Extended and Clustered Conformers of Epothilone A

Abstract

The conformational properties of epothilone A have been analyzed in detail using electronic structure calculations to better understand the effect of intramolecular hydrogen bonding on the conformational energies of this highly potent anticancer molecule. Single-point second-order Møller-Plesset calculations done in vacuo at the MP2/6-31+G(d,p)//B3LYP/6-31+G(d,p) level yielded data on the relative stability of conformers that were more distinct than data obtained from the standard DFT model, although the structural trends are in fair agreement. We studied torsional profiles of both hydroxyl groups and sampled energies of the side chain and thiazole moiety rotamers within the whole set of all experimentally accessible conformers. The aldol hydrogen bonds, though relatively weak, generally contribute to the conformational profile, while dipole-dipole interactions, ester group puckering, transannular repulsions between hydrogen atoms, steric effects, and syn-pentane effects have a limited influence. A salient result of our calculations is the determination that the energy of the clustered exo conformer P01 lays 9.3 kcal/mol below that of the extended, experimental conformer P11, apparently due to the unconstrained, near linear 3-OH hydrogen bond to thiazole. Another finding to be noted is the corroboration of the remarkable ability of 3-OH to form transannular hydrogen bonding with the epoxide, which releases the conformational strain of the macroring and thus leads to extra stabilization energy within the endoW subset. Finally, we found that the general trend of the conformer populations of epothilone A obtained from conformational energies resembles those derived from experiments and can be used to interpret values of NMR vicinal coupling constants. The calculated geometries and energies provide essential data for further discussion of the mechanism of biological activity of epothilone A and might be of importance in the explanation of its ADME properties.

Patupilone and Ixabepilone: The Effect of a Point Structural Change on the Exo–Endo Conformational Profile

“…The hydrogen bonds from 3-OH to the thiazole ring and from 7-OH to the ketone carbonyl are marked features of the most stable epothilone B conformers. These structures dictate their compact shape 42 and appear to account fairly well for the total energy of the molecule. It is not astonishing that the most stable structure, bP01, has the shortest 3-OH hydrogen bond (2.039 Å ́), whereas bX27, which is less stable by 13 kcal/mol, has the longest hydrogen bond (2.227 Å ́)…”

“…I observed that the model chemistry used predicts the relative interaction energies spread over a much larger range than those calculated using the standard B3LYP6-31+G(d,p)// B3LYP6-31+G(d,p) optimization model. 42 The selected geometries were transformed into the patupilone and ixabepilone starting structures, as appropriate, and all of these molecules were optimized using B3LYP/6-31+G(d,p) calculations with Gaussian 09. 49 The loose convergence criteria of Gaussian program were applied (requiring the root-mean-square (rms) forces to be smaller than 1.667 × 10 −3 hartree•bohr −1 ).…”

“…Because experimental data referring to ixabepilone are scarce and data on the conformational energy surface of epothilone B are still incomplete, I extended my studies on epothilone A to this compound following the same strategy. 42 My aim is to supply an overview of the possible unbound conformers of ixabepilone and compare them with those of patupilone, which is reported as a reference. The solvent dependence of the PES is also briefly discussed.…”

Conformational Properties of the Chemotherapeutic Drug Analogue Epothilone A: How to Model a Flexible Protein Ligand Using Scarcely Available Experimental Data

“…Epothilone A (EpoA) is a cyclic molecule that can be extracted from the bacterium Sorangium cellulosum. − It consists of a 16-membered ring, contains 34 non-hydrogen atoms, and can adopt various conformations. This has induced research on the conformational characteristics of the molecule and its derivatives. , Quantum-chemical methods , or molecular dynamics (MD) simulations − were used, but no comparison with X-ray diffraction intensities or NOE atom–atom distance bounds was reported. Using nuclear magnetic resonance (NMR) techniques and molecular dynamics (MD) simulation, the stereochemistry of the seven chiral centers of EpoA was determined. , The Cambridge Structural Database (CSD) contains a crystal structure of EpoA derived from X-ray diffraction intensities, here indicated as X-ray_unbound (Figure ).…”

“…This has induced research on the conformational characteristics of the molecule and its derivatives. 8,9 Quantum-chemical methods 10,11 or molecular dynamics (MD) simulations 12−14 were used, but no comparison with X-ray diffraction intensities or NOE atom−atom distance bounds was reported. Using nuclear magnetic resonance (NMR) techniques and molecular dynamics (MD) simulation, the stereochemistry of the seven chiral centers of EpoA was determined.…”