Chapter 19 Related Material

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Presentation transcript:

Chapter 19 Related Material Imines – Biosynthesis of histamine Pyrazoles from dicarbonyl compounds and hydrazine: Synthesis of Celebrex® Conjugate addition – Acetaminophen metabolism

Pyridoxal phosphate (PLP) Biosynthesis of Histamine from Histidine Decarboxylation of histidine is mediated by pyridoxal phosphate (PLP) Histidine decarboxylase PLP Histidine Essential amino acid Histamine Allergy symptoms (binding to H1 receptors) Gastric acid secretion (binding to H2 receptors) Pyridoxal phosphate (PLP)

Marketed Histamine Receptor Antagonists H1 receptor antagonists: antihistamines Benadryl® Diphenhydramine H2 receptor antagonists: inhibit gastric secretion Tagamet® Cimetidine

PLP-Mediated Histidine Decarboxylation Proceeds via an Imine Intermediate Histidine-PLP imine Histamine Histamine-PLP imine

Mechanism – inhibition of prostaglandin synthesis Non-Steroidal Antiinflammatory Celebrex® Is a Selective Cyclooxygenase 2 (COX2) Inhibitor Celebrex® (celecoxib) Mechanism – inhibition of prostaglandin synthesis Selective inhibition of COX2 versus COX1 reduces gastrointestinal side-effects of NSAID

Two regioisomers possible Synthesis of Celebrex® Two regioisomers possible More basic terminal nitrogen attacks more electrophilic trifluoromethyl ketone

Acetaminophen Metabolism Proceeds Through Multiple Pathways Glucuronidation Sulfation Acetaminophen (Tylenol®) Oxidation NAPQI Glucuronide and sulfate are more polar and thus more water soluble, facilitating excretion

Under Normal Conditions NAPQI Is Detoxified by Glutathione Conjugate addition (1,4-addition) Glutathione (GSH) NAPQI The NAPQI metabolite is an electrophilc intermediate which can undergo conjugate addition

If Glutathione Stores Become Depleted NAPQI Accumulates and Can React with Proteins Conjugate addition (1,4-addition) Cysteine residue of protein Alkylation leads to disruption of protein function NAPQI The NAPQI metabolite is an electrophilc intermediate which can undergo conjugate addition

N-Acetyl Cysteine Administered for Tylenol® Overdose Acetadote® – antidote for acetaminophen poisoning Mucomyst® – thins mucus by breaking disulfide bonds Glutathione (GSH)