3,5-Di-tert-butyl-4-hydroxybenzylidenemalononitrile; a new powerful uncoupler of respiratory-chain phosphorylation

Muraoka, Saburo; Terada, Hiroshi

doi:10.1016/0005-2728(72)90047-3

Cited by 60 publications

(8 citation statements)

References 11 publications

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“…Originally synthesized for agricultural fungicidal and acaricidal usage, 12 (tyrphostin A9/SF-6847) is a tyrosine kinase inhibitor , with protonophoric uncoupling activity, increasing mitochondrial respiration at concentrations as low as 0.02 μM. , Its anionic state (p K a = 6.7) is hypothesized as the active structure during the uncoupling process . NMR studies and energy barrier calculations indicate that a restricted rotational barrier localizes the negative charge, which is also shielded by the two tert -butyl moieties on the benzene ring, allowing 12 to retain its lipophilicity when deprotonated. − The therapeutic potential of 12 has only been partially explored due to its cytotoxicity.…”

Section: Repurposed Chemicalsmentioning

confidence: 99%

Small Molecule Mitochondrial Uncouplers and Their Therapeutic Potential

et al. 2017

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Small molecule mitochondrial uncouplers transport protons from the mitochondrial inner membrane space into the mitochondrial matrix independent of ATP synthase, uncoupling nutrient metabolism from ATP generation. The therapeutic potential of mitochondrial uncouplers has been investigated for the treatment of metabolic diseases such as obesity and type 2 diabetes (T2D), ischemia-reperfusion injury, and neurodegenerative diseases. This communication will review the small molecule mitochondrial uncouplers reported to date and explore their potential as therapeutics.

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Section: Repurposed Chemicalsmentioning

confidence: 99%

Small Molecule Mitochondrial Uncouplers and Their Therapeutic Potential

et al. 2017

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“…As the lipid environment is important in determining the degree of inhibition (8), and isopropenyl groups increase the molecule's liposolubility (15), this would explain the decreased inhibitory effect of elliptone. Further, the insecticidal activity of rotenone is decreased by the removal of alkyl groups (14).…”

Section: Resultsmentioning

confidence: 99%

The Effect of Rotenone on Respiration in Pea Cotyledon Mitochondria

Johnson‐Flanagan

Spencer²

1981

Plant Physiol.

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Respiration utilizing NAD-linked substrates in mitochondria isolated from cotyledons of etiolated peas (Pisum sativum L. var Palmer (18) questions the biochemical benefit to be derived from density gradient purification of mitochondria, and many workers have used mitochondria prepared by simple differential centrifugation in their studies of rotenone resistance. The validity of this procedure for such studies is investigated in this paper. Another practice that could lead to erroneous results is the seemingly indiscriminate use of inhibitors and cofactors to activate and stimulate the rotenone-resistant pathway. The present investigation was done using only rotenone as the activator of the pathway.Aspects of this study included the relationship of the rotenoneresistant pathway to the cyanide-resistant pathway, substrate and cofactor effects, and the mechanism for deactivation of rotenone. The enzymes for the oxidation of malate were also studied. On the basis of these results, a possible explanation for the control and operation of the rotenone-resistant pathway was developed. Miracloth, and the filtrate was then centrifuged at 700g for 7 min in a Beckman J-21B centrifuge in a JA-20 rotor. The pellet was discarded, and the supernatant layer was centrifuged at 21,000g for 5 min in a Beckman JA-20 rotor. The pellet was resuspended in 50 ml ice cold wash medium (0.3 M mannitol, 25 mm Tes, and 0.3% fatty-acid-poor BSA) and recentrifuged at 21,000g for 5 min. The pellet was then resuspended in 3 ml suspension medium (0.3 M mannitol, 4 mm MgC12, and 25 mm Tes) and loaded onto a sucrose density gradient (26 ml 0.6 M sucrose and 10 ml 1.6 M sucrose, both with 50 mi Tes and 0.1% BSA) or used as such for mitochondria prepared by differential centrifugation. After loading it onto the gradient, the pellet was centrifuged for 1 h at 30,000g in a Beckman L2-65B ultracentrifuge with a SW27 rotor. The fraction at the interface was removed and diluted slowly with a buffered solution (25 mim Tes and 0.1% BSA). The fraction was then centrifuged for 5 min at 21,000g, and the pellet was resuspended in the suspension medium used above. All solutions were adjusted to pH 7.1 at 25 C with KOH. All steps of the isolation were carried out at 0 to 4 C.Respiratory

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“…Distances are not drawn to scale. uptake activities in the membrane vesicles absolutely depended on D-lactate and were inhibited completely by 2 uM SF6847, a potent uncoupler (25), suggesting that the transport system is coupled to a protonmotive force (14,30).…”

Section: Resultsmentioning

confidence: 99%

Proline transport carrier-defective mutants of Escherichia coli K-12: properties and mapping

Motojima¹,

Yamato²,

Anraku³

1978

J Bacteriol

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A series of mutants of Escherichia coli K-12 requiring a high concentration of L-proline for growth were isolated from a proline auxotroph strain, JE2133. Genetic studies of the mutants, PT19, PT21, and PT22, showed that all the mutations (proT) were point mutations, and these were mapped at 82 min on the E. coli genetic map. Intact cells and cytoplasmic membrane vesicles of these mutants were specifically defective in L-proline transport activity. Strain PT21 had no detectable activity of the L-proline transport carrier at all, and strains PT19 and PT22 had only 1/35 and 1/70, respectively, of the transport activity of the parental strain. The mutants were also shown to have a defect in prolinebinding function of the carrier by measuring specific binding of proline to sonically disrupted membranes. These results indicate that the gene proT determines the

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3,5-Di-tert-butyl-4-hydroxybenzylidenemalononitrile; a new powerful uncoupler of respiratory-chain phosphorylation

Cited by 60 publications

References 11 publications

Small Molecule Mitochondrial Uncouplers and Their Therapeutic Potential

Small Molecule Mitochondrial Uncouplers and Their Therapeutic Potential

The Effect of Rotenone on Respiration in Pea Cotyledon Mitochondria

Proline transport carrier-defective mutants of Escherichia coli K-12: properties and mapping

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