A common pharmacophore for epothilone and taxanes: Molecular basis for drug resistance conferred by tubulin mutations in human cancer cells
Paraskevi Giannakakou, Rick Gussio, Eva Nogales, Kenneth Giannakakou, H. Downing, Daniel Zaharevitz, Birgit Bollbuck, George Poy, Zaharevitz, Bollbuck, Poy, Dan Sackett, K. C. Nicolaou, and Tito Fojo Sackett, Nicolaou,
Jargon n. Nonsensical, incoherent, or meaningless
talk.
Pharmacophore-3D description in space of relevant groups on a molecule that interact with a receptor and are responsible for the activity Tubulin-protein found in the centrosome that assists with the formation of microtubules during the cell cycle Taxane-a type of chemical compound that prohibits cell growth by stabilizing microtubules within the cell
Presented by Jennifer Greene and assisted by John Jara
Paclitaxel and Docetaxel


Known as Taxol and Taxotere, respectively Taxol Belong to the family of chemotherapeutic drugs called taxanes Occurs in very small quantities Almost completely insoluble Use carrying agent called Cremophor which is a combination of ethanol, castor oil, and saline that is taken intravenously Gives only 30 to 40% response and is used for very aggressive tumors
Identified 3 nontaxane chemical classes of natural products:

Marine sponge -derived Discodermolide sponge-

CoralCoral-derived Sarcodictyins

Soil bacteria-derived Epothilones A and B bacteria-
1
Taxanes
Epothilones
Epothilones

Water soluble Available in large quantities Retain activity against multidrug -resistant multidrugcell lines (MDR) and tumors

Sarcodictyins Discodermolide

Images courtesy of Rick Gussio
The Big Picture
Taxane, epothilone, and sarcodictyin chemistries used to form single pharmacophore Use of human cancer cells with -tubulin mutations to demonstrate their structure activity relationships (SARs) Explanation of SARs through modeling and docking studies

下一页