as a Complement to Classic SAR
little attention has been paid to the relationship
between conformation and biological activity in these stereochemically
complex systems. This fact is almost certainly due to a misconception
about their presumed flexibility. In fact, these compounds do
have specific preferred conformations. Unfortunately, even minor
substitution or stereochemical changes can significantly affect the
conformational preferences of polyketides and thus alter binding
affinity and biological activity. Thus, our group has designed a
program that complements classic SAR with an appreciation for the
conformational consequences of structural modification with the aim of
creating a complete and accurate pharmacophe model.
Molecular modeling coupled with high-field NMR analysis is being used
to gain an understanding of the conformation preferences for specific
torsions found within a target polyketide.
our program is the design
of analogues which alter the conformation preferences via minimal
substitution. Conformational analysis coupled with biological activity
data allows for an improved understanding of the structural and
conformational constraints of binding and the development of a more
complete pharmacophore model.
Taylor, R. E.;
"The Conformational Properties of Epothilone" J.
Org. Chem. 1999,
maps were used to display the results of extensive
monte carlo-based conformational analysis. Boltzmann-modified
values suggested the C1-C10 region populated two main conformational
families. NMR analysis supported the presence of both in polar as well
as non-polar solvents.
|Carlomagno, T.; Blommers, M. J. J.;
Meiler, J.; Jahnke, W.; Schupp, T.; Peterson, F.; Schinzer, D.;
Altmann, K.-H.; Griesinger, C. “The High-Resolution Solution Structure
of Epothilone A Bound to Tubulin: An Understanding of the
Structure—Activity Relationships for Powerful Class of Antitumor
Agents.” Angew. Chem. Int. Ed.
|Nagano, S.; Li, H.; Shimizu, H.;
Nishida, C.; Ogura, H.; Ortiz de Montellano, P. R.; Poulos, T. L.
“Crystal Structures of Epothilone D-bound, Epothilone B-bound, and
Substrate-free Forms of Cytochrome P450 epoK” J. Biol. Chem. 2003, 278, 44886-44893.
|Conformer A has significant resemblance
to the conformation of epothilone A bound to tubulin as determined by
NMR-based methods. This conformation is also supported by analogues
prepared in our laboratories as well as others.
|Remarkably, conformer B has
significant resemblance to the conformation of epothilone D and B bound
to the post-PKS cytochrome p450 epoK. Thus, the flexibility observed in
polyketides like epothilone may have important biological function.