Radiosensitization of Bacterial and Mammalian Cells by Substituted Glyoxals

Mj, Ashwood-Smith; Dm, Robinson; Jh, Barnes; Ba, Bridges

doi:10.1038/216137a0

Cited by 33 publications

(3 citation statements)

References 10 publications

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“…Glyoxals or α-keto-β-aldehydes (RCOCHO) are reactive compounds which have been used as radiosensitizers of cells [29] and as arginine reactivity probes [30].…”

Section: Substrate-derived Glyoxal Inhibitorsmentioning

confidence: 99%

13C- and 1H-NMR studies of oxyanion and tetrahedral intermediate stabilization by the serine proteinases: optimizing inhibitor warhead specificity and potency by studying the inhibition of the serine proteinases by peptide-derived chloromethane and glyoxal inhibitors

Malthouse

2007

Biochemical Society Transactions

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Catalysis by the serine proteinases proceeds via a tetrahedral intermediate whose oxyanion is stabilized by hydrogen-bonding in the oxyanion hole. There have been extensive (13)C-NMR studies of oxyanion and tetrahedral intermediate stabilization in trypsin, subtilisin and chymotrypsin using substrate-derived chloromethane inhibitors. One of the limitations of these inhibitors is that they irreversibly alkylate the active-site histidine residue which results in the oxyanion not being in the optimal position in the oxyanion hole. Substrate-derived glyoxal inhibitors are reversible inhibitors which, if they form tetrahedral adducts in the same way as substrates form tetrahedral intermediates, will overcome this limitation. Therefore we have synthesized (13)C-enriched substrate-derived glyoxal inhibitors which have allowed us to use (13)C-NMR and (1)H-NMR to determine how they interact with proteinases. It is hoped that these studies will help in the design of specific and highly potent warheads for serine proteinase inhibitors.

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“…Glyoxals or α-keto-β-aldehydes (RCOCHO) are reactive compounds which have been used as radiosensitizers of cells [29] and as arginine reactivity probes [30].…”

Section: Substrate-derived Glyoxal Inhibitorsmentioning

confidence: 99%

13C- and 1H-NMR studies of oxyanion and tetrahedral intermediate stabilization by the serine proteinases: optimizing inhibitor warhead specificity and potency by studying the inhibition of the serine proteinases by peptide-derived chloromethane and glyoxal inhibitors

Malthouse

2007

Biochemical Society Transactions

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“…Glyoxals, or α-keto-β-aldehydes (RCOCHO), are reactive compounds which have been shown to be cytotoxic [1,2]. They have been used as radiosensitizers of cells [3] and as arginine reactivity probes [4].…”

Section: Introductionmentioning

confidence: 99%

13C-NMR study of the inhibition of δ-chymotrypsin by a tripeptide-glyoxal inhibitor

2002

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A new inhibitor, Z-Ala-Pro-Phe-glyoxal (where Z is benzyloxycarbonyl),has been synthesized and shown to be a competitive inhibitor of delta-chymotrypsin, with a K(i) of 25+/-8 nM at pH 7.0 and 25 degrees C. Z-Ala-Pro-[1-(13)C]Phe-glyoxal and Z-Ala-Pro-[2-(13)C]Phe-glyoxal have been synthesized, and (13)C-NMR has been used to determine how they interact with delta-chymotrypsin. Using Z-Ala-Pro-[2-(13)C]Phe-glyoxal we have detected a signal at 100.7 p.p.m. which we assign to the tetrahedral adduct formed between the hydroxy group of Ser-195 and the (13)C-enriched keto-carbon of the inhibitor. This signal is in a pH-dependent slow exchange with a signal at 107.6 p.p.m. which depends on a pK(a) of approximately 4.5, which we assign to oxyanion formation. Thus we are the first to detect an oxyanion pK(a) in a reversible chymotrypsin-inhibitor complex. A smaller titration shift of 100.7 p.p.m. to 103.9 p.p.m. with a pK(a) of approximately 5.3 is also detected due to a rapid exchange process. This pK(a) is also detected with the Z-Ala-Pro-[1-(13)C]Phe-glyoxal inhibitor and gives a larger titration shift of 91.4 p.p.m. to 97.3 p.p.m., which we assign to the ionization of the hydrated aldehyde hydroxy groups of the enzyme-bound inhibitor. Protonation of the oxyanion in the oxyanion hole decreases the binding efficiency of the inhibitor. From this decrease in binding efficiency we estimate that oxyanion binding in the oxyanion hole reduces the oxyanion pK(a) by 1.3 pK(a) units. We calculate that the pK(a)s of the oxyanions of the hemiketal and hydrated aldehyde moieties of the glyoxal inhibitor are both lowered by 6.4-6.9 pK(a) units on binding to chymotrypsin. Therefore we conclude that oxyanion binding in the oxyanion hole has only a minor role in decreasing the oxyanion pK(a). We also investigate how the inhibitor breaks down at alkaline pH, and how it breaks down at neutral pH in the presence of chymotrypsin.

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“…DISCUSSION The major significance of these experiments is the discovery that diamide sensitizes anoxic mammalian cells only at doses well above those required for complete oxidation of cellular GSH to GSSG and that it does so largely by decreasing the extrapolation number. This effect is apparently different from the sensitization caused by most other compounds, which affect only the slope of the anoxic survival curve (20)(21)(22)(23)(24). Since there is considerable information about the reaction between diamide and cellular NPSH, our results may provide insight into the role of NPSH in anoxic radioresistance.…”

Section: Comparison Of Diamide and Nifuroxime As Anoxic Radiosensitizersmentioning

confidence: 63%

Diamide: A New Radiosensitizer for Anoxic Cells

Harris¹,

Power²

1973

Radiation Research

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Radiosensitization of Bacterial and Mammalian Cells by Substituted Glyoxals

Cited by 33 publications

References 10 publications

13C- and 1H-NMR studies of oxyanion and tetrahedral intermediate stabilization by the serine proteinases: optimizing inhibitor warhead specificity and potency by studying the inhibition of the serine proteinases by peptide-derived chloromethane and glyoxal inhibitors

13C- and 1H-NMR studies of oxyanion and tetrahedral intermediate stabilization by the serine proteinases: optimizing inhibitor warhead specificity and potency by studying the inhibition of the serine proteinases by peptide-derived chloromethane and glyoxal inhibitors

13C-NMR study of the inhibition of δ-chymotrypsin by a tripeptide-glyoxal inhibitor

Diamide: A New Radiosensitizer for Anoxic Cells

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