Synthesis and characterization of Δlac-acetogenins that potently inhibit mitochondrial complex I

Chapuis, Jean‐Charles; Khdour, Omar M.; Cai, Xiaoqing; Lu, Jun; Hecht, Sidney M.

doi:10.1016/j.bmc.2008.10.071

Cited by 6 publications

(3 citation statements)

References 24 publications

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“…Such relative extents of inhibitory potencies have been noted previously for other complex I inhibitors. 1,14,15 The substrate concentration was higher in Q 1 -dependent NADH oxidation than in the integrated NADH oxidase assay (which contained only ~0.1–0.2 Mm Q 10 16,17 ), consistent with the interpretation that these inhibitors compete with ubiquinone for binding to complex I.…”

Section: Resultssupporting

confidence: 69%

“…19 Since glycolysis in the absence of mitochondrial function yields two ATP and two lactate molecules per glucose catabolized, it follows that the incremental lactate production arising from inhibition of respiration is proportional to the extent of inhibition of mitochondrial ATP production, assuming that the Pasteur effect 20 compensates for respiratory inhibition in proportion to the extent of inhibition. We have used this principle (the Pasteur effect) to evaluate known mitochondrial toxins, such as the Δ lacacetogenins, 14 as well as the verticipyrones that are the focus of this study. While the basal lactate levels reflect glycolytic ATP, the difference in the lactate concentrations ( Δ -lactate) measured in presence (mitochondrial inhibition) and absence (basal condition) of antimycin A represent an amount of energy which correlates well with that produced by the mitochondria prior to the respiratory chain inhibition.…”

Section: Resultsmentioning

confidence: 99%

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Synthesis and evaluation of verticipyrone analogues as mitochondrial complex I inhibitors

Leiris

Khdour

Segerman

et al. 2010

Bioorganic & Medicinal Chemistry

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Verticipyrone has recently been isolated from the culture broth of Verticillium sp. and shown to inhibit NADH fumarate reductase, as well as NADH oxidoreductase (complex I) of the mitochondrial electron transport chain. In order to assess the structural elements in verticipyrone essential for complex I inhibitor, 15 structural analogues were prepared and analyzed for their effects on mitochondrial NADH oxidoreductase and NADH oxidase activities. Also measured were the abilities of several of the analogues to inhibit respiration as judged by a shift to glycolysis, and to inhibit the growth of several mammalian cell lines. The nature of the pyrone ring was shown to be important to potency of inhibition, as was the length and nature of substituents in the side chain of the analogues.

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Section: Resultssupporting

confidence: 69%

Section: Resultsmentioning

confidence: 99%

Synthesis and evaluation of verticipyrone analogues as mitochondrial complex I inhibitors

Leiris

Khdour

Segerman

et al. 2010

Bioorganic & Medicinal Chemistry

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“…HCl, followed by oxidation using oxone. 45 The final products ( 1a, 1b, 1c, 1d, 1e, 1f, 1g, 1h and 1i) were purified using silica gel column chromatography to purities > 95% as indicated by HPLC (UV detection) and/or LC-MS.…”

Section: Resultsmentioning

confidence: 99%

Identification of a novel class of covalent modifiers of hemoglobin as potential antisickling agents

et al. 2015

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Aromatic aldehydes and ethacrynic acid (ECA) exhibit antipolymerization properties that are beneficial for sickle cell disease therapy. Based on ECA pharmacophore and its atomic interaction with hemoglobin, we designed and synthesized several compounds--designated as KAUS (imidazolylacryloyl derivatives)--that we hypothesized would bind covalently to βCys93 of hemoglobin and inhibit sickling. The compounds surprisingly showed weak allosteric and antisickling properties. X-ray studies of hemoglobin in complex with representative KAUS compounds revealed an unanticipated mode of Michael addition reaction between the β-unsaturated carbon and the N-terminal αVal1 nitrogen at the α-cleft of hemoglobin, with no observable interaction with βCys93. Interestingly, the compounds exhibited almost no reactivity with the free amino acids, L-Val, L-His and L-Lys, however showed some reactivity with both glutathione and L-Cys. Our findings provide a molecular level explanation to the compounds biological activities and an important framework for targeted modifications that would yield novel potent antisickling agents.

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Opportunities in discovery and delivery of anticancer drugs targeting mitochondria and cancer cell metabolism☆

Pathania¹,

Millard²,

Neamati³

2009

Advanced Drug Delivery Reviews

234

179

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Synthesis and characterization of Δlac-acetogenins that potently inhibit mitochondrial complex I

Cited by 6 publications

References 24 publications

Synthesis and evaluation of verticipyrone analogues as mitochondrial complex I inhibitors

Synthesis and evaluation of verticipyrone analogues as mitochondrial complex I inhibitors

Identification of a novel class of covalent modifiers of hemoglobin as potential antisickling agents

Opportunities in discovery and delivery of anticancer drugs targeting mitochondria and cancer cell metabolism☆

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