Small molecule natural products represent a valuable collection of ligands for use in the study of protein and cellular function. A detailed understanding of receptor-ligand interactions at the molecular level will allow for the design and preparation of new chemotherapeutic agents. Specifically, the relationship between conformation and biological activity of a number of complex natural products is being investigated. The power of synthesis in combination with high field nuclear magnetic resonance (NMR) and computer-based molecular modeling analysis will provide a detailed understanding of the solution conformational properties of these important compounds. In addition, NMR, molecular modeling, and biological activity data of conformationally-altered analogues will provide important information about the conformation of these ligands while bound to their respective biological receptor. Two important criteria must be met for success with this approach; 1) targets must be selected which contain regions where structural modifications can be made without significant loss of binding affinity and 2) the structural units used to control conformation must minimally alter the sterics and electronics of the molecule. Epothilone A and B represent an important new lead in the search for improved chemotherapeutic agents. Synthetic, biological, and analytic techniques are being used to explore the conformation of the epothilone class and its relationship to their interesting biological activity. A practical synthetic route to epothilone A has already been developed. A novel route to epothilone B is proposed. Analogues of both parent compounds are being prepared which contain strategically placed conformational control elements. Biological activity studies as well as conformational analysis should provide the conformation of epothilone while bound to microtubules. This increased understanding of epothilone's mode of action at the molecular level will allow for the preparation of the next generation of microtubule-stabilizing anti-mitotic agents.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA085499-04
Application #
6633650
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Fu, Yali
Project Start
2000-03-01
Project End
2005-02-28
Budget Start
2003-03-01
Budget End
2005-02-28
Support Year
4
Fiscal Year
2003
Total Cost
$167,063
Indirect Cost
Name
University of Notre Dame
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
824910376
City
Notre Dame
State
IN
Country
United States
Zip Code
46556
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