A DFT Study on the Demethylation Reaction between Methylamine, Dimethylamine, Trimethylamine and Tamoxifen Catalyzed by a Fe(IV)-oxo Porphyrin Complex
The journal of physical chemistry. A | 13 Jan 2018
N Alberro, M Torrent-Sucarrat, A Arrieta, G Rubiales and FP Cossio
In this work, we have studied computationally the N-demethylation reaction of methylamine, dimethylamine and trimethylamine as archetypal examples of primary, secondary and tertiary amines catalyzed by high field low spin Fe-containing enzymes such as cytochromes P450. Using DFT calculations, we have obtained that the expected C-H hydroxylation process is achieved for trimethylamine. When dimethylamine and methylamine were studied, two different reaction mechanisms (C-H hydroxylation and a double hydrogen atom transfer) were computed to be energetically accessible and both are equally preferred. Both processes lead to the formation of formaldehyde and the N-demethylated substrate. Finally, as an illustrative example, the relative contribution of the three primary oxidation routes of tamoxifen is rationalized through energetic barriers obtained from density functional calculations and docking experiments involving CYP3A4 and CYP2D6 isoforms. We have found that the N-demethylation process is the intrinsically favored one, whereas other oxidation reactions require most likely preorganization imposed by the residues close to the active sites.
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