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

2. 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)

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

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

5. 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

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

7. 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

8. 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

9. 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

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