Patupilone and ixabepilone: the effect of a point structural change on the exo-endo conformational profile.
The natural product patupilone (epothilone B) and its synthetic aza-analogue, ixabepilone, are effective agents against a broad range of human cancers. A detailed conformational analysis was conducted on the basis of single-point MP2 energy calculations for density functional theory (DFT) geometries at the MP2/6-31+G(d,p)//B3LYP/6-31+G(d,p) level. In a vacuum, patupilone exclusively adopts compact exo conformations due to short, near-linear hydrogen bonding between the 3-hydroxyl group and the side-chain thiazole. In contrast, ixabepilone can be described as a competitive mixture of exo and endo conformers with a large population of the above-mentioned compact exo conformations. The stability of the endo form is consistent with the cooperativity of hydrogen bonds. The relative energies of some patupilone and ixabepilone conformers were found to be sensitive to solvent effects within the integral equation formalism polarizable continuum model (IEF-PCM). This study contributes to a better understanding of the important structural features of patupilone and ixabepilone. This conformational analysis lends support to previous observations concerning their different pharmaceutical profiles.
Institute of Chemical Technology and Engineering, Poznan University of Technology, Pl. M. Sklodowskiej-Curie 5, 60-965 Poznan, Poland. Marek.Lozynski@put.poznan.pl
Marek
M
Lozynski
D000970:Antineoplastic Agents / Q000737:chemistry*; D034261:Epothilones / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008968:Molecular Conformation; D013816:Thermodynamics
D000970:Antineoplastic Agents; D034261:Epothilones; C430592:ixabepilone; C093788:epothilone B