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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

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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
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

biosynthesis of epothilones
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

laboratory synthesis of epothilones
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

slide5

Aldol

Condensation

Wittig

Reaction

Difficulties: Stereochemistry

Esterification

Olefin

Metathesis

Figures: Nicolaou, K. C. et al. Angew. Chem Int. Ed. Engl.1997

characterization of epothilone a
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

of interest two conformers
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

summary
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

epothilone a the nature synthesis characterization and conformation of an anti cancer drug1

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

University of Notre Dame

Benjamin Doe Thursday, April 12, 2007

laborartory synthesis of epothilones
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

conformers involved in binding
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