Bioactive conformations of epothilones

The question of the bioactive conformation of epothilones has also been addressed by density functional theory calculations. One such study has reached similar conclusions on the conformational preferences of the macrolactone ring as had been derived previously by Erdelyi et al. in their NMR work. ... 

The design of these analogs was guided by preliminary nuclear magnetic resonance (NMR) data on the bioactive (tubulin-bound) conformation of epothilones, which indicated that the C16/C17 double bond and the aromatic C18-N bond were present in a transoid arrangement (corresponding to a 180° C16-C17-C18-N22 torsion angle). (These data have subsequently been consolidated and have recently appeared in the literature ). 

The study of the tubulin-bound conformation of paclitaxel has resulted in a number of protein-ligand models, partially or fully based on the electron diffraction structure of aP-tubulin in paclitaxel-stabilized Zn2+-induced sheets [5, 12], Obviously, the nature of the paclitaxel binding site and the paclitaxel conformation in the binding site have key implications for the design of new MSA. A deep knowledge of the bioactive conformation would also help to explain how compounds as structurally diverse as the epothilones [48], discodermolide [49], and eleutherobin [50] have very similar mechanisms of action. 

As for all MSAs, the investigation of the complex of epothilones [57] with tubulin has also been attempted. The solid state (deduced by either X-ray or solid state NMR) structure of free epothilone B is known, as well as its conformations in organic solvents [84-86], However, its actual bioactive conformation is also a matter of debate. 

---