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Artificial Metalloenzymes with the Neocarzinostatin Scaffold: Toward a Biocatalyst for the Diels–Alder Reaction
Author(s) -
Ghattas Wadih,
CotchicoAlonso Lur,
Maréchal JeanDidier,
Urvoas Agathe,
Rousseau Maëva,
Mahy JeanPierre,
Ricoux Rémy
Publication year - 2016
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201500445
Subject(s) - chemistry , biocatalysis , neocarzinostatin , selectivity , stereochemistry , combinatorial chemistry , diels–alder reaction , copper , catalysis , organic chemistry , reaction mechanism , biochemistry , dna
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 ( K D =3 μ m ), 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 ( K D =13 μ m ) 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.