317801-83-5Relevant articles and documents
An optimized pyrimidinol multifunctional radical quencher
Khdour, Omar M.,Arce, Pablo M.,Roy, Basab,Hecht, Sidney M.
supporting information, p. 724 - 729 (2013/09/02)
A series of aza analogues (4-9) of the experimental neuroprotective drug idebenone (1) have been prepared and evaluated for their ability to attenuate oxidative stress induced by glutathione depletion and to compensate for the decrease in oxidative phosphorylation efficiency in cultured Friedreich's ataxia (FRDA) fibroblasts and lymphocytes and also coenzyme Q10-deficient lymphocytes. Modification of the redox core of the previously reported 3 improved its antioxidant and cytoprotective properties. Compounds 4-9, having the same redox core, exhibited a range of antioxidant activities, reflecting side chain differences. Compounds having side chains extending 14-16 atoms from the pyrimidinol ring (6, 7, and 9) were potent antioxidants. They were superior to idebenone and more active than 3, 4, 5, and 8. Optimized analogue 7 and its acetate (7a) are of interest in defining potential therapeutic agents capable of blocking oxidative stress, maintaining mitochondrial membrane integrity, and augmenting ATP levels. Compounds with such properties may find utility in treating mitochondrial and neurodegenerative diseases such as FRDA and Alzheimer's disease.
Analysis of the structural and mechanistic factors in antioxidants that preserve mitochondrial function and confer cytoprotection
Arce, Pablo M.,Goldschmidt, Ruth,Khdour, Omar M.,Madathil, Manikandadas M.,Jaruvangsanti, Jennifer,Dey, Sriloy,Fash, David M.,Armstrong, Jeffrey S.,Hecht, Sidney M.
, p. 5188 - 5201 (2012/11/07)
Selected pyridinol analogues of the experimental neuroprotective drug idebenone have been synthesized and evaluated as antioxidants capable of preserving mitochondrial function. The compounds, having a different redox core but the same side chain as idebenone, exhibited a range of potencies, reflecting differences in their structures. The results obtained provide guidance in the design of such analogues with improved properties. Analogues were identified that have significantly improved antioxidant activity compared with idebenone in cultured lymphocytes, and which exhibit lesser inhibition of the electron transport chain.
A strategy for suppressing redox stress within mitochondria
Arce, Pablo M.,Khdour, Omar M.,Goldschmidt, Ruth,Armstrong, Jeffrey S.,Hecht, Sidney M.
supporting information; experimental part, p. 608 - 613 (2011/10/04)
An aza analogue (1) of the experimental neuroprotective drug idebenone has been prepared and evaluated. The compound quenches lipid peroxidation more effectively than α-tocopherol and potently suppresses reactive oxygen species in cells under oxidative stress. It is thought to do so via a catalytic cycle in which both forms of oxidative stress are suppressed simultaneously. Consequently, the compound effectively protects cultured CEM leukemia cells and Friedreich's ataxia fibroblasts from oxidative stress more effectively than idebenone or idebenol.
Synthesis of dideuterated and enantiomers of monodeuterated tridecanoic acids at C-9 and C-10 positions
Abad,Fabrias,Camps
, p. 8582 - 8588 (2007/10/03)
We report a route for the preparation of mono and dideuterated tridecanoic acids: (R)-[9-2H1]-,(S)-[9-2H1]-,(R)-[10-2H1]-,(S)-[10-2H1]-,[9,9-2H2]-, and [10,10-2H2]-tridecanoic acids required as probes for biochemical studies on desaturases. The key intermediates in the synthesis of all these probes are ketones 9, which give rise to the corresponding alcohols 10 and 13 by reduction with LiAlD4 and LiAlH4, respectively. Derivatization of nondeuterated racemic alcohols 13 with (S)-(+)-9-anthranylmethoxyacetic acid ((S)-(+)-9-AMA) and chromatographic resolution of both diastereoisomers allowed us to determine the absolute configuration of the stereogenic centers by 1H NMR using an adaptation of the model proposed by Riguera and co-workers which was validated with alcohols of known absolute configuration. Both enantiomeric alcohols (R)- and (S)-13 were recovered by reduction of each diastereomeric ester with LiAlH4. Mesylation of alcohols 10 and 13 followed by nucleophilic substitution by LiAlD4 generated the saturated methoxymethyl derivatives 12 and 16, respectively. Final deprotection and Jones oxidation of the resulting alcohols afforded the above deuterated tridecanoic acids.
