synthesis of discodermolides useful for investigating microtubule binding and stabilization
DESCRIPTION
Synthesis of Discodermolides Useful for Investigating Microtubule Binding and Stabilization. Melissa G. Morris CHEM 635 February 12, 2013. Hung, D. T.; Nerenberg , J. B.; Schreiber, S. L. J. Am. Chem. Soc. 1996, 118, 11054-11080. Stuart L. Schreiber, Ph.D. Born February 6, 1956 - PowerPoint PPT PresentationTRANSCRIPT
Synthesis of Discodermolides Useful for Investigating Microtubule Binding and
StabilizationMelissa G. Morris
CHEM 635February 12, 2013
Hung, D. T.; Nerenberg, J. B.; Schreiber, S. L. J. Am. Chem. Soc. 1996, 118, 11054-11080
Stuart L. Schreiber, Ph.D. • Born February 6, 1956• B.A. in chemistry from UVA, 1977• Ph.D. from Harvard University • Joined Yale University faculty in 1981
Promoted to associate professor in 1984
Full Professor in 1986• Retuned to Harvard in 1988–present
Morris Loeb Professor of Chemistry and Biology Director of Chemistry Biology A Founding Member of the Broad
Institute of Harvard and MIT.• His research is focused in chemical
biology• >460 publications
History1990–isolated by Gunasekera and co-workers at the Harbor
Branch Oceranographic Institute from the deep-sea marine sponge Discodermolide dissoluta
1993–Schreiber and co-workers reported the first total synthesis of Discodermolide, but unfortunately the unantural antipode, (-)-Discodermolide
They also determined the absolute stereochemistry, something Gunasekera was unable to determine
Retro-synthesis
• 2 = C-C7• 3 = C9-C15• 4 = C16-C24
Forward Synthesis Synthesis of C1-C7
Synthesis of C9-C15
Forward Synthesis Cont. Synthesis of C16-C24
Combining the Fragments
Reduction of acetylene was too problematic in the presence of the terminal diene
C16-C24
C9-C15
Revision of Coupling
…doesn’t work!
The Final Step…
Final Step Revised
Stereochemistry
His original total synthesize provided: ([a]20
D = -13.0(c = 0.6, methanol)).
The current synthesis provided: ([a]20
D = +14.0 (C = 0.6, methanol)), which was obtained via biological characterization
Synthesizing Derivatives for Biological Studies Purpose: To further characterize the interactions between
Discodermolide and its receptor How: Synthesize an array of targets that can be analyzed when
subjected in vivo
Why: Disocdermolide comprises numerous biological properties: Immunisuppressive Antiproliferative/antimitotic Potent microtubule-stabilizing agent
Structural Variants for Studying Interactions with Discodermolide Receptor
• Before these variants were made, truncated version of Discodermolide were tested to see if the full length is needed for receptor recognition
Structural Variants Cont.
32 and 35 were not active in vivo, suggesting that the full length of Discodermolide was necessary for receptor recognition
Binding Reagent Syntheses
Binding Reagents Cont.
Binding Reagents Cont.
Substrate Product R1 R2 IC50
27b50a
a-PhS S-Me 6nM
27a50b
a-PhS S-Me 4nM
26b51
b-PhS H 4nM
Summary of Reagents and Activities
no. IC50a(nM) no. IC50
a (nM)
1 1a 6 8 372 31 10 9 45 703 1c 300 10 50a 64 1b 11 50b 45 32 12 51 46 35 13 597 36 70
Final Biological Assay Results
Conclusion
A total synthesis of (+)-Discodermolide in 36 steps, with an overal yield of 4.3% over 24 steps (the longest linear sequence)
Discodermolide remains the most potent natural promoter of tubulin assembly
(Extra) Synthesis of 59