Structural elucidation of epalrestat(ONO-2235), a potent aldose reductase inhibitor, and isomerization of its double bonds

Ishida, Toshimasa; In, Yasuko; Inoue, Masatoshi; Ueno, Y.; Tanaka, Chiaki; Hamanaka, Nobuyuki

doi:10.1016/s0040-4039(00)95290-0

Cited by 45 publications

(41 citation statements)

References 2 publications

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“…Thus, the 5-arylmethylidenethiazolidin-4-ones 22 – 26 were obtained in 68–94% yield. The presence of only one signal for the benzylidene proton at 7.83–7.98 ppm in the 1 H NMR spectra of 22 – 26 suggested the formation of a single isomer, which was assigned to the Z -configuration according to the literature for similar compounds [47–48]. Interestingly, close analogues of these structures, i.e., the 5-arylmethylidene rhodanines, possess photosynthesis-inhibiting and antialgal properties [49], show anticancer activity [50–51], and are inhibitors of bacterial enzyme synthetase MurD with E. coli [52].…”

Section: Resultsmentioning

confidence: 99%

Chemistry of polyhalogenated nitrobutadienes, 14: Efficient synthesis of functionalized (Z)-2-allylidenethiazolidin-4-ones

Zapol’skii¹,

Namyslo²,

Gjikaj³

et al. 2014

Beilstein J. Org. Chem.

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SummaryThe reaction of mercaptoacetic acid esters with pentachloro-2-nitro-1,3-butadiene (1) provides an appropriate precursor for the synthesis of special thiazolidin-4-ones. Applying different anilines as the second constituent for the requisite cyclization step, a series of (Z)-2-allylidenethiazolidin-4-ones was obtained in yields up to 81%. Some subsequent reactions have been examined too, such as the formation of perfunctionalized 1H-pyrazoles upon treatment with hydrazine. Thiazolidinones are as well known for their physiological activities as for their application in optoelectronics.

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Section: Resultsmentioning

confidence: 99%

Chemistry of polyhalogenated nitrobutadienes, 14: Efficient synthesis of functionalized (Z)-2-allylidenethiazolidin-4-ones

Zapol’skii¹,

Namyslo²,

Gjikaj³

et al. 2014

Beilstein J. Org. Chem.

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“…In addition, binding of these compounds was diminished when the assays were conducted either in a 37°C incubator or a 4°C refrigerator. Because molecules like 1 are readily excited͞isomerized photochemically (20), we examined the interaction of these compounds with the TNFRc1 in the absence of light. Indeed, when the binding assays were performed in the dark, the potencies of all of the compounds tested were attenuated 50-fold to Ͼ1000-fold (IC 50 's Ͼ 30 M).…”

Section: Resultsmentioning

confidence: 99%

Photochemically enhanced binding of small molecules to the tumor necrosis factor receptor-1 inhibits the binding of TNF-α

Carter

Scherle

Muckelbauer

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

128

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The binding of tumor necrosis factor alpha (TNF-α) to the type-1 TNF receptor (TNFRc1) plays an important role in inflammation. Despite the clinical success of biologics (antibodies, soluble receptors) for treating TNF-based autoimmune conditions, no potent small molecule antagonists have been developed. Our screening of chemical libraries revealed that N -alkyl 5-arylidene-2-thioxo-1,3-thiazolidin-4-ones were antagonists of this protein–protein interaction. After chemical optimization, we discovered IW927, which potently disrupted the binding of TNF-α to TNFRc1 (IC 50 = 50 nM) and also blocked TNF-stimulated phosphorylation of Iκ-B in Ramos cells (IC 50 = 600 nM). This compound did not bind detectably to the related cytokine receptors TNFRc2 or CD40, and did not display any cytotoxicity at concentrations as high as 100 μM. Detailed evaluation of this and related molecules revealed that compounds in this class are “photochemically enhanced” inhibitors, in that they bind reversibly to the TNFRc1 with weak affinity ( ca. 40–100 μM) and then covalently modify the receptor via a photochemical reaction. We obtained a crystal structure of IV703 (a close analog of IW927) bound to the TNFRc1. This structure clearly revealed that one of the aromatic rings of the inhibitor was covalently linked to the receptor through the main-chain nitrogen of Ala-62, a residue that has already been implicated in the binding of TNF-α to the TNFRc1. When combined with the fact that our inhibitors are reversible binders in light-excluded conditions, the results of the crystallography provide the basis for the rational design of nonphotoreactive inhibitors of the TNF-α–TNFRc1 interaction.

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“…The 1 H NMR spectra of compounds ( 3 ) show only one signal for the methyne proton in the range δ 7.70 ppm, at lower field values than those expected for the E ‐isomers, which was strongly indicated that the compounds have the Z ‐configuration. The latter has been reported as thermodynamically more stable than the E ‐configuration . The compound ( 4 ) was synthesized from the compound ( 3 ), and the structures of the desired compounds were confirmed by IR, 1 H NMR, 13 C NMR, and mass spectral analysis.…”

Section: Resultsmentioning

confidence: 99%

A Facial Synthesis and Anticancer Activity of (Z)‐2‐((5‐(4‐nitrobenzylidene)‐4‐oxo‐4,5‐dihydrothiazol‐2‐yl)amino)‐substituted Acid

Pansare

Shelke

Shinde

2017

Journal of Heterocyclic Chem

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In order to explore the anticancer and antimicrobial activity associated with the thiazole framework, we synthesized the new series (Z)‐2‐((5‐(4‐nitrobenzylidene)‐4‐oxo‐4,5‐dihydrothiazol‐2‐yl)amino)‐substituted acid derivatives 6a–l. All the synthesized compounds were evaluated for anticancer and antimicrobial activity in vitro. Among these, the compounds 6a, 6b, 6c, 6e, 6f, 6g, 6h, 6i, 6j, and 6k showed highest antibacterial and antifungal activity. The compound 6a exhibited significant antibacterial activity against Bacillussubtilis, whereas compound 6j displays significant antifungal activity against fungal strains, that is, A. oryzae. The in vitro anticancer studies revealed that 6e, 6g, 6h, 6k, and 6l are the most active compounds against MCF‐7 and BT‐474 human breast cancer cell lines, which can be regarded as the promising drug candidate for development of anticancer drugs.

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Structural elucidation of epalrestat(ONO-2235), a potent aldose reductase inhibitor, and isomerization of its double bonds

Cited by 45 publications

References 2 publications

Chemistry of polyhalogenated nitrobutadienes, 14: Efficient synthesis of functionalized (Z)-2-allylidenethiazolidin-4-ones

Chemistry of polyhalogenated nitrobutadienes, 14: Efficient synthesis of functionalized (Z)-2-allylidenethiazolidin-4-ones

Photochemically enhanced binding of small molecules to the tumor necrosis factor receptor-1 inhibits the binding of TNF-α

A Facial Synthesis and Anticancer Activity of (Z)‐2‐((5‐(4‐nitrobenzylidene)‐4‐oxo‐4,5‐dihydrothiazol‐2‐yl)amino)‐substituted Acid

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