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De(side chain) model of epothilone: bioconformer interconversions DFT study

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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.

DFT Model of Epothilone Interconversions

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Acknowledgments

This study was supported by Poznan University of Technology /DS 32/045/2007. The authors are grateful to Professor M. Botta (Università degli Studi di Siena, Siena, Italy), Professor R. E. Taylor (University of Notre Dame, Notre Dame, IN), Professor J. P. Snyder and Dr M. Wang (Emory University, Atlanta, GA), Professor J. Meiler (Vanderbilt University, Nashville, TN) for providing original coordinates of conformers to prepare initial guesses for the generation of epothilone representatives. We also acknowledge Poznanskie Centrum Superkomputerowo-Sieciowe, Poland for computational time.

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  1. Institute of Chemical Technology and Engineering, Poznan University of Technology, Pl. M. Sklodowskiej-Curie 2, 60–965, Poznan, Poland

    Danuta Rusinska-Roszak & Marek Lozynski

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  1. Danuta Rusinska-Roszak
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  2. Marek Lozynski
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Correspondence to Marek Lozynski.

Supporting information available

Tables containing energies for the optimized conformers, intermediates and transition states of epothilone A 2 derivative and their other structural data are available free of charge at doi://10.1007/s00894-008-0428-3 or from the authors.

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Rusinska-Roszak, D., Lozynski, M. De(side chain) model of epothilone: bioconformer interconversions DFT study. J Mol Model 15, 859–869 (2009). https://doi.org/10.1007/s00894-008-0428-3

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