Download Kardelen C. Ergin – Seminar

Galantamine: Extraction, Synthesis
and Use in Alzheimer’s Disease
Treatment
PRESENTED BY: KARDELEN CANAN ERGIN
Outline
1- INTRODUCTION: GALANTHUS NIVALIS
2- EXTRACTION OF GALANTAMINE
3- SYNTHESIS OF GALANTAMINE
4- AREAS OF USE FOR GALANTAMINE
5- CONCLUSION
6- REFERENCES
Introduction
γαλα
(gala)
milk
ἄνθος
(anthos)
flower
First historical appearance
Odysseus
Circe
Native areas for snowdrop
First
etnopharmacological
use
documented
in 1950
Ethnopharmacology: traditional
medicine practiced by ethnical
groups.
Reminyl – Razadyne – Lycoremine – Nivalin - Beklamen
Daffodil
Red Spider Lily
Snowflake
Amaryllidaceae
Extraction
Dry and
mince
Extract
with
heptane
and H2SO4
Set pH5
with
concentrated
ammonia
Extract
with
diethyl
ether
Purify
through
column
chromatography
Synthesis
• Biomimetic
• Asymmetric
• Poor yielding
• Not cost-effective
Galantamine Hydrobromide
• Classical Resolution
• Oxidative Ring Closure
Retrosynthetic Analysis
reduction + dehalogenation
reduction
oxidative coupling + furan derivative formation
amide tether
p-hydroxy ethyl-Nmethyl-phenyl amine
derivative
Bromobenzoic
acid derivative
Northern Part
Southern Part
Synthesis of The Northern Part
isovanilline
benzylation
bromination
Bromobenzoic
acid derivative
oxidation
Synthesis of The Southern Part
p-hydroxybenzylmethyl carboxylate
benzylation
amidation
p-hydroxy ethyl-Nmethyl-phenyl amine
derivative
reduction
Southern + Northern Parts
+
Southern Part
Northern Part
phenyl boronic acid-catalyzed amidation
Amide
Intramolecular Oxidative Coupling
hydrogenolysis
tetracyclic framework
Tetracyclic Skeleton Formation
Southern part serves as
a source of Michael
acceptor that facilitates
the caging
Mediated by redox potential of
ferric ions
Northern part serves
as a donor afforded
the tetracyclic
skeleton
Spirocyclic intermediate
80% yield
99% stereoselectivity
L-selectride mediated
→
𝛼, 𝛽-unsaturated ketone
𝑎𝑙𝑐𝑜ℎ𝑜𝑙
Final Step
Vitride = Red-Al
Classical resolution
HBr salt formation
Galantamine
Hydrobromide
Areas of Use
First
Use
Antagonise the effects of nondepolarizing muscle relaxants
Post-polio paralysis
Reversal of neuromuscular
blockade
Alzheimer’s Disease
• 15 million people with the condition
•
•
•
•
•
Decline in cognitive functions: Memory
Activities of daily living
Sleep quality
Behavioral disturbances
Caregiver burden
Acetylcholine
Acetylcholine
Attention & Learning
Both
Central Nervous System
and
Peripheral Nervous System
Both
Inhibitory
and
Excitatory
Effects of Galantamine on Nerve Cells
Acethylcholinesterase
inhibitor
Allosterically
potentiating nicotinic
receptors
Neuromodulator of
neurotransmitter
release
Neuroprotective
agent
AChE Inhibition
Acethylcholinesterase
breaks down the
acetylcholine
Modulation of nAChRs
Augments
cellular
response
Increase in
receptors in
long term
Neuromodulator of Neurotransmitter
1- Presynaptic Neuron
2- Synaptic Cleft
3- Postsynaptic Neuron
•
•
•
•
Dopamine
Glutamate
Serotonin
GABA
Neuroprotectant Effects
Increased synthesis of neurotropic factors
Protect against:
toxic effects of glutamate
tropic factor deprivation
hypoxia
β-amyloid
Treatment
Alzheimer’s
Disease
Characteristics
Decline in ability to
perform daily tasks
Behavioral
disturbances
Caregiver burden
Treatment
• Galantamine using
patients significantly
superior to the placebo
group
Treatment
• Once the ability to
perform daily activities
is lost, it is rarely recovered
Treatment: Behavioral Disturbances
Anxiety
Depression
Hallucination
Agitation
Aggression
Non-medical Area of Use
Cognitive Clarity
Lucidity
Recall
Control
Bizarreness
Visual Vividness
Stephen LaBerge
• ACh is responsible
of generation and
maintenance of
REM sleep
Side Effects
Nausea
Vomiting
Diarrhea
Sleep Paralysis
Conclusion
47% of aged 85+
Slows down the process
Not a cure
Future work lies in the area of curing Alzheimer’s Disease
References
 Reddy, Jambula Mukunda, et al. "Alternative Total Synthesis of (−)-Galanthamine
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Hydrobromide." Synthetic Communications® 38.13 (2008): 2138-2149.
Marco-Contelles, José, et al. "Synthesis and pharmacology of
galantamine."Chemical reviews 106.1 (2006): 116-133.
Heinrich, Michael, and Hooi Lee Teoh. "Galanthamine from snowdrop—the
development of a modern drug against Alzheimer’s disease from local Caucasian
knowledge." Journal of Ethnopharmacology 92.2 (2004): 147-162.
Lilienfeld, Sean. "Galantamine—a novel cholinergic drug with a unique dual mode of
action for the treatment of patients with Alzheimer's disease." CNS drug reviews 8.2
(2002): 159-176.
Blesa, Rafael. "Galantamine: therapeutic effects beyond cognition."Dementia and
geriatric cognitive disorders 11.Suppl. 1 (2000): 28-34.
LaBerge, Stephen P. "Substances that enhance recall and lucidity during dreaming."
U.S. Patent Application 10/604,138.
Berger, Stefan, and Dieter Sicker. Classics in Spectroscopy: Isolation and Structure
Elucidation of Natural Products. 1st. Weinheim: Wiley-Vch, 2009. 83-91. Print.
Additional Definitions
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Nicotinic acetylcholine receptor: cholinergic receptors that form ligand-gated ion
channels in the plasma membranes of certain neurons and on the presynaptic and postsynaptic
sides of neuromuscular junction. Directly linked to ion channels and do not use second
messengers .
Cholinergic neuron: All the neurons that use acetylcholine as a neurotransmitter.
Neurotropic factors: A family of proteins that are responsible for the growth and survival of
developing neurons and maintenance of mature neurons.
Hypoxia: Reduced supply of oxygen
Β-amyloid: Is a peptide and the main component of certain deposits found in the brains of AD
patients.
Apoptosis: programed cell death which biochemical events lead to.
Lucid Dreaming: A lucid dream is any dream in which one, for an uninterrupted and
prolonged amount of time, is aware that one is dreaming. In a lucid dream, the dreamer has
greater chances to exert some degree of control over their participation within the dream or be
able to manipulate their imaginary experiences in the dream environment.
REM sleep: Rapid eye movement (REM) sleep is a normal stage of sleep characterized by the
rapid and random movement of the eyes.
Sleep Paralysis: Sleep paralysis is a phenomenon in which people, either when
falling asleep or wakening, temporarily experience an inability to move. More formally, it is a
transition state between wakefulness and rest characterized by complete muscle atonia (muscle
weakness). It can occur at sleep onset or upon awakening, and it is often associated with
terrifying visions (e.g. an intruder in the room), to which one is unable to react due to paralysis.
Additional Definitions
 Alkaloid: Alkaloids are a group of naturally occurring chemical compounds, that
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contain mostly basic nitrogen atoms
Biomimetic: a biomimetic synthesis is a chemical synthesis inspired by
biochemical processes.
Asymmetric Synthesis: a chemical reaction (or reaction sequence) in which one
or more new elements of chirality are formed in a substrate molecule and which
produces the stereoisomeric (enantiomeric ordiastereoisomeric) products
in unequal amounts.
Classical Resolution: Chiral resolution in stereochemistry is a process for the
separation of racemic compounds into their enantiomers.
Spirocyclic: A spiro compound is a bicyclic organic compound with rings
connected through just one atom.
Michael Reaction: It is the nucleophilic addition of a carbanion or
another nucleophile to an α,β-unsaturated carbonyl compound.
L-selectride is an organoborane. It is used in organic chemistry as a reducing
agent.
Treatment: Caregiver Burden
Treatment: Quality of Sleep
• Usually cholinergic
treatments have
adverse effects
on sleep