De(side chain) model of epothilone: bioconformer interconversions DFT study |
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Authors: | Danuta Rusinska-Roszak Marek Lozynski |
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Institution: | (1) Institute of Chemical Technology and Engineering, Poznan University of Technology, Pl. M. Sklodowskiej-Curie 2, 60–965 Poznan, Poland |
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Abstract: | Using ab initio methods, we have studied conformations of the de(sidechain)de(dioxy)difluoroepothilone model to quantify the effect of stability
change between the exo and endo conformers of the epoxy ring. The DFT minimization of the macrolactone ring reveals four low energy conformers, although
MP2 predicted five stable structures. The model tested with DFT hybride functional (B3LYP/6–31+G(d,p)) exhibits the global
minimum for one of the exo forms (C), experimentally observed in the solid state, but unexpectedly with the MP2 electron correlation method for the virtual endo form (W). Using the QST3 technique, several pathways were found for the conversion of the low energy conformers to the other low
energy exo representatives, as well as within the endo analog subset. The potential energy relationships obtained for several exo forms suggest a high conformational mobility between three, experimentally observed, conformers. The high rotational barrier,
however, excludes direct equilibrium with experimental EC-derived endo form S. The highest calculated transition state for the conversion of the most stable exo
M interligand to the endo
S form is approximately a 28 kcal/mol above the energy of the former. The two-step interconversion of the exo
H conformer to the endo
S requires at least 28 kcal/mol. Surprisingly, we found that the transition state energy of the H form to the virtual endo
W has the acceptable value of about 9 kcal/mol and the next energy barrier for free interconversion of endo
W to endo
S is 13 kcal/mol.
Figure DFT Model of Epothilone Interconversions
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. |
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Keywords: | Anti-cancer B3LYP Exo-endo Intermediates Transition state |
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