Rational Design of Novel Pyridinol-Fused Ring Acetaminophen Analogues.
Acetaminophen (ApAP) is an electron donor capable of reducing radicals generated by redox cycling of hemeproteins. It acts on the prostaglandin H synthases (cyclooxygenases; COXs) to reduce the protoporphyrin radical cation in the peroxidase site of the enzyme, thus preventing the intra-molecular electron transfer that generates the Tyr385 radical required for abstraction of a hydrogen from arachidonic acid to initiate prostaglandin synthesis. Unrelated to this pharmacological action, metabolism of ApAP by CYPs yields an iminoquinone electrophile that is responsible for the hepatotoxicity, which results from high doses of the drug. We synthesized novel heterocyclic phenols predicted to be electron donors. Two of these inhibited the oxygenation of arachidonic acid by PGHS-1 and myoglobin and also were shown to be more metabolically stable and exhibited less direct cytotoxicity than acetaminophen. They are leading candidates for studies to determine whether they are free of the metabolism-based hepatotoxicity produced by acetaminophen.
Department of Chemistry, Vanderbilt University, 7330 Stevenson Center, Station B 351822, Nashville, Tennessee 37235, United States.
Roman V
RV
Shchepin
Department of Chemistry, Vanderbilt University, 7330 Stevenson Center, Station B 351822, Nashville, Tennessee 37235, United States.
Wei
W
Liu
Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, 536 Robinson Research Building, Nashville, Tennessee 37232-6602, United States.
Huiyong
H
Yin
Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, 536 Robinson Research Building, Nashville, Tennessee 37232-6602, United States.
Irene
I
Zagol-Ikapitte
Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, 536 Robinson Research Building, Nashville, Tennessee 37232-6602, United States.
Taneem
T
Amin
Department of Chemistry, Vanderbilt University, 7330 Stevenson Center, Station B 351822, Nashville, Tennessee 37235, United States.
Byeong-Seon
BS
Jeong
Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, 536 Robinson Research Building, Nashville, Tennessee 37232-6602, United States ; Department of Pharmacology, Division of Clinical Pharmacology, Vanderbilt University Medical Center, 536 Robinson Research Building, Nashville, Tennessee 37232-6602, United States.
L Jackson
LJ
Roberts
Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, 536 Robinson Research Building, Nashville, Tennessee 37232-6602, United States.
John A
JA
Oates
Department of Chemistry, Vanderbilt University, 7330 Stevenson Center, Station B 351822, Nashville, Tennessee 37235, United States.
Ned A
NA
Porter
Department of Pharmacology, Division of Clinical Pharmacology, Vanderbilt University Medical Center, 536 Robinson Research Building, Nashville, Tennessee 37232-6602, United States.
Olivier
O
Boutaud
Acetaminophen; heterocyclic phenols; stability; synthesis; toxicity