Abstract:
:The goal of this research was to test the hypothesis that bioactivation reactions could be exploited to deliver and activate mitochondria-targeted antioxidant prodrugs. The concept that bioactivation reactions could be used for prodrug delivery and activation has received little attention. Most bioactivation reactions result in the conversion of the parent drug to a reactive electrophilic metabolite, but bioactivating enzymes that catalyze elimination or hydrolytic reactions may offer potential for targeted drug delivery. Because mitochondria are the major cellular source of reactive oxygen species, there is much interest in targeting antioxidants to mitochondria. Previous studies showed that the mitochondrial fatty acid β-oxidation pathway biotransforms a range of xenobiotic alkanoates, including ω-(phenyl)alkanoates and ω-(phenoxy)alkanoates. 5,6-Dichloro-4-thia-5-hexenoate, the desamino analog of S-(1,2-dichlorovinyl)-l-cysteine, is biotransformed by the fatty acid β-oxidation pathway. Hence, the prodrugs ω-(phenoxy)alkanoates, 3-(phenoxy)acrylates, and ω-(1-methyl-1H-imidazol-2-ylthio)alkanoates were expected to undergo biotransformation by the mitochondrial β-oxidation pathway to release phenolic antioxidants and the antioxidant methimazole (Roser et al., Bioorg. Med. Chem. 18 (2010) 1441-1448). The rates of biotransformation of ω-(phenoxy)alkanoates varied with the structure, and bulky substituents on the phenoxy moiety reduced rates of biotransformation; this was attributed to substrate limitations imposed by the medium-chain acyl-CoA dehydrogenase. Hence, 3-(2,6-dimethylphenoxy)acrylate was prepared; it was expected that, after conversion to its CoA thioester, 3-(2,6-dimethylphenoxy)acryloyl-CoA would be a substrate for enoyl-CoA hydratase. This expectation was correct: 3-(2,6-dimethylphenoxy)acrylate was an excellent substrate. ω-(1-Methyl-1H-imidazol-2-ylthio)alkanoates were also good substrates for the β-oxidation pathway. Significantly, 3-(2,6-dimethylphenoxy)propanoate, 3-(2,6-dimethylphenoxy)acrylate, and 3-(1-methyl-1H-imidazol-2-ylthio)propanoate were cytoprotective in a hypoxia-reoxygenation model in rat cardiomyocytes. These results demonstrate the feasibility of exploiting bioactivation reactions for targeted drug delivery.
journal_name
Chem Biol Interactjournal_title
Chemico-biological interactionsauthors
Anders MWdoi
10.1016/j.cbi.2010.10.004subject
Has Abstractpub_date
2011-06-30 00:00:00pages
8-13issue
1-2eissn
0009-2797issn
1872-7786pii
S0009-2797(10)00583-1journal_volume
192pub_type
杂志文章,评审abstract::Flavonls are natural compounds present in edible plants and possess several biological activities that can be useful in drug design. Conversely some of these compounds have been shown to be genotoxic to prokaryotic and eukaryotic cells. In this study we tried to establish the chemical features responsible for the geno...
journal_title:Chemico-biological interactions
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journal_title:Chemico-biological interactions
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doi:10.1016/0009-2797(90)90025-i
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journal_title:Chemico-biological interactions
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journal_title:Chemico-biological interactions
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journal_title:Chemico-biological interactions
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journal_title:Chemico-biological interactions
pub_type: 杂志文章
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journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/0009-2797(81)90169-1
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journal_title:Chemico-biological interactions
pub_type: 杂志文章
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abstract::Treatment of animals with hydrazine causes the accumulation of triglycerides in the liver but the mechanism remains unclear. Therefore, the effect of hydrazine on hepatic triglyceride synthesis and subsequent transport was studied in a hepatocyte model, in vitro in order to isolate liver cells from extrahepatic influe...
journal_title:Chemico-biological interactions
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journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/0009-2797(79)90100-5
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journal_title:Chemico-biological interactions
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doi:10.1016/j.cbi.2020.108980
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journal_title:Chemico-biological interactions
pub_type: 杂志文章
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更新日期:2005-12-15 00:00:00
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journal_title:Chemico-biological interactions
pub_type: 杂志文章
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journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2015.12.021
更新日期:2016-02-05 00:00:00
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journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2016.10.020
更新日期:2017-01-05 00:00:00
abstract::Several species of columnar cacti in the Sonoran Desert contain isoquinoline alkaloids that are toxic to all but the resident drosophilids that feed and breed in necrotic stems. Cytochrome P450 enzymes are known to be involved in the metabolic detoxification of these alkaloids by the desert Drosophila and are conseque...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
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journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2015.03.003
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abstract::Arthritis is one of the most prevalent chronic inflammatory diseases, and it is characterized by structural and biochemical changes in major tissues of the joint, including degradation of the cartilage matrix, insufficient synthesis of extracellular matrix (ECM). Ecklonia cava (EC) is a member of the family of Laminar...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2009.01.006
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journal_title:Chemico-biological interactions
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doi:10.1016/j.cbi.2008.09.012
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journal_title:Chemico-biological interactions
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journal_title:Chemico-biological interactions
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journal_title:Chemico-biological interactions
pub_type: 杂志文章,评审
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journal_title:Chemico-biological interactions
pub_type: 杂志文章
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abstract::Medium-chain dehydrogenases/reductases (MDR) alcohol dehydrogenases exhibit multiple forms through a number of gene duplications. A crucial duplication was the one leading from the glutathione-dependent formaldehyde dehydrogenase line to the liver alcohol dehydrogenase (ADH) lines of vertebrates, the first duplication...
journal_title:Chemico-biological interactions
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journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2009.11.017
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journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2009.07.009
更新日期:2009-11-10 00:00:00
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journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2013.05.003
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abstract::Many flavonoids have been shown to present good results for the treatment of gastric ulcers. Baicalein, a bioactive flavonoid derived from the Scutellaria baicalensis Georgi root, possesses several biological effects, such as anti-inflammatory and antioxidant. This study was conducted to assess the gastroprotective pr...
journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/j.cbi.2016.10.016
更新日期:2016-12-25 00:00:00
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journal_title:Chemico-biological interactions
pub_type: 杂志文章
doi:10.1016/s0009-2797(02)00023-6
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abstract::This study evaluates the possible protective effects of gallic acid (GaA) and ferulic acid (FeA) against an experimentally induced liver fibrosis by thioacetamide (TAA) in rats. Animals were divided into: Control group, GaA group (20 mg/kg/day, p.o), FeA (20 mg/kg/day, p.o), TAA group (receiving 250 mg/kg twice/week, ...
journal_title:Chemico-biological interactions
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