Optimization of pyrimidinol antioxidants as mitochondrial protective agents: ATP production and metabolic stability

Arnaud Chevalier, Mohammad Parvez Alam, Omar Khdour, Margaret Schmierer, Pablo M. Arce, Cameron D. Cripe, Sidney Hecht

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Previously we described a novel series of pyrimidinol antioxidants and their structural optimization as potential therapeutic agents for neurodegenerative and mitochondrial disorders. Our initial lead compound was a potent antioxidant in vitro, but was subsequently found to exhibit poor stability to oxidative metabolism. The current study focused on balancing potency with metabolic stability through structural modification, and involved modifications at positions 2 and 4 of the pyrimidinol redox core, likely sites of oxidative metabolism. Eight new analogues have been prepared and their ability to suppress lipid peroxidation and reactive oxygen species (ROS), and to preserve mitochondrial membrane potential (Δψm) and support ATP production, has been investigated. The metabolic stability of the prepared compounds was also assessed in vitro using bovine liver microsomes to obtain preliminary insight on this class of compounds. This study revealed the complexity of balancing reasonable metabolic stability with efficient antioxidant properties. While a few analogues appear promising, especially in terms of metabolic stability, a 4-isopropoxy derivative conserved the favorable biological activity and exhibited good metabolic stability. The favorable metabolic stability conferred by the combination of the azetidine and isopropoxy moieties in analogue 6 makes this compound an excellent candidate for further evaluation.

Original languageEnglish (US)
Pages (from-to)5206-5220
Number of pages15
JournalBioorganic and Medicinal Chemistry
Volume24
Issue number21
DOIs
StatePublished - Nov 1 2016

Fingerprint

Protective Agents
Antioxidants
Adenosine Triphosphate
Mitochondrial Diseases
Mitochondrial Membrane Potential
Liver Microsomes
Neurodegenerative Diseases
Lipid Peroxidation
Oxidation-Reduction
Reactive Oxygen Species
Metabolism
Lead compounds
Structural optimization
Bioactivity
Liver
In Vitro Techniques
Derivatives
Membranes
Lipids
Therapeutics

Keywords

  • Cytoprotection
  • Lipid peroxidation
  • Microsomal stability
  • Mitochondria
  • Reactive oxygen species

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Optimization of pyrimidinol antioxidants as mitochondrial protective agents : ATP production and metabolic stability. / Chevalier, Arnaud; Alam, Mohammad Parvez; Khdour, Omar; Schmierer, Margaret; Arce, Pablo M.; Cripe, Cameron D.; Hecht, Sidney.

In: Bioorganic and Medicinal Chemistry, Vol. 24, No. 21, 01.11.2016, p. 5206-5220.

Research output: Contribution to journalArticle

Chevalier, Arnaud ; Alam, Mohammad Parvez ; Khdour, Omar ; Schmierer, Margaret ; Arce, Pablo M. ; Cripe, Cameron D. ; Hecht, Sidney. / Optimization of pyrimidinol antioxidants as mitochondrial protective agents : ATP production and metabolic stability. In: Bioorganic and Medicinal Chemistry. 2016 ; Vol. 24, No. 21. pp. 5206-5220.
@article{0c64fa71c3534546a139a3ce417437f1,
title = "Optimization of pyrimidinol antioxidants as mitochondrial protective agents: ATP production and metabolic stability",
abstract = "Previously we described a novel series of pyrimidinol antioxidants and their structural optimization as potential therapeutic agents for neurodegenerative and mitochondrial disorders. Our initial lead compound was a potent antioxidant in vitro, but was subsequently found to exhibit poor stability to oxidative metabolism. The current study focused on balancing potency with metabolic stability through structural modification, and involved modifications at positions 2 and 4 of the pyrimidinol redox core, likely sites of oxidative metabolism. Eight new analogues have been prepared and their ability to suppress lipid peroxidation and reactive oxygen species (ROS), and to preserve mitochondrial membrane potential (Δψm) and support ATP production, has been investigated. The metabolic stability of the prepared compounds was also assessed in vitro using bovine liver microsomes to obtain preliminary insight on this class of compounds. This study revealed the complexity of balancing reasonable metabolic stability with efficient antioxidant properties. While a few analogues appear promising, especially in terms of metabolic stability, a 4-isopropoxy derivative conserved the favorable biological activity and exhibited good metabolic stability. The favorable metabolic stability conferred by the combination of the azetidine and isopropoxy moieties in analogue 6 makes this compound an excellent candidate for further evaluation.",
keywords = "Cytoprotection, Lipid peroxidation, Microsomal stability, Mitochondria, Reactive oxygen species",
author = "Arnaud Chevalier and Alam, {Mohammad Parvez} and Omar Khdour and Margaret Schmierer and Arce, {Pablo M.} and Cripe, {Cameron D.} and Sidney Hecht",
year = "2016",
month = "11",
day = "1",
doi = "10.1016/j.bmc.2016.08.039",
language = "English (US)",
volume = "24",
pages = "5206--5220",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier Limited",
number = "21",

}

TY - JOUR

T1 - Optimization of pyrimidinol antioxidants as mitochondrial protective agents

T2 - ATP production and metabolic stability

AU - Chevalier, Arnaud

AU - Alam, Mohammad Parvez

AU - Khdour, Omar

AU - Schmierer, Margaret

AU - Arce, Pablo M.

AU - Cripe, Cameron D.

AU - Hecht, Sidney

PY - 2016/11/1

Y1 - 2016/11/1

N2 - Previously we described a novel series of pyrimidinol antioxidants and their structural optimization as potential therapeutic agents for neurodegenerative and mitochondrial disorders. Our initial lead compound was a potent antioxidant in vitro, but was subsequently found to exhibit poor stability to oxidative metabolism. The current study focused on balancing potency with metabolic stability through structural modification, and involved modifications at positions 2 and 4 of the pyrimidinol redox core, likely sites of oxidative metabolism. Eight new analogues have been prepared and their ability to suppress lipid peroxidation and reactive oxygen species (ROS), and to preserve mitochondrial membrane potential (Δψm) and support ATP production, has been investigated. The metabolic stability of the prepared compounds was also assessed in vitro using bovine liver microsomes to obtain preliminary insight on this class of compounds. This study revealed the complexity of balancing reasonable metabolic stability with efficient antioxidant properties. While a few analogues appear promising, especially in terms of metabolic stability, a 4-isopropoxy derivative conserved the favorable biological activity and exhibited good metabolic stability. The favorable metabolic stability conferred by the combination of the azetidine and isopropoxy moieties in analogue 6 makes this compound an excellent candidate for further evaluation.

AB - Previously we described a novel series of pyrimidinol antioxidants and their structural optimization as potential therapeutic agents for neurodegenerative and mitochondrial disorders. Our initial lead compound was a potent antioxidant in vitro, but was subsequently found to exhibit poor stability to oxidative metabolism. The current study focused on balancing potency with metabolic stability through structural modification, and involved modifications at positions 2 and 4 of the pyrimidinol redox core, likely sites of oxidative metabolism. Eight new analogues have been prepared and their ability to suppress lipid peroxidation and reactive oxygen species (ROS), and to preserve mitochondrial membrane potential (Δψm) and support ATP production, has been investigated. The metabolic stability of the prepared compounds was also assessed in vitro using bovine liver microsomes to obtain preliminary insight on this class of compounds. This study revealed the complexity of balancing reasonable metabolic stability with efficient antioxidant properties. While a few analogues appear promising, especially in terms of metabolic stability, a 4-isopropoxy derivative conserved the favorable biological activity and exhibited good metabolic stability. The favorable metabolic stability conferred by the combination of the azetidine and isopropoxy moieties in analogue 6 makes this compound an excellent candidate for further evaluation.

KW - Cytoprotection

KW - Lipid peroxidation

KW - Microsomal stability

KW - Mitochondria

KW - Reactive oxygen species

UR - http://www.scopus.com/inward/record.url?scp=84991730391&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84991730391&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2016.08.039

DO - 10.1016/j.bmc.2016.08.039

M3 - Article

C2 - 27624526

AN - SCOPUS:84991730391

VL - 24

SP - 5206

EP - 5220

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 21

ER -