TY - JOUR
T1 - N-Arylhydroxamic acids as novel oxidoreductase substrates
AU - Kulys, Juozas
AU - Deussen, Heinz Josef
AU - Krikstopaitis, Kastis
AU - Lolck, Rikke
AU - Schneider, Palle
AU - Ziemys, Arturas
PY - 2001/9
Y1 - 2001/9
N2 - N-Arylhydroxamic acids (AHAs) are promising novel N-OH mediators for oxidoreductase catalysis. They are electrochemically active compounds with a redox potential of 0.31-0.41 V vs. SCE. Representative oxidoreductases, e.g. fungal peroxidase from Coprinus cinereus (rCiP), catalyze the oxidation of AHAs with apparent bimolecular constants (kox) of 7.1·103 to 1.5·107 m-1s-1 at pH = 8.5 and 25°C. The limiting step in substrate oxidation was the reduction of compound II (Cpd II). The oxidation constants of N-hydroxyacetanilide (1a) and N-hydroxy-N-phenylbenzamide (2a), determined by a stopped-flow and steady-state method, were similar. The decrease in the reduction rate of Cpd II reduction rate decrease occurred at pKa = 8.5 for 1a and 7.7 for 2a. The nitroxyl radical of 1a, an intermediate in the oxidation, shows decreasing stability at alkaline pH. The structure-activity relationships (SARs) of these AHAs were analyzed within the framework of Marcus cross-relationship, and by using ab initio quantum chemical calculations. A linear correlation of log(kox) vs. redox potential was only indicated for benzamides, as predicted by electron transfer theory. Acetamides showed the opposite tendency: the constant (kox) increased if the potential of substrate increased. The correlation between log(kox) and HOMO (Highest Occupied Molecular Orbital) energy revealed that for benzamides the reactivity decreased with decreasing HOMO energy, whereas for acetamides the reactivity increased if the HOMO energy decreased. The rather low reactivity of these AHAs and the unexpected dependence on the redox potential and the HOMO energy could be explained by the electronic structure of the AHAs and the substrates docking in the active center of the enzyme.
AB - N-Arylhydroxamic acids (AHAs) are promising novel N-OH mediators for oxidoreductase catalysis. They are electrochemically active compounds with a redox potential of 0.31-0.41 V vs. SCE. Representative oxidoreductases, e.g. fungal peroxidase from Coprinus cinereus (rCiP), catalyze the oxidation of AHAs with apparent bimolecular constants (kox) of 7.1·103 to 1.5·107 m-1s-1 at pH = 8.5 and 25°C. The limiting step in substrate oxidation was the reduction of compound II (Cpd II). The oxidation constants of N-hydroxyacetanilide (1a) and N-hydroxy-N-phenylbenzamide (2a), determined by a stopped-flow and steady-state method, were similar. The decrease in the reduction rate of Cpd II reduction rate decrease occurred at pKa = 8.5 for 1a and 7.7 for 2a. The nitroxyl radical of 1a, an intermediate in the oxidation, shows decreasing stability at alkaline pH. The structure-activity relationships (SARs) of these AHAs were analyzed within the framework of Marcus cross-relationship, and by using ab initio quantum chemical calculations. A linear correlation of log(kox) vs. redox potential was only indicated for benzamides, as predicted by electron transfer theory. Acetamides showed the opposite tendency: the constant (kox) increased if the potential of substrate increased. The correlation between log(kox) and HOMO (Highest Occupied Molecular Orbital) energy revealed that for benzamides the reactivity decreased with decreasing HOMO energy, whereas for acetamides the reactivity increased if the HOMO energy decreased. The rather low reactivity of these AHAs and the unexpected dependence on the redox potential and the HOMO energy could be explained by the electronic structure of the AHAs and the substrates docking in the active center of the enzyme.
KW - Ab initio calculations
KW - Electrochemistry
KW - Oxidoreductases
KW - Redox chemistry
KW - Structure - activity relationships
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U2 - 10.1002/1099-0690(200109)2001:18<3475::AID-EJOC3475>3.0.CO;2-K
DO - 10.1002/1099-0690(200109)2001:18<3475::AID-EJOC3475>3.0.CO;2-K
M3 - Article
AN - SCOPUS:0034801662
SP - 3475
EP - 3484
JO - European Journal of Organic Chemistry
JF - European Journal of Organic Chemistry
SN - 1434-193X
IS - 18
ER -