Will 1,2-dihydro-1,2-azaborine-based drugs resist metabolism by cytochrome P450 compound I?

  FP-ENAS/Fac. de Ciências da Saúde, Universidade Fernando Pessoa, Porto, Portugal
DOI
10.7287/peerj.preprints.1989v2
Published
Accepted
Subject Areas
Biochemistry, Biophysics
Keywords
reaction mechanism, P450, xenobiotics, azaborine, bioisostere
Copyright
© 2016 Silva
Licence
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ Preprints) and either DOI or URL of the article must be cited.
Cite this article
Silva PJ. 2016. Will 1,2-dihydro-1,2-azaborine-based drugs resist metabolism by cytochrome P450 compound I? PeerJ Preprints 4:e1989v2

Abstract

1,2-dihydro-1,2-azaborine is a structural and electronic analogue of benzene which is able to occupy benzene-binding pockets in T4 lysozyme and has been proposed as suitable arene-mimicking group for biological and pharmaceutical applications. Its applicability in a biological context requires it to be able to resist modification by xenobiotic-degrading enzymes like the P450 cytochromes. Quantum chemical computations described in this work show that 1,2-dihydro-1,2-azaborine is much more prone to modification by these enzymes than benzene, unless steric crowding of the ring prevents it from reaching the active site, or otherwise only allows reaction at the very sluggish C4-position. This novel heterocyclic compound is therefore expected to be of limited usefulness as an aryl bioisostere.

Author Comment

The last portion of the results has been rewritten for clarity. Tables 2 and 3 now also state whether the reaction product analysed is an epoxide, a sigma adduct or 3 H -1,3,2-oxazaborepine. This version was submitted to PeerJ on May 16th, 2016.

Supplemental Information

Single-point energies computed with different basis sets, ZPVE, -D3 corrections, etc

DOI: 10.7287/peerj.preprints.1989v2/supp-1

Geometries of all intermediates, in .xyz

These geometries may be visualized with most common molecular viewers (Molden, ChemCraft, YASARA, Mercury, etc.)

DOI: 10.7287/peerj.preprints.1989v2/supp-2

Löwdin charges on the different moieties of each intermediate in every mechanism studied

DOI: 10.7287/peerj.preprints.1989v2/supp-3

Spins on the different moieties of each intermediate in every mechanism studied

DOI: 10.7287/peerj.preprints.1989v2/supp-4

Relevant distances between substrate and the iron-oxo portion of compount I

DOI: 10.7287/peerj.preprints.1989v2/supp-5