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!

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

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 51.1 g by column chromatography 3X: (a) chloroform/methanol mobile phase (b) cyclohexane/acetone/diethyl amine mobile phase (c) chloroform/methanol mobile phase Only 6.0 mg of Nakadomarin A was isolated! Other related compounds were also isolated from this procedure.

Nakadomarin A Structure Determination: 1. Molecular formula was established as C 26 H 36 N 2 O by mass spectrometry 2. 1 H and 13 C NMR data 3. Advanced two-dimensional NMR studies to confirm structure and determine stereochemistry of stereocenters

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:

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

Taxol® Discovered in 1967 Isolated from the bark of the Pacific 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

A Taxol Derivative 1 H NMR Spectrum:

Molecular Modification 1. A compound is isolated from nature 2. Its basic structure serves as a prototype (a.k.a. a lead compound) in search for other biologically active compounds 3. Analogs of the lead compound are synthesized and tested for biological activity Process: Classic example: cocaine

Cocaine 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 ester methyl ester 7-membered ring Amine (tertiary)

Molecular Modification of Cocaine Identify the beneficial portion: Degrade the cocaine molecule step by step by: 1. Removing the CO 2 CH 3 group 2. Cleaving the 7-membered ring Result: An improved lead compound: 1. Aromatic ester 2. Terminal tertiary amine

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

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

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