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
H
O
Nakadomarin A
N
H
N
Why an attractive target?
• Unusual ring system
• Anticancer, antibacterial and antifungal
properties
Nakadomarin A
H
O
N
H
N
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
H
O
Structure Determination:
N
H
N
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
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:
H
O
N
H
O
O
N
1
HN
P
O
SO2Ar
N
N
H P'
N
2
3
P
SnBu3
N
N
P'
4
O2N
O
N
+
H
N
SiMe3
5
6
P'
Taxol®
AcO
O
Ph
O
NH
OH
O
Ph
O
H
O
OH
OH
Treatment of:
• Lung, ovarian, and breast cancers
• Prevention of restenosis
Marketed by Bristol-Myers Squibb in 1993
2000 annual sales - $1.6 billion
OAc
OCOPh
Taxol®
AcO
O
Ph
NH
O
OH
O
Ph
O
H
O
OH
OH
OAc
OCOPh
• 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
1H
NMR Spectrum:
QuickTime™ and a
TIFF (LZW) decompressor
are needed to see this picture.
Molecular Modification
Process:
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
Classic example: cocaine
Cocaine
Amine (tertiary)
methyl ester
H3C
N
7-membered
ring
CO2CH3
ester
O
O
• 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
Molecular Modification of Cocaine
Identify the beneficial portion:
Degrade the cocaine molecule
step by step by:
1. Removing the CO2CH3 group
2. Cleaving the 7-membered ring
Result:
An improved lead compound:
1. Aromatic ester
2. Terminal tertiary amine
H3C
N
CO2CH3
O
O
CH3
N
O
H3C
O
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
CH3
N
O
H3C
O
New lead compound
Successful Anesthetics
NH2
H3CH2C
O
N
CH2CH3
Procaine
(Novocain)
O
• 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
H3C
H3CH2C
H3CH2C
N
Lidocaine
(Xylocaine)
HN
C
O
H3C
• 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