhat more complicated. Our recent studies have hence focused on a smaller, sterically less demanding ligand for cyclometalation and we developed 4-(pyridin-2-yl)phthalimide as novel ligand for the highly efficient design of cyclometalated metallo-phthalimide protein kinase inhibitors.…”

Organometallic Complexes as Enzyme Inhibitors: A Conceptual Overview

“…It includes GSK3α [22,47], GSK3β [33,49], Pim1 [31,44], Pim2 [27], PAK1 [25,46], MST1 [29], BRAF [36], PI3Kγ [37], FLT4 [39,40], TrkA [35], DAPK1 [24], MYLK [48], PKCδ [45], among others (Figure 1.9). It includes GSK3α [22,47], GSK3β [33,49], Pim1 [31,44], Pim2 [27], PAK1 [25,46], MST1 [29], BRAF [36], PI3Kγ [37], FLT4 [39,40], TrkA [35], DAPK1 [24], MYLK [48], PKCδ [45], among others (Figure 1.9).…”

“…Binding selectivities of selected Meggers-type kinase inhibitors within the human kinase dendrogram that displays the evolutionary relationship between kinases.Adapted with permission from Blanck et al[48]. Copyright 2011, Reproduced with permission of the American Chemical Society.…”

The Art of Filling Protein Pockets Efficiently with Octahedral Metal Complexes

“…[4,6] In order to better understand the design of metal-based enzyme inhibitors, we wondered whether this design is unique or whether other scaffolds with metals located at different positions within the active site could yield similar or even better results. To address this question, we designed new scaffolds [9] and discovered the simple ruthenium complex (R)-1, which places the metal at a distinct position within the ATPbinding site, contains a completely different set of coordinating ligands, and yet shows an improved affinity for PAK1 compared to that of the much more complicated pyridocarbazole complex L-FL172.Ruthenium complex 1 is based on a simple pyridylphthalimide scaffold, which can be synthesized in just a few steps (Scheme 1). Accordingly, a Suzuki cross-coupling of bromophthalimide 2 with 2-trimethylstannylpyridine afforded the pyridylphthalimide 3 (49 %), which was sub-Figure 1.…”