Solution Phase Synthesis of a Combinatorial Library of Chalcones and Flavones as Potent Cathepsin V Inhibitors

Alvim, Joel; Severino, Richele P.; Marques, Emerson Finco; Martinelli, A.; Vieira, Paulo C.; Fernandes, João B.; Silva, Maria Fátima das Graças Fernandes da; Corrêa, Arlene G.

doi:10.1021/cc100076k

Cited by 28 publications

(4 citation statements)

References 59 publications

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“…Soon after its identification, recombinant cathepsin V was shown to be strongly inhibited by general cysteine peptidase inhibitors, such as E-64, cystatins, peptidyl vinyl sulfones, and iodoacetic acid [4] . Later, some natural products were described as cathepsin V inhibitors, e.g., macrocypins [34] , natural flavones and their synthetic derivatives [35] , acridione alkaloids isolated from Swinglea glutinosa [36] , and dimeric chalcone derivatives [37] . Based on the structure of acridone alkaloid inhibitors, new synthetic N -arylanthranilic acid, acridone, and 4-quinolone inhibitors were prepared as cathepsin V and L inhibitors [38] .…”

Section: Introductionmentioning

confidence: 99%

New inhibitors of cathepsin V impair tumor cell proliferation and elastin degradation and increase immune cell cytotoxicity

Mitrović

Senjor²,

Jukič³

et al. 2022

Computational and Structural Biotechnology Journal

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Section: Introductionmentioning

confidence: 99%

New inhibitors of cathepsin V impair tumor cell proliferation and elastin degradation and increase immune cell cytotoxicity

Mitrović

Senjor²,

Jukič³

et al. 2022

Computational and Structural Biotechnology Journal

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“…The in vitro enzyme inhibition experiments were carried out in triplicate (in 96well black plates) as previously described. 20 The final volume of the reaction mixture was 200 mL, kept under stirring. Each well contained 191 mL of a 100 mM sodium acetate buffer pH 5.5 containing 5 mM EDTA and 5 mM dithioerythritol (DTE), 2 mL of 1 mM Z-Phe-Arg-MCA dissolved in dimethyl sulfoxide, 5 mL of sample, and 32 nM of cat-V.…”

Section: Inhibitory Activity Studiesmentioning

confidence: 99%

Inhibitory Activity and Docking Studies of Cathepsin V for Isoflavanoids from Dalbergia miscolobium Benth

Silva¹,

Moreira²,

Cardoso³

et al. 2021

Rev. Virtual Quim.

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Resumo: Os extratos de plantas do gênero Dalbergia demonstram uma ampla gama de atividades biológicas, incluindo analgésica, antidiabética, anti-inflamatória e antimicrobiana. Neste trabalho, o estudo químico dos extratos das folhas e galhos de Dalbergia miscolobium levou ao isolamento e identificação de cinco isoflavonoides: prunetina, di-O-metildaidzeína, 8-O-metilretusina, duartina e sativan por meio de dados de ressonância magnética nuclear. A atividade de inibição enzimática desses Isoflavonoides foi avaliada na catepsina V na concentração de 100 µM. Duartin e sativan mostraram uma atividade notável contra a catepsina V, exibindo valores de inibição de 89% e 88%, respectivamente. Além disso, foram realizadas simulações de docking molecular para predizer o modo de ligação dos isoflavonoides a essa proteína e os resultados mostraram que a duartina está muito bem ligada à catepsina V e estabilizada por duas ligações de hidrogênio. Os isoflavanonoides duartina e sativan mostraram uma importante porcentagem de inibição da catepsina V, que pode ser considerada como alvo na investigação dos inibidores da catepsina V e estudos químicos adicionais de espécies de Dalbergia podem proporcionar novos isoflavonoides inibidores da catepsina V. Plant extracts from Dalbergia genus have demonstrated a wide range of biological activities including, analgesic, antidiabetic, anti-inflammatory, and antimicrobial. In this work, the chemical study of the extracts from the leaves and branches of Dalbergia miscolobium led to the isolation and identification of five isoflavonoids: prunetin, di-O-methyldaidzein, 8-O-methylretusin, duartin and sativan employing nuclear magnetic resonance data. The inhibition activity of these isoflavonoids was screened against cathepsin V at a concentration of 100 µM. Duartin and sativan showed remarkable activity against cathepsin V displaying 89% and 88% inhibition values, respectively. Also, docking simulations to predict the binding mode of isoflavonoids into this protein were performed and results showed that the duartin is nicely bound to the cathepsin V and stabilized by two hydrogen bonds. The isoflavans duartin and sativan showed a significant inhibition percentage of cathepsin V, which can be considered as targets into cathepsin V inhibitors investigation and further chemical study of Dalbergia species may afford novels isoflavonoids cathepsin inhibitors.

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“…From this viewpoint, the α,β-unsaturated carbonyls are unarguably a very important class of compounds that need a sustainable synthesis protocol. These carbonyls have been employed in intermediate steps in various synthesis strategies like Michael type addition, Diels–Alder reactions, , and Morita–Baylis–Hillman reaction , and as key substrates for conjugate addition − and epoxidation reaction. − Moreover, α,β-unsaturated carbonyls house numerous functionally important and diverse molecules with applications in pharmaceuticals, biologicals, agrochemicals, materials, etc. − Several molecules of this class have also demonstrated exceptional medicinal properties such as hypocholesterolemic activity or cholesterol-lowering activity, anticancer, , antiangiogenics or angiogenesis inhibition, HIV-1 integrase inhibition, antimalarial, etc. The α,β-unsaturated ketones have two isomeric forms, i.e., cis and trans forms.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of α,β-Unsaturated Ketones in Water: The Claisen–Schmidt Condensation Revisited

Choudhury

Mahapatra

Sahu

et al. 2022

ACS Sustainable Chem. Eng.

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Carrying out organic synthesis in an aqueous medium is always challenging. Herein, we present a highly efficient method for the synthesis of α,β-unsaturated ketones in water through the Claisen−Schmidt condensation by using a green catalyst, choline hydroxide (ChOH). The products were isolated without any chromatographic separation technique. The catalyst shows high substrate tolerance and works well with electrondonating and electron-withdrawing substituted aromatic aldehydes. Not only is the catalyst metal-free and nontoxic, but it also offers the advantage of forming strong hydrogen bonds with the transition state and intermediates, facilitating the reaction and enhancing the product yield. A variety of substrate scopes has been explored. The catalysis happens at 50 °C in water which is the significant finding of this study. The reaction mechanism of this hydrogen-bond-mediated catalysis was thoroughly investigated with density functional theory (DFT). The plausible reaction pathway was proposed based on the energetics of the reactants, intermediates, transition states, and product. Further, quantum theory of atoms in molecules (QTAIM) and noncovalent interactions (NCI) index analyses were done to demonstrate the effects of strong hydrogen bonds in the crucial steps of the reaction pathway. The obtained results correlate well with our hypothesis and validate our proposed mechanism, suggesting that the hydrogen-bond-mediated catalysis needs special attention in carrying out organic synthesis in water.

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Solution Phase Synthesis of a Combinatorial Library of Chalcones and Flavones as Potent Cathepsin V Inhibitors

Cited by 28 publications

References 59 publications

New inhibitors of cathepsin V impair tumor cell proliferation and elastin degradation and increase immune cell cytotoxicity

New inhibitors of cathepsin V impair tumor cell proliferation and elastin degradation and increase immune cell cytotoxicity

Inhibitory Activity and Docking Studies of Cathepsin V for Isoflavanoids from Dalbergia miscolobium Benth

Synthesis of α,β-Unsaturated Ketones in Water: The Claisen–Schmidt Condensation Revisited

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