ChemInform Abstract: Reaction of Dialkyl Phosphites with Acyl Chlorides in the Presence of Vinyl Alkyl Ethers.

Газизов, М. Б.; Nikolaeva, V. G.; Zakharov, V. M.; Khairullin, R. A.; Москва, В. В.

doi:10.1002/chin.198844235

Cited by 2 publications

(3 citation statements)

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“…O , O ′-Dimethyl acetylphosphonate ( AcPMe 2 ) was obtained according to [ 13 ]. A mixture of dimethyl phosphite and ethyl vinyl ether was added dropwise to acetyl chloride at 0 °C.…”

Section: Methodsmentioning

confidence: 99%

“…1 H-NMR (400 MHz, D 2 O), δ, ppm: 3.65 (d, J = 10.5 Hz, 3H, (CH 3 O)P(O), 3.14 (m, 1H, C H CH 3 ), 1.79 (m, 1H, C H 2 CH 3 ), 1.49 (m, 1H, C H 2 CH 3 ), 1.13 (d, J = 7.0 Hz, 3H, CHC H 3 ,), 0.91 (t, J = 7.5 Hz, 3H, CH 2 C H 3 ); 13 C-NMR (100.6 MHz, D 2 O), δ, ppm: 226.0 (d, J = 154.3 Hz, C (O)CH), 52.9 (d, J = 5.9 Hz, (CH 3 O)P(O)), 47.5 (d, J = 43.8 Hz, C HCH 3 ), 24.7 ( C H 2 CH 3 ), 14.4 (CH( C H 3 )), 10.9 (CH 2 C H 3 ); 31 P-NMR (161.9 MHz, D 2 O), δ, ppm: −0.1. The precursor O , O ′-dimethyl (2-methylbutanoyl)phosphonate was prepared according to [ 13 ] from dimethyl phosphite, ethyl vinyl ether, and 2-methylbutanoyl chloride with 60% yield, b.p. 60–61 °C/0.9 mm.…”

Section: Methodsmentioning

confidence: 99%

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Mitochondrial Impairment May Increase Cellular NAD(P)H: Resazurin Oxidoreductase Activity, Perturbing the NAD(P)H-Based Viability Assays

Aleshin

Artiukhov

Oppermann

et al. 2015

Cells

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Cellular NAD(P)H-dependent oxidoreductase activity with artificial dyes (NAD(P)H-OR) is an indicator of viability, as the cellular redox state is important for biosynthesis and antioxidant defense. However, high NAD(P)H due to impaired mitochondrial oxidation, known as reductive stress, should increase NAD(P)H-OR yet perturb viability. To better understand this complex behavior, we assayed NAD(P)H-OR with resazurin (Alamar Blue) in glioblastoma cell lines U87 and T98G, treated with inhibitors of central metabolism, oxythiamin, and phosphonate analogs of 2-oxo acids. Targeting the thiamin diphosphate (ThDP)-dependent enzymes, the inhibitors are known to decrease the NAD(P)H production in the pentose phosphate shuttle and/or upon mitochondrial oxidation of 2-oxo acids. Nevertheless, the inhibitors elevated NAD(P)H-OR with resazurin in a time- and concentration-dependent manner, suggesting impaired NAD(P)H oxidation rather than increased viability. In particular, inhibition of the ThDP-dependent enzymes affects metabolism of malate, which mediates mitochondrial oxidation of cytosolic NAD(P)H. We showed that oxythiamin not only inhibited mitochondrial 2-oxo acid dehydrogenases, but also induced cell-specific changes in glutamate and malate dehydrogenases and/or malic enzyme. As a result, inhibition of the 2-oxo acid dehydrogenases compromises mitochondrial metabolism, with the dysregulated electron fluxes leading to increases in cellular NAD(P)H-OR. Perturbed mitochondrial oxidation of NAD(P)H may thus complicate the NAD(P)H-based viability assay.

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“…O , O ′-Dimethyl acetylphosphonate ( AcPMe 2 ) was obtained according to [ 13 ]. A mixture of dimethyl phosphite and ethyl vinyl ether was added dropwise to acetyl chloride at 0 °C.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Mitochondrial Impairment May Increase Cellular NAD(P)H: Resazurin Oxidoreductase Activity, Perturbing the NAD(P)H-Based Viability Assays

Aleshin

Artiukhov

Oppermann

et al. 2015

Cells

View full text Add to dashboard Cite

show abstract

“…O,O'-Dimethyl acetylphosphonate was obtained according to [ 44 ]. A mixture of dimethyl phosphite (3.3 g, 2.75 ml, 30 mmol) and ethyl vinyl ether (3.24 g, 4.3 ml, 45 mmol) was added dropwise to acetyl chloride (4.71 g, 4.27 ml, 60 mmol) stirred at 0°C.…”

Section: Methodsmentioning

confidence: 99%

Specific inhibition by synthetic analogs of pyruvate reveals that the pyruvate dehydrogenase reaction is essential for metabolism and viability of glioblastoma cells

et al. 2015

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The pyruvate dehydrogenase complex (PDHC) and its phosphorylation are considered essential for oncotransformation, but it is unclear whether cancer cells require PDHC to be functional or silenced. We used specific inhibition of PDHC by synthetic structural analogs of pyruvate to resolve this question. With isolated and intramitochondrial PDHC, acetyl phosphinate (AcPH, K i AcPH = 0.1 μM) was a much more potent competitive inhibitor than the methyl ester of acetyl phosphonate (AcPMe, K i AcPMe = 40 μM). When preincubated with the complex, AcPH also irreversibly inactivated PDHC. Pyruvate prevented, but did not reverse the inactivation. The pyruvate analogs did not significantly inhibit other 2-oxo acid dehydrogenases. Different cell lines were exposed to the inhibitors and a membrane-permeable precursor of AcPMe, dimethyl acetyl phosphonate, which did not inhibit isolated PDHC. Using an ATP-based assay, dependence of cellular viability on the concentration of the pyruvate analogs was followed. The highest toxicity of the membrane-permeable precursor suggested that the cellular action of charged AcPH and AcPMe requires monocarboxylate transporters. The relevant cell-specific transcripts extracted from Gene Expression Omnibus database indicated that cell lines with higher expression of monocarboxylate transporters and PDHC components were more sensitive to the PDHC inhibitors. Prior to a detectable antiproliferative action, AcPH significantly changed metabolic profiles of the investigated glioblastoma cell lines. We conclude that catalytic transformation of pyruvate by pyruvate dehydrogenase is essential for the metabolism and viability of glioblastoma cell lines, although metabolic heterogeneity causes different cellular sensitivities and/or abilities to cope with PDHC inhibition.

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ChemInform Abstract: Reaction of Dialkyl Phosphites with Acyl Chlorides in the Presence of Vinyl Alkyl Ethers.

Abstract: The phosphites (I) react with the acyl chlorides (II) in the presence of the vinyl ethers (III) to give the α‐keto phosphonates (IV), together with the phosphonates (V).

Cited by 2 publications

References 0 publications

Mitochondrial Impairment May Increase Cellular NAD(P)H: Resazurin Oxidoreductase Activity, Perturbing the NAD(P)H-Based Viability Assays

Mitochondrial Impairment May Increase Cellular NAD(P)H: Resazurin Oxidoreductase Activity, Perturbing the NAD(P)H-Based Viability Assays

Specific inhibition by synthetic analogs of pyruvate reveals that the pyruvate dehydrogenase reaction is essential for metabolism and viability of glioblastoma cells

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