New inhibitors of dihydroorotate dehydrogenase (DHODH) based on the 4-hydroxy-1,2,5-oxadiazol-3-yl (hydroxyfurazanyl) scaffold

Lolli, Marco Lucio; Giorgis, Marta; Tosco, Paolo; Foti, Antonio; Fruttero, Roberta; Gasco, Alberto

doi:10.1016/j.ejmech.2011.12.038

Cited by 28 publications

(31 citation statements)

References 38 publications

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“…It means that DCPIP could not be reduced by the enzymatic reaction. It was thus suggested that the reductive efficiency for DCPIP was inhibited by some oxidants co-existing in the sample lysates21. This colourimetric assay method may require purification in advance of DHODH from the complex lysate samples.…”

Section: Resultsmentioning

confidence: 99%

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Fluorescence assay of dihydroorotate dehydrogenase that may become a cancer biomarker

Yin

Kabashima

Zhu

et al. 2017

Sci Rep

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We developed an assay method for measuring dihydroorotate dehydrogenase (DHODH) activity in cultured HeLa cells and fibroblasts, and in stage III stomach cancer and adjacent normal tissues from the same patient. The assay comprised enzymatic reaction of DHODH with a large amount of dihydroorotic acid substrate, followed by fluorescence (FL) detection specific for orotic acid using the 4-trifluoromethyl-benzamidoxime fluorogenic reagent. The DHODH activities in the biologically complex samples were readily measured by the assay method. Our data indicate significantly higher DHODH activity in HeLa cells (340 ± 25.9 pmol/105 cells/h) than in normal fibroblasts (54.1 ± 7.40 pmol/105 cells/h), and in malignant tumour tissue (1.10 ± 0.19 nmol/mg total proteins/h) than in adjacent normal tissue (0.24 ± 0.11 nmol/mg total proteins/h). This is the first report that DHODH activity may be a diagnostic biomarker for cancer.

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Section: Resultsmentioning

confidence: 99%

“…This method has been used to evaluate synthetic inhibitors of recombinant human DHODH20. However, when used for assaying DHODH activity in biologically complex samples containing mitochondrial membranes, the respiration chain complex in the mitochondrial membrane matrix significantly inhibited the redox reaction between DCPIP and DHO21.…”

mentioning

confidence: 99%

Fluorescence assay of dihydroorotate dehydrogenase that may become a cancer biomarker

Yin

Kabashima

Zhu

et al. 2017

Sci Rep

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“…compound 7, Figure 2). In the second example [45], structural analogies present in two well-known DHODH inhibitors (Leflunomide and Brequinar) were identified and resulted in the design of a new class of inhibitors based on the 4-hydroxy-1,2,5-oxadiazol-3-yl scaffold (e.g. compound 8, Figure 2).…”

Section: Insert Figurementioning

confidence: 99%

Refining the chemical toolbox to be fit for educational and practical purpose for drug discovery in the 21st Century

Lolli

Narramore

Fishwick

et al. 2015

Drug Discovery Today

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“…As the search for new agents that are active in the central nervous system gathers pace, this moiety has led to promising glutamate analogues , novel sortilin inhibitors , new anticancer drugs , and new immunosuppressive agents being produced . Unlike with other hydroxyazole systems that are frequently used to mimic the carboxylic function , regio‐substitution at the nitrogen atoms of the hydroxytriazole ring allows for improved exploration of the chemical space of the biological target . The effective application of this system in designing biologically active compounds requires the development of straightforward chemical strategies for the synthesis of the three possible 4‐hydroxy‐1,2,3‐triazole N‐substituted regioisomers.…”

Section: Introductionmentioning

confidence: 99%

Regioselective N‐Alkylation of Ethyl 4‐Benzyloxy‐1,2,3‐triazolecarboxylate: A Useful Tool for the Synthesis of Carboxylic Acid Bioisosteres

Sainas

Pippione

Giraudo

et al. 2018

Journal of Heterocyclic Chem

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Acidic 4‐hydroxy‐1,2,3‐triazole is a proven bioisostere of acidic functions that has recently been used to replace the acidic moieties of biologically active leads. Straightforward chemical strategies for the synthesis of the three possible N‐alkylated 4‐hydroxy‐1,2,3‐triazole regioisomers have been designed and reported herein, by identifying the optimal conditions under which the alkylation of ethyl 4‐benzyloxy‐1,2,3‐triazolecarboxylate (compound 19) can be regiodirected to the triazole N(b) position and thus produce the only isomer that cannot be obtained via the cycloaddition reaction. Furthermore, an innovative platform for parallel synthesis, called Arachno and which has been patented by the authors' group, has been used to speed up the process, and an NMR study has been carried out to better understand the reactivity of compound 19 towards the N(b) position. A library of benzyloxy protected 4‐hydroxy‐1,2,3‐triazoles has been prepared using the two strategies: regiodirection for the N(b) and N(c) isomers and cycloaddition for the N(a) isomers; the processes are described herein. The three N‐alkylated regioisomer series have been characterized spectroscopically (NMR and MS). The subsequent catalytic hydrogenation of the 4‐benzyloxy protective group on the N‐alkylated‐4‐benzyloxy‐5‐ethoxycarbonyl‐1,2,3‐triazoles provided the corresponding substituted 4‐hydroxy‐1,2,3‐triazoles.

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New inhibitors of dihydroorotate dehydrogenase (DHODH) based on the 4-hydroxy-1,2,5-oxadiazol-3-yl (hydroxyfurazanyl) scaffold

Cited by 28 publications

References 38 publications

Fluorescence assay of dihydroorotate dehydrogenase that may become a cancer biomarker

Fluorescence assay of dihydroorotate dehydrogenase that may become a cancer biomarker

Refining the chemical toolbox to be fit for educational and practical purpose for drug discovery in the 21st Century

Regioselective N‐Alkylation of Ethyl 4‐Benzyloxy‐1,2,3‐triazolecarboxylate: A Useful Tool for the Synthesis of Carboxylic Acid Bioisosteres

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