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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 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 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 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