Modulation of the stacking interaction of MN4 (M = Pt, Pd, Au) complexes with tryptophan through N-heterocyclic ligands

A survey of selected N-heterocycle ligands showed that platination of 4-N-dimethylaminopyridine (DMAP) in [Pt(dien)L]2 + (dien = diethylenetriamine) gave especially strong π–π stacking interactions with tryptophan and the tryptophan-containing C-terminal zinc finger (ZF) of the HIV (human immunodeficiency virus) nucleocapsid protein NCp7. The association constants (all at 103 M− 1) were significantly stronger (25.0 and 28.1 for tryptophan and ZF respectively) than those previously measured for the purine nucleobase 9-ethylguanine (9EtG) in [Pt(dien)(9EtG)]2 + (6.88 and 7.55 for tryptophan and ZF respectively). Extension to Pd and Au complexes also confirmed the utility of DMAP in assisting stacking interactions. The results confirm the utility of a “bioinorganic” approach to targeting and inactivation of medicinal chemistry targets using the dual approach of target recognition (non-covalent) followed by target fixation (covalent).

Metallation of certain N-heterocycle ligands enhances dramatically the stacking affinity with tryptophan and tryptophan-containing zinc fingers. The results confirm the utility of a “bioinorganic” approach to targeting and inactivation of medicinal chemistry targets using the dual approach of target recognition (non-covalent) followed by target fixation (covalent).Figure optionsDownload as PowerPoint slide