The reaction of [Au(dien)(N-heterocycle)](3+) (AuN4) coordination compounds with simple amino acids and zinc finger proteins is reported. Compared to [AuCl(dien)](2+), NMR studies show that the presence of a more substitution-inert N-donor as the putative leaving group slows the reaction with the sulfur-containing amino acids N-acetylmethionine (NAcMet) and N-acetylcysteine (NAcCys). Lack of ligand dissociation upon reaction with NAcCys indicates, to our knowledge, the first long-lived N-heterocycle-Au-S species in solution. Reactions with zinc finger proteins show a higher reactivity with the Cys3His zinc finger than with Cys2His2, likely due to the presence of fewer aurophilic cysteines in the latter. Of the Au(III) compounds studied, [Au(dien)(DMAP)](3+) (DMAP = 4-dimethylaminopyridine) appears to be the least reactive, with ESI-MS studies showing the presence of intact zinc fingers at initial reaction times. These results, in combination with previously reported characterization and pH dependency studies, will further aid in optimizing the structure of these AuN4 species to obtain a substitution-reactive yet selective compound for targeting zinc finger proteins.

The HIV nucleocapsid NCp7-SL2 RNA interaction is interrupted in the presence of a formally substitution-inert gold(dien)-nucleobase/N-heterocycle AuN compound where the N-heterocycle serves the dual purposes of a template for "non-covalent" molecular recognition of the essential tryptophan of the protein, mimicking the natural reaction and subsequent "fixation" by Au-Cys bond formation providing a chemotype for a new distinct class of nucleocapsid-nucleic acid antagonist.

Novel Au(III)(dien)(N-heterocycle) compounds, including the first Au(III)N3(N-purine) examples, are reported. The acidity of the dien ligand is affected by the nature of the fourth ligand as a leaving group. The metal center of [Au(dien)(N-heterocycle)](3+) compounds was shown to be more stable to reduction than when Cl(-) is present, with consequences for reactivity with biomolecules: specifically, significant enhancement of π-π-stacking interactions with tryptophan relative to isostructural and isoelectronic platinum(II) and palladium(II) compounds.