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Lecture 27

Lecture 27. Special Topics - Drug Discovery: Synthetic Research: Natural Product Isolation Molecular Modification Anesthetics This Week in Lab: Spec Unknown (Ch 12) Final Report Next Week in Lab: Synthetic #2 Final Report; Lab Clean-up & Check-out! Bring in your graded PreLabs!.

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Lecture 27

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  1. Lecture 27 Special Topics - Drug Discovery: Synthetic Research: Natural Product Isolation Molecular Modification Anesthetics This Week in Lab: Spec Unknown (Ch 12) Final Report Next Week in Lab: Synthetic #2 Final Report; Lab Clean-up & Check-out! Bring in your graded PreLabs!

  2. Synthesis Research Nakadomarin A • Why an attractive target? • Unusual ring system • Anticancer, antibacterial and antifungal • properties

  3. Nakadomarin A Isolated in 1997 by Kobayashi and co-workers from an Okinawan marine sponge: 1. Extracted sponge (1 kg) with methanol 2. Extracted methanol layer with ethyl acetate 3. Purified 51.1g by column chromatography 3X: chloroform/methanol mobile phase cyclohexane/acetone/diethyl amine mobile phase chloroform/methanol mobile phase Only 6.0 mg of Nakadomarin A was isolated! Other related compounds were also isolated from this procedure.

  4. Nakadomarin A Structure Determination: 1. Molecular formula was established as C26H36N2O by mass spectrometry 2. 1H and 13C NMR data 3. Advanced two-dimensional NMR studies to confirm structure and determine stereochemistry of stereocenters

  5. Nakadomarin A Only 6.0 mg of Nakadomarin A was isolated from 1 kg of sponge! Therefore, synthesis is needed to produce mass quantities. Retrosynthetic Analysis:

  6. Taxol® • Treatment of: • Lung, ovarian, and breast cancers • Prevention of restenosis • Marketed by Bristol-Myers Squibb in 1993 • 2000 annual sales - $1.6 billion

  7. Taxol® • Discovered in 1967 • Isolated from the bark of thePacific yew tree • Need six 100-year old trees to treat one patient! Thus, a • need for synthesis! • Can be made from 10-deacetylbaccatin (an extract from • various yew-related species) in several steps (semisynthesis) • OR • Can be made from plant cell fermentation technology: (1) propagation of • a specific taxus cell line (2) taxol is isolated via extraction, purified by • chromatography and crystallization

  8. A Taxol Derivative 1H NMR Spectrum:

  9. Molecular Modification Process: A compound is isolated from nature Its basic structure serves as a prototype (a.k.a. a lead compound) in search for other biologically active compounds Analogs of the lead compound are synthesized and tested for biological activity Classic example: cocaine

  10. Cocaine Amine (tertiary) methyl ester 7-membered ring ester • Isolated from the leaves of Erythroxylon coca (South • American Andes) • Effective local anesthetic • Produces disturbing effects on the central nervous • system (CNS); initial euphoria to severe depression • Goal: identify the portion of cocaine that serves as • the local anesthetic; make an anesthetic with no • CNS effects

  11. Molecular Modification of Cocaine Identify the beneficial portion: Degrade the cocaine molecule step by step by: Removing the CO2CH3 group Cleaving the 7-membered ring Result: An improved lead compound: Aromatic ester Terminal tertiary amine

  12. Molecular Modification of Cocaine • Hundreds of esters synthesized: • Putting groups on aromatic ring • Changing the alkyl groups bonded • to nitrogen • Changing the length of the alkyl chain New lead compound

  13. Successful Anesthetics Procaine (Novocain) • Contains an ester that is easily hydrolyzed, thus a short lifetime. • First synthesized in 1905 • Used primarily in dentistry • Primary ingredient in the preparation of Gerovital H3 (remedy aging effects), but this claim was studied and discredited in the 1960’s

  14. Successful Anesthetics Lidocaine (Xylocaine) • Contains amide that is not so easily hydrolyzed - faster acting and longer lasting than Novocain • Popular local anesthetic used in dentistry or topically • Developed in 1943

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