Artificial Metalloenzymes with the Neocarzinostatin Scaffold: Toward a Biocatalyst for the Diels-Alder Reaction
Résumé
A copper(II) cofactor coupled to a testosterone anchor, copper(II)-(5-(Piperazin-1-yl)-1,10-phenanthroline)testosterone-17-hemisuccinamide (10) was synthesized and associated with a neocarzinostatin variant, NCS-3.24 (KD =3 μm), thus generating a new artificial metalloenzyme by following a "Trojan horse" strategy. Interestingly, the artificial enzyme was able to efficiently catalyze the Diels-Alder cyclization reaction of cyclopentadiene (1) with 2-azachalcone (2). In comparison with what was observed with cofactor 10 alone, the artificial enzymes favored formation of the exo products (endo/exo ratios of 84:16 and 62:38, respectively, after 12 h). Molecular modeling studies assigned the synergy between the copper complex and the testosterone (KD =13 μm) moieties in the binding of 10 to good van der Waals complementarity. Moreover, by pushing the modeling exercise to its limits, we hypothesize on the molecular grounds that are responsible for the observed selectivity.
Mots clés
Molecular Docking Simulation
molecular modeling
Biocatalysis
artificial metalloenzymes
Carbon-13 Magnetic Resonance Spectroscopy
copper complexes
Cycloaddition Reaction
diels-alder cyclization reaction
Enzymes
Metalloproteins
Proton Magnetic Resonance Spectroscopy
Spectrometry
Mass
Electrospray Ionization
Zinostatin