Cytoprotective pyridinol antioxidants as potential therapeutic agents for neurodegenerative and mitochondrial diseases

Mohammad Parvez Alam, Omar Khdour, Pablo M. Arce, Yana Chen, Basab Roy, Walter G. Johnson, Sriloy Dey, Sidney Hecht

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

As part of our ongoing efforts to identify compounds having potential utility in treating neurodegenerative and mitochondrial disorders, a series of pyridinol analogues have been prepared. The synthetic route employed for the preparation of the new analogues is different, and considerably more efficient, than that used in previously reported studies. The new route yields a pair of pyridinol regioisomers that can be readily separated and evaluated. Their ability to quench lipid peroxidation and reactive oxygen species (ROS), and to preserve mitochondrial membrane potential (Δψm) and support ATP synthesis is reported. The optimal side chain length was found to be 16 carbon atoms. The metabolic stability of those compounds having optimal biological activities was evaluated in vitro using bovine liver microsomes. The omission of any side chain hydroxyl group and introduction of an azetidine moiety at position 6 of the pyridinol redox core (8 and 9) increased their microsomal stability as compared to the exocyclic dimethylamino group. The favorable metabolic stability conferred by the azetidine moiety in compounds 8 and 9 makes these compounds excellent candidates for further evaluation.

Original languageEnglish (US)
Pages (from-to)4935-4947
Number of pages13
JournalBioorganic and Medicinal Chemistry
Volume22
Issue number17
DOIs
StatePublished - Sep 1 2014

Fingerprint

Mitochondrial Diseases
Neurodegenerative Diseases
Antioxidants
Mitochondrial Membrane Potential
Liver Microsomes
Hydroxyl Radical
Lipid Peroxidation
Oxidation-Reduction
Reactive Oxygen Species
Carbon
Adenosine Triphosphate
Bioactivity
Chain length
Liver
Therapeutics
Membranes
Lipids
Atoms
azetidine
In Vitro Techniques

Keywords

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

ASJC Scopus subject areas

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

Cite this

Cytoprotective pyridinol antioxidants as potential therapeutic agents for neurodegenerative and mitochondrial diseases. / Alam, Mohammad Parvez; Khdour, Omar; Arce, Pablo M.; Chen, Yana; Roy, Basab; Johnson, Walter G.; Dey, Sriloy; Hecht, Sidney.

In: Bioorganic and Medicinal Chemistry, Vol. 22, No. 17, 01.09.2014, p. 4935-4947.

Research output: Contribution to journalArticle

Alam, Mohammad Parvez ; Khdour, Omar ; Arce, Pablo M. ; Chen, Yana ; Roy, Basab ; Johnson, Walter G. ; Dey, Sriloy ; Hecht, Sidney. / Cytoprotective pyridinol antioxidants as potential therapeutic agents for neurodegenerative and mitochondrial diseases. In: Bioorganic and Medicinal Chemistry. 2014 ; Vol. 22, No. 17. pp. 4935-4947.
@article{72e053b413544bfb8be9f4b8e74b2265,
title = "Cytoprotective pyridinol antioxidants as potential therapeutic agents for neurodegenerative and mitochondrial diseases",
abstract = "As part of our ongoing efforts to identify compounds having potential utility in treating neurodegenerative and mitochondrial disorders, a series of pyridinol analogues have been prepared. The synthetic route employed for the preparation of the new analogues is different, and considerably more efficient, than that used in previously reported studies. The new route yields a pair of pyridinol regioisomers that can be readily separated and evaluated. Their ability to quench lipid peroxidation and reactive oxygen species (ROS), and to preserve mitochondrial membrane potential (Δψm) and support ATP synthesis is reported. The optimal side chain length was found to be 16 carbon atoms. The metabolic stability of those compounds having optimal biological activities was evaluated in vitro using bovine liver microsomes. The omission of any side chain hydroxyl group and introduction of an azetidine moiety at position 6 of the pyridinol redox core (8 and 9) increased their microsomal stability as compared to the exocyclic dimethylamino group. The favorable metabolic stability conferred by the azetidine moiety in compounds 8 and 9 makes these compounds excellent candidates for further evaluation.",
keywords = "Cytoprotection, Lipid peroxidation, Microsomal stability, Mitochondria, Reactive oxygen species",
author = "Alam, {Mohammad Parvez} and Omar Khdour and Arce, {Pablo M.} and Yana Chen and Basab Roy and Johnson, {Walter G.} and Sriloy Dey and Sidney Hecht",
year = "2014",
month = "9",
day = "1",
doi = "10.1016/j.bmc.2014.06.040",
language = "English (US)",
volume = "22",
pages = "4935--4947",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier Limited",
number = "17",

}

TY - JOUR

T1 - Cytoprotective pyridinol antioxidants as potential therapeutic agents for neurodegenerative and mitochondrial diseases

AU - Alam, Mohammad Parvez

AU - Khdour, Omar

AU - Arce, Pablo M.

AU - Chen, Yana

AU - Roy, Basab

AU - Johnson, Walter G.

AU - Dey, Sriloy

AU - Hecht, Sidney

PY - 2014/9/1

Y1 - 2014/9/1

N2 - As part of our ongoing efforts to identify compounds having potential utility in treating neurodegenerative and mitochondrial disorders, a series of pyridinol analogues have been prepared. The synthetic route employed for the preparation of the new analogues is different, and considerably more efficient, than that used in previously reported studies. The new route yields a pair of pyridinol regioisomers that can be readily separated and evaluated. Their ability to quench lipid peroxidation and reactive oxygen species (ROS), and to preserve mitochondrial membrane potential (Δψm) and support ATP synthesis is reported. The optimal side chain length was found to be 16 carbon atoms. The metabolic stability of those compounds having optimal biological activities was evaluated in vitro using bovine liver microsomes. The omission of any side chain hydroxyl group and introduction of an azetidine moiety at position 6 of the pyridinol redox core (8 and 9) increased their microsomal stability as compared to the exocyclic dimethylamino group. The favorable metabolic stability conferred by the azetidine moiety in compounds 8 and 9 makes these compounds excellent candidates for further evaluation.

AB - As part of our ongoing efforts to identify compounds having potential utility in treating neurodegenerative and mitochondrial disorders, a series of pyridinol analogues have been prepared. The synthetic route employed for the preparation of the new analogues is different, and considerably more efficient, than that used in previously reported studies. The new route yields a pair of pyridinol regioisomers that can be readily separated and evaluated. Their ability to quench lipid peroxidation and reactive oxygen species (ROS), and to preserve mitochondrial membrane potential (Δψm) and support ATP synthesis is reported. The optimal side chain length was found to be 16 carbon atoms. The metabolic stability of those compounds having optimal biological activities was evaluated in vitro using bovine liver microsomes. The omission of any side chain hydroxyl group and introduction of an azetidine moiety at position 6 of the pyridinol redox core (8 and 9) increased their microsomal stability as compared to the exocyclic dimethylamino group. The favorable metabolic stability conferred by the azetidine moiety in compounds 8 and 9 makes these compounds excellent candidates 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=84906936978&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84906936978&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2014.06.040

DO - 10.1016/j.bmc.2014.06.040

M3 - Article

C2 - 25088548

AN - SCOPUS:84906936978

VL - 22

SP - 4935

EP - 4947

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 17

ER -