Inhibitors of glycolic acid oxidase. 4-Substituted 3-hydroxy-1H-pyrrole-2,5-dione derivatives

Rooney, C. S.; Randall, William C.; Streeter, K. B.; Ziegler, Christopher J.; Cragoe, Edward J.; Schwam, H.; Michelson, Stuart R.; Williams, Hollis R.; Eichler, Eva; Duggan, D E; Ulm, Edgar H.; Noll, R.M.

doi:10.1021/jm00359a015

Cited by 49 publications

(20 citation statements)

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“…It should be noted that compound 4 and various mono-and diacidic molecules with lipophilic substituents have previously been described to be competitive inhibitors of porcine glycolate oxidase (GAO) (30,38). However, several reported inhibitors of GAO had no effect on influenza virus transcription when the inhibitors were tested at up to 100-fold above the GAO IC50s (data not shown).…”

Section: Methodsmentioning

confidence: 94%

Inhibition of cap (m7GpppXm)-dependent endonuclease of influenza virus by 4-substituted 2,4-dioxobutanoic acid compounds

Tomassini

Selnick

Davies

et al. 1994

Antimicrob Agents Chemother

180

188

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Synthesis of influenza virus mRNA is primed by capped and methylated (cap 1, m7GpppXm) RNAs which the virus derives by endonucleolytic cleavage from RNA polymerase II transcripts in host cells. The conserved nature of the endonucleolytic processing provides a unique target for the development of antiviral agents for influenza viruses. A series of 4-substituted 2,4-dioxobutanoic acid compounds has been identified as selective inhibitors of this activity in both influenza A and B viruses. These inhibitors exhibited 50%o inhibitory concentrations in the range of 0.2 to 29.0 ,uM for cap-dependent influenza virus transcription and had no effect on the activity of other viral and cellular polymerases when tested at 100-to 500-fold higher concentrations. The compounds did not inhibit the initiation or elongation of influenza virus mRNA synthesis but specifically inhibited the cleavage of capped RNAs by the influenza virus endonuclease and were not inhibitory to the activities of other nucleases. Additionally, the compounds specifically inhibited replication of influenza A and B viruses in cell culture with potencies comparable to the 50% inhibitory concentrations obtained for transcription.

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Section: Methodsmentioning

confidence: 94%

Inhibition of cap (m7GpppXm)-dependent endonuclease of influenza virus by 4-substituted 2,4-dioxobutanoic acid compounds

Tomassini

Selnick

Davies

et al. 1994

Antimicrob Agents Chemother

180

188

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“…In plants, the inhibition of COX has been studied in the search of a herbicide. In humans, inhibition of COX has been considered as a possibility in treatment of some oxalate-mediated disorders, like hyperoxaluria and renal lithiasis Williams et al, 1983;Jayanthi et al, 1994), and inhibitor studies have been carried out using both mammalian and plant COX (Fendrich & Ghisla, 1982;Rooney et al, 1983). Highsequence identity (45%) between the spinach enzyme and its isozyme, long-chain a-hydroxy acid oxidase from rat (L& & indicates that results from the spinach enzyme can to some extent be extrapolated to mammals.…”

mentioning

confidence: 99%

Three‐dimensional structures of glycolate oxidase with bound active‐site inhibitors

Stenberg

Lindqvist

1997

Protein Science

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A key step in plant photorespiration, the oxidation of glycolate to glyoxylate, is canied out by the peroxisomal flavoprotein glycolate oxidase (EC 1.1.3.15). The three-dimensional structure of this a@ barrel protein has been refined to 2 8, resolution (Lindqvist Y. 1989. J Mol Biol209151-166). FMN dependent glycolate oxidase is a member of the family of a-hydroxy acid oxidases. Here we describe the crystallization and structure determination of two inhibitor complexes of the enzyme, TKP (3-Decyl-2,5-dioxo-4-hydroxy-3-pyrroline) and TACA (4-Carboxy-5-( 1-pentyl)hexylsulfanyl-1,2,3-triazole). The structure of the TACA complex has been refined to 2.6 8, resolution and the TKP complex, solved with molecular replacement, to 2.2 8, resolution. The Rf,, for the TACA and TKP complexes are 24.2 and 25.1%, respectively. The overall structures are very similar to the unliganded holoenzyme, but a closer examination of the active site reveals differences in the positioning of the flavin isoalloxazine ring and a displaced flexible loop in the TKF' complex. The two inhibitors differ in binding mode and hydrophobic interactions, and these differences are reflected by the very different K, values for the inhibitors, 16 nM for TACA and 4.8 p M for TKP. Implications of the structures of these enzyme-inhibitor complexes for the model for substrate binding and catalysis proposed from the holo-enzyme structure are discussed.Keywords: drug design; flavin enzyme; glycolate oxidase; inhibitor binding; molecular replacement; protein crystallography Glycolate oxidase (EC 1.1.3.15, GOX) is a FMN-dependent a-hydroxy acid-oxidizing protein. In plants, the enzyme is located in the peroxisomes and performs a key step in photorespiration, the oxidation of glycolate to glyoxylate. In animals, the enzyme is located in the liver peroxisomes and is involved in oxalate production. The reaction catalyzed by the enzyme can be divided into two half-reactions. In the first half-reaction glycolate is oxidized by the flavin, and in the second part of the reaction, FMN is reoxidized by oxygen and hydrogen peroxide is formed (Macheroux et al., 1991).The three-dimensional structure for GOX from spinach with bound FMN has been determined to 2 A resolution (Lindqvist, 1989). The enzyme belongs to the class of eight stranded a@-barrels, the most common structural motif found so far, with over 45 known examples. The known a/P-barrel folds do not share any recognizable sequence identity fingerprints, but do show extensive structural similarity.Reprint requests to: Ylva Lindqvist, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Doktorsringen 4, S17177 Stockholm, Sweden; e-mail: ylva@alfa.mbh.ki.se. However, a significant proportion of the residues in GOX are highly conserved in several other FMN-dependent a-hydroxy acidoxidizing enzymes. These proteins include (sequence identity % to GOX in brackets, values from L i ? & Lederer, 1991) flavocytochrome bZ (37.2) from Saccharomyces cerevisiae and Hansenula anomala (41.1), lactate oxi...

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“…Treatment of indole-3-acetamide with dimethyl oxalate under basic conditions provided 3-hydroxymaleimide 9. [10,11] Subsequent reaction with the same subset of amines employed for libraries 2 and 3, in refluxing aqueous acetic acid (AcOH), [11] furnished maleimidebridged analogues 4 a-d. However, none of these compounds displayed any efficacy in the SMB assay, underlining the importance of the glyoxylamide moiety to the potent antiprion activity of lead series 1.…”

Section: Modifications To the Glyoxylamide Substructurementioning

confidence: 99%

Structure–Activity Relationship Refinement and Further Assessment of Indole‐3‐glyoxylamides as a Lead Series against Prion Disease

et al. 2010

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Structure-activity relationships within the indole-3-glyoxylamide series of antiprion agents have been explored further, resulting in discovery of several new compounds demonstrating excellent activity in a cell line model of prion disease (EC₅₀ <10 nM). After examining a range of substituents at the para-position of the N-phenylglyoxylamide moiety, five-membered heterocycles containing at least two heteroatoms were found to be optimal for the antiprion effect. A number of modifications were made to probe the importance of the glyoxylamide substructure, although none were well tolerated. The most potent compounds did, however, prove largely stable towards microsomal metabolism, and the most active library member cured scrapie-infected cells indefinitely on administration of a single treatment. The present results thereby confirm the indole-3-glyoxylamides as a promising lead series for continuing in vitro and in vivo evaluation against prion disease.

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Inhibitors of glycolic acid oxidase. 4-Substituted 3-hydroxy-1H-pyrrole-2,5-dione derivatives

Cited by 49 publications

References 0 publications

Inhibition of cap (m7GpppXm)-dependent endonuclease of influenza virus by 4-substituted 2,4-dioxobutanoic acid compounds

Inhibition of cap (m7GpppXm)-dependent endonuclease of influenza virus by 4-substituted 2,4-dioxobutanoic acid compounds

Three‐dimensional structures of glycolate oxidase with bound active‐site inhibitors

Structure–Activity Relationship Refinement and Further Assessment of Indole‐3‐glyoxylamides as a Lead Series against Prion Disease

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