1 / 11

Epothilone A: The Nature, Synthesis, Characterization, and Conformation of an Anti-Cancer Drug

Epothilone A: The Nature, Synthesis, Characterization, and Conformation of an Anti-Cancer Drug. University of Notre Dame Benjamin L. Hechler Thursday, April 12, 2007. Discovery, Nature, Prospects. 1995 – potency determined Myxobacterium Sorangium cellulosum ( So ce 90) 1

mikel
Download Presentation

Epothilone A: The Nature, Synthesis, Characterization, and Conformation of an Anti-Cancer Drug

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. Epothilone A: The Nature, Synthesis, Characterization, and Conformation of an Anti-Cancer Drug University of Notre Dame Benjamin L. Hechler Thursday, April 12, 2007

  2. Discovery, Nature, Prospects 1995 – potency determined Myxobacterium Sorangium cellulosum (So ce 90)1 Stabilizes microtubules, initiating apoptosis Advantages over Taxol: 1) highly effective against Taxol- resistant strains 2) structure more manageable 3) fewer side effects2 1 Taylor, R.E.; Zajicek, J., J. Org. Chem. 1999 2 Nicolaou, K. C. et al., Angew. Chem. Int. Ed., 1998 Title slide image: Nicolaou, K. C. et al., Angew. Chem. Int. Ed., 1998

  3. Biosynthesis of Epothilones Epothilones C and D are primary products Epoxidation by enzymes produces epothilones A and B Hydroxylation of terminal carbon produces epothilones E and F1 epoxidation hydroxylation 1 Hofle, G. et al., J. Nat. Prod. 2001

  4. Laboratory Synthesis of Epothilones Danishefsky, Nicolaou, and Schinzer groups first to synthesize1 Nicolaou approach #1: Olefin Metathesis 1 Nicolaou, K. C. et al., Angew. Chem. Int. Ed. Engl. 1996

  5. Aldol Condensation Wittig Reaction Difficulties: Stereochemistry Esterification Olefin Metathesis Figures: Nicolaou, K. C. et al. Angew. Chem Int. Ed. Engl.1997

  6. Characterization of Epothilone A Was my synthesis successful? Formula: C26H39NO6S Molecular Weight: 493.66 Appearance: colorless crystals Melting Point: 95 Celsius1 Water Solubility: .7 g/L2 IR: characteristic peaks at 3464 (-OH), 1737, 1689 (carbonyl) cm- 1 1 Hofle, G. et al., J. Nat. Prod. 2001 2 Hofle, G. et al., Angew. Chem. 1996 H1 NMR: Taylor, R.E.; Zajicek, J., J. Org. Chem. 1999 C13 NMR: Meiler, J. et al., J. Chem. Inf. Comput. Sci., 2000

  7. Of Interest: Two Conformers Richard E. Taylor – University of Notre Dame (1999) Energetic Consequences1 (1) polypropionate rigidity (2) other regions see flexibility 1 Taylor, R.E.; Zajicek, J., J. Org. Chem. 1999

  8. Summary • Action determined in 1995, prospects are favorable • Biosynthetic Pathways of Epothilones A-F identified • Laboratory syntheses continually manipulated1 - Assumes two conformations in solution… - …Yet studies on tubulin binding remain 1 Taylor, R. E.; Haley, J. D., Tetrahedron Lett., 1997

  9. Epothilone A: The Nature, Synthesis, Characterization, and Conformation of an Anti-Cancer Drug University of Notre Dame Benjamin Doe Thursday, April 12, 2007

  10. Laborartory Synthesis of Epothilones Problems with Olefin Metathesis Approach (1) aldol condensation stereoselectivity(3:2) (2) olefin metathesis stereoselectivity(~1:1) Benefits of MacrolactonizationApproach (1) wittig reaction largely favors Z-isomer1 (2) olefin metathesis more difficult with tri-substituted DB2 1 Bergelson, L. D.; Shemyakin, M. M., Angew. Chem. Int. Ed. Engl. 1964 2 Nicolaou, K. C. et al., Angew. Chem. Int. Ed., 1998

  11. Conformers Involved in Binding (?) Higher-Energy Conformations Appears that a the syn-pentane- esque conformation assumed1 Major differences: C3 –OH and thiazole side chain rotatation2 Experimentation involving FRET suggests “the emission maximum of the microtubule-bound species was similar to that of the fluorophore in DMSO”3 1 Heinz, D. W., et al., Agnew. Chem. Int. Ed.,2005 2 Griesinger, C. et al., Agnew. Chem. Int. Ed., 2003 3 Kingston, D. G. I. et al., Tetrahedron, 2003

More Related