Rational Design of Novel Pyridinol-Fused Ring Acetaminophen Analogues

Title
Rational Design of Novel Pyridinol-Fused Ring Acetaminophen Analogues
Author(s)
정병선Roman V. Shchepin[Roman V. Shchepin]Wei Liu[Wei Liu]Huiyong Yin[Huiyong Yin]Irene Zagol-Ikapitte[Irene Zagol-Ikapitte]Taneem Amin[Taneem Amin]L. Jackson Roberts, II[L. Jackson Roberts, II]John A. Oates[John A. Oates]Ned A. Porter[Ned A. Porter]Olivier Boutaud[Olivier Boutaud]
Keywords
INDUCED HEPATIC-NECROSIS; ACUTE LIVER-FAILURE; AMINOPYRIDINOL ANTIOXIDANTS; LIPID-PEROXIDATION; CYTOTOXICITY; DERIVATIVES; ADDUCTS; ASSAY
Issue Date
201308
Publisher
AMER CHEMICAL SOC
Citation
ACS MEDICINAL CHEMISTRY LETTERS, v.4, no.8, pp.710 - 714
Abstract
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 intramolecular 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.
URI
http://hdl.handle.net/YU.REPOSITORY/29192http://dx.doi.org/10.1021/ml4000904
ISSN
1948-5875
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약학대학 > 약학부 > Articles
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