Non-tethered organometallic phosphonate inhibitors for lipase inhibition: positioning of the metal center in the active site of cutinase

Abstract

Organometallic NCN-pincer complexes, bearing either a p-nitrophenyl phosphonate ester or a phosphonic acid group directly attached to the aromatic ring of the pincer complex, were synthesized. These compounds were tested as covalent inhibitors for the lipase cutinase. In a stoichiometric reaction of the NCN-pincer platinum phosphonate p-nitrophenyl ester 2 with cutinase, a 94 % conversion to the protein-pincer metal complex hybrid was obtained in 48 h. The NCN-pincer metal phosphonic acid derivatives (3, 4) appeared to be inactive as cutinase inhibitors. In contrast to our previous work which entails propyl tethered phosphonate esters connected to pincer metal complexes, the presented strategy allows positioning of metal complexes inside the active site of lipases. This opens up the possibility for fine-tuning the chemical environment (second coordination sphere) around a synthetic metal center inside the pocket of an enzyme for diagnostic and catalytic purposes.