Chapter 1 Dimedone: A Versatile Precursor for Annulated Heterocycles

Ashry, El Sayed H. El; Awad, Laila F.; Kilany, Yeldez El; Ibrahim, El‐Sayed I.

doi:10.1016/s0065-2725(09)09801-8

Cited by 25 publications

(11 citation statements)

References 381 publications

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“…Latent cyclic C-nucleophiles such as 1,3-dimethylbarbituric acid (1,3-DMB), dimedone and Meldrum's acid, to name just the three most popular ones, are versatile reagents useful for many transformations in organic synthesis. [1,2,3] For example, they are often involved as nucleophilic partners in multicomponent condensation reactions, especially for the synthesis of diverse heterocyclic scaffolds. [1,2,4] Indeed, owing both to the facile deprotonation of their activated methylene and other positive attributes (e. g., wide variety of biological activities for barbituric acid and its derivatives, ambivalent electrophilic and nucleophilic reactivity modes for Meldrum's acid, …), they are therefore regarded as superior alternatives to malonate esters.…”

Section: Introductionmentioning

confidence: 99%

Arylidene Meldrum's Acid: A Versatile Structural Motif for the Design of Enzyme‐Responsive “Covalent‐Assembly” Fluorescent Probes with Tailor‐Made Properties**

Renault

Capello

Yao

et al. 2023

Chemistry An Asian Journal

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Latent cyclic carbon‐centered nucleophiles (latent C‐nucleophiles) are recently proving their value in the field of reaction‐based fluorescent probes, far beyond their primary utility in organic synthesis. They are typically used to introduce a Michael acceptor moiety acting as a recognition/reaction site for analyte to be detected or as a kinetic promoter of fluorogenic cascade reactions triggered by a reactive species. C‐nucleophiles bearing a further reactive handle offer an additional opportunity for tuning the physicochemical/targeting properties or providing drug‐releasing capabilities to these probes, through the covalent attachment of ad hoc chemical moiety. In order to implement such strategy to fluorogenic/chromogenic enzyme substrates based on the “covalent‐assembly” principle, we have explored the potential of some functionalized derivatives of barbituric acid, piperidine‐2,4‐dione and Meldrum's acid. Our investigations based on the rational design and analytical validations of enzyme‐responsive caged precursors of fluorescent pyronin dyes and 7‐(diethylamino)coumarin‐3‐carboxylic acid, led to identify a versatile candidate suitable for this late‐stage structural optimization approach. This Meldrum's acid derivative enables to either enhance water solubility or achieve the reversible conjugation of a targeting ligand, while promoting in situ formation of fluorophore upon enzymatic activation. This study opens the way to novel multifunctional fluorescence imaging probes and optically modulated small conjugate‐based theranostics.

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Section: Introductionmentioning

confidence: 99%

Arylidene Meldrum's Acid: A Versatile Structural Motif for the Design of Enzyme‐Responsive “Covalent‐Assembly” Fluorescent Probes with Tailor‐Made Properties**

Renault

Capello

Yao

et al. 2023

Chemistry An Asian Journal

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“…[9] Furthermore, in vitro assays conducted with glutathione (GSH) have clearly shown the protective effect of biological thiols against non-enzymatic hydrolysis of these xanthene-based "covalentassembly" fluorescent probes, produced by a reversible Michael addition process. [9b] Interestingly, recent achievements in the chemistry of functionalized latent cyclic C-nucleophiles (e.g., barbituric acid, piperidine-2,4-dione and Meldrum's acid derivatives) usable as versatile "clickable" platforms [10] , may lead to consider additional roles for these malonate esters substitutes in the context of such enzyme-activated fluorogenic probes: (1) to permit the release of a second molecule of interest (e.g., drug or second fluorescent reporter), concomitant with in situ formation of fluorophore; (2) to achieve facile (bio)conjugation to a further (bio)molecule aimed at enhancing water solubility, cell permeability and/or targeting ability for specific tissues or cell organelles (Figure 2). In order to demonstrate the feasibility of this original "structural tuning" method, we have assessed several cyclic C-nucleophiles, some of them being reported in the literature recently, in the construction of novel pyronin precursors responsive to PGA.…”

Section: Introductionmentioning

confidence: 99%

Arylidene Meldrum's Acid: A Versatile Structural Motif for the Design of Enzyme-Responsive "Covalent-Assembly" Fluorescent Probes with Tailor-Made Properties

Renault

Capello

Yao

et al. 2023

Preprint

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Latent cyclic carbon-centered nucleophiles (latent C-nucleophiles) are recently proving their value in the field of reaction-based fluorescent probes, far beyond their primary utility in organic synthesis. They are typically used to introduce a Michael acceptor moiety acting as a recognition/reaction site for analyte to be detected or as a kinetic promoter of fluorogenic cascade reactions triggered by a reactive species. C-nucleophiles bearing a further reactive handle offer an additional opportunity for tuning the physicochemical/targeting properties or providing drug-releasing capabilities to these probes, through the covalent attachment of ad hoc chemical moiety. In order to implement such strategy to fluorogenic/chromogenic enzyme substrates based on the "covalent-assembly" principle, we have explored the potential of some functionalized derivatives of barbituric acid, piperidine-2,4-dione and Meldrum's acid. Our investigations based on the rational design and analytical validations of enzyme-responsive caged precursors of fluorescent pyronin dyes and 7-(diethylamino)coumarin-3-carboxylic acid, led to identify a versatile candidate suitable for this late-stage structural optimization approach with a minor impact on stability and activation kinetics of probe. This Meldrum's acid derivative, synthesized from levulinic acid, enables to either enhance water solubility or achieve the reversible conjugation of a targeting ligand, while promoting in situ formation of fluorophore upon enzymatic activation. This study opens the way to novel multifunctional fluorescence imaging probes and optically modulated small conjugate-based theranostics drawing on the promising "covalent-assembly" strategy.

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“…Among these, dimedone and barbutericacid are some of the most significant substrates having 1,3‐dicarbonyl groups flanked by active methylene groups. Moreover, it has been used as a source for the preparation of various classes of heterocyclic and spirocyclic compounds . Large numbers of dimedone‐derived heterocyclic and non‐heterocyclic compounds have been reported in the literature for their biological properties such as fused spiroketal derivatives, 5‐aminouracil derivatives, fused 1,4‐dihydro‐pyridines, spirocarbocycles, and 9‐aryl‐1,8‐dioxooctahydroxanthene derivatives in the presence of catalysts.…”

Section: Introductionmentioning

confidence: 99%

Catalyst‐Free Synthesis of Xanthene and Pyrimidine‐Fused Heterocyclic Derivatives at Water‐Ethanol Medium and Their Antioxidant Properties

et al. 2019

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Water‐ethanol (1:1 v/v) reaction medium has been demonstrated to be an efficient system for the catalyst‐free synthesis of biologically potent xanthene and pyrimidine‐fused heterocyclic derivatives at 60 °C. Reactions of various substituted benzaldehydes or salicylaldehydes with dimedone or barbituric acid in water‐ethanol yield corresponding xanthene and pyrimidine‐fused heterocyclic derivatives, respectively, in good yields (90−93%) within a short time frame (1−2 h). This synthetic protocol is eco‐friendly and economically viable and has a facile workup procedure and a wide scope. The synthesized compounds were screened for their antioxidant activities against 2,2‐diphenyl‐1‐picryl hydrazyl (DPPH) and ferric‐reducing antioxidant power (FRAP) assays. Compounds 13 and 23 are excellent free radical scavengers toward DPPH free radicals and compounds 12 and 23 show good activities in FRAP assay compared with standard Vitamin C.

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Chapter 1 Dimedone: A Versatile Precursor for Annulated Heterocycles

Cited by 25 publications

References 381 publications

Arylidene Meldrum's Acid: A Versatile Structural Motif for the Design of Enzyme‐Responsive “Covalent‐Assembly” Fluorescent Probes with Tailor‐Made Properties**

Arylidene Meldrum's Acid: A Versatile Structural Motif for the Design of Enzyme‐Responsive “Covalent‐Assembly” Fluorescent Probes with Tailor‐Made Properties**

Arylidene Meldrum's Acid: A Versatile Structural Motif for the Design of Enzyme-Responsive "Covalent-Assembly" Fluorescent Probes with Tailor-Made Properties

Catalyst‐Free Synthesis of Xanthene and Pyrimidine‐Fused Heterocyclic Derivatives at Water‐Ethanol Medium and Their Antioxidant Properties

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