Optimization of pyrimidinol antioxidants as mitochondrial protective agents: ATP production and metabolic stability.
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.
Biodesign Center for BioEnergetics, and School of Molecular Sciences, Arizona State University, Tempe, AZ 85287, United States.
Arnaud
A
Chevalier
Biodesign Center for BioEnergetics, and School of Molecular Sciences, Arizona State University, Tempe, AZ 85287, United States.
Mohammad Parvez
MP
Alam
Biodesign Center for BioEnergetics, and School of Molecular Sciences, Arizona State University, Tempe, AZ 85287, United States.
Omar M
OM
Khdour
Biodesign Center for BioEnergetics, and School of Molecular Sciences, Arizona State University, Tempe, AZ 85287, United States.
Margaret
M
Schmierer
Biodesign Center for BioEnergetics, and School of Molecular Sciences, Arizona State University, Tempe, AZ 85287, United States.
Pablo M
PM
Arce
Biodesign Center for BioEnergetics, and School of Molecular Sciences, Arizona State University, Tempe, AZ 85287, United States.
Cameron D
CD
Cripe
Biodesign Center for BioEnergetics, and School of Molecular Sciences, Arizona State University, Tempe, AZ 85287, United States. Electronic address: sidney.hecht@asu.edu.
Sidney M
SM
Hecht
D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008862:Microsomes, Liver / Q000737:chemistry* / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects*; D015394:Molecular Structure; D020011:Protective Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D013552:Swine
D000975:Antioxidants; D020011:Protective Agents; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate
Cytoprotection; Lipid peroxidation; Microsomal stability; Mitochondria; Reactive oxygen species