Fluorescent Hg<sup>2+</sup> Sensors: Synthesis and Evaluation of a Tren‐Based Starburst Molecule Containing Fluorinated 1,2,4‐Oxadiazoles

Pibiri, Ivana; Piccionello, Antonio Palumbo; Calabrese, Alessandro; Buscemi, Silvestre; Vivona, Nicolò; Pace, Andrea

doi:10.1002/ejoc.201000763

Cited by 19 publications

(8 citation statements)

References 45 publications

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“…Chromatography was performed by using silica gel (0.040-0.063 mm) and mixtures of ethyl acetate and petroleum ether (fraction boiling in the range of 40-60 C) in various ratios (v/v). Compounds 8 64 and 9 66 , used in the synthesis of inhibitors 4 and 7 , have been prepared as previously reported.…”

Section: Methodsmentioning

confidence: 99%

The dimer-monomer equilibrium of SARS-CoV-2 main protease is affected by small molecule inhibitors

Silvestrini

Belhaj

Comez

et al. 2021

Sci Rep

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The maturation of coronavirus SARS-CoV-2, which is the etiological agent at the origin of the COVID-19 pandemic, requires a main protease Mpro to cleave the virus-encoded polyproteins. Despite a wealth of experimental information already available, there is wide disagreement about the Mpro monomer-dimer equilibrium dissociation constant. Since the functional unit of Mpro is a homodimer, the detailed knowledge of the thermodynamics of this equilibrium is a key piece of information for possible therapeutic intervention, with small molecules interfering with dimerization being potential broad-spectrum antiviral drug leads. In the present study, we exploit Small Angle X-ray Scattering (SAXS) to investigate the structural features of SARS-CoV-2 Mpro in solution as a function of protein concentration and temperature. A detailed thermodynamic picture of the monomer-dimer equilibrium is derived, together with the temperature-dependent value of the dissociation constant. SAXS is also used to study how the Mpro dissociation process is affected by small inhibitors selected by virtual screening. We find that these inhibitors affect dimerization and enzymatic activity to a different extent and sometimes in an opposite way, likely due to the different molecular mechanisms underlying the two processes. The Mpro residues that emerge as key to optimize both dissociation and enzymatic activity inhibition are discussed.

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Section: Methodsmentioning

confidence: 99%

The dimer-monomer equilibrium of SARS-CoV-2 main protease is affected by small molecule inhibitors

Silvestrini

Belhaj

Comez

et al. 2021

Sci Rep

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“… 16 1,2,4-Oxadiazoles 17 are a class of small molecules which have gained attention for their pharmaceutical properties 18 − 20 and potential application in materials. 21 − 24 Originally, PTC124 was selected on the basis of a high throughput screening based on firefly luciferase (Fluc) reporter assays. 16 The PTC124-induced readthrough was estimated in HEK293 cells transfected with a luciferase reporter gene (Luc190) harboring a PTC at Thr190, replacing the normal ACA with UAA, UAG, and UGA.…”

Section: Introductionmentioning

confidence: 99%

Toward a Rationale for the PTC124 (Ataluren) Promoted Readthrough of Premature Stop Codons: A Computational Approach and GFP-Reporter Cell-Based Assay

et al. 2014

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The presence in the mRNA of premature stop codons (PTCs) results in protein truncation responsible for several inherited (genetic) diseases. A well-known example of these diseases is cystic fibrosis (CF), where approximately 10% (worldwide) of patients have nonsense mutations in the CF transmembrane regulator (CFTR) gene. PTC124 (3-(5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)-benzoic acid), also known as Ataluren, is a small molecule that has been suggested to allow PTC readthrough even though its target has yet to be identified. In the lack of a general consensus about its mechanism of action, we experimentally tested the ability of PTC124 to promote the readthrough of premature termination codons by using a new reporter. The reporter vector was based on a plasmid harboring the H2B histone coding sequence fused in frame with the green fluorescent protein (GFP) cDNA, and a TGA stop codon was introduced in the H2B-GFP gene by site-directed mutagenesis. Additionally, an unprecedented computational study on the putative supramolecular interaction between PTC124 and an 11-codon (33-nucleotides) sequence corresponding to a CFTR mRNA fragment containing a central UGA nonsense mutation showed a specific interaction between PTC124 and the UGA codon. Altogether, the H2B-GFP-opal based assay and the molecular dynamics (MD) simulation support the hypothesis that PTC124 is able to promote the specific readthrough of internal TGA premature stop codons.

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“…For the biological activity of 1,2,4-oxadiazole derivatives, see: Street et al (1990). For metal complexes of related compounds, see: da Silva et al (1999); Pibiri et al (2010); Terenzi et al (2011). For bond-length data, see: Allen et al (1987).…”

Section: Related Literaturementioning

confidence: 99%

“…They are therefore widely used in medicinal chemistry and as pesticides. 1,2,4-Oxadiazole derivatives in combination with metal ions can also be used in fluorescent recognition (da Silva et al, 1999;Pibiri et al, 2010;Terenzi et al, 2011). The title compound 5-(quinoline-8-ylmethoxy)-3-p-tolyl-1,2,4-oxadiazole was also used in metal ions fluorescent recognition.…”

Section: S1 Commentmentioning

confidence: 99%

3-(3-Methylphenyl)-5-(quinolin-8-ylmethoxy)-1,2,4-oxadiazole monohydrate

et al. 2013

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In the title compound, C19H15N3O2·H2O, the oxadiazole ring and the quinoline unit are almost coplanar, making a dihedral angle of 7.66 (8)°. The dihedral angle between the benzene ring and the quinoline system is 25.95 (8)° while that between the benzene and the oxadiazole rings is 18.88 (9)°. The water molecule is hydrogen bonded to an oxadiazole N atom and to the quinoline N atom. In the crystal, these units are linked via C—H⋯O hydrogen bonds, forming two-dimensional networks lying parallel to the ab plane.

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Fluorescent Hg²⁺ Sensors: Synthesis and Evaluation of a Tren‐Based Starburst Molecule Containing Fluorinated 1,2,4‐Oxadiazoles

Abstract: A new tren-based starburst molecule containing fluorinated 1,2,4-oxadiazoles as fluorophores has been synthesized and its sensing behavior toward several metal cations has been investigated by UV/Vis, fluorescence,

Cited by 19 publications

References 45 publications

The dimer-monomer equilibrium of SARS-CoV-2 main protease is affected by small molecule inhibitors

The dimer-monomer equilibrium of SARS-CoV-2 main protease is affected by small molecule inhibitors

Toward a Rationale for the PTC124 (Ataluren) Promoted Readthrough of Premature Stop Codons: A Computational Approach and GFP-Reporter Cell-Based Assay

3-(3-Methylphenyl)-5-(quinolin-8-ylmethoxy)-1,2,4-oxadiazole monohydrate

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Fluorescent Hg2+ Sensors: Synthesis and Evaluation of a Tren‐Based Starburst Molecule Containing Fluorinated 1,2,4‐Oxadiazoles

Abstract: A new tren-based starburst molecule containing fluorinated 1,2,4-oxadiazoles as fluorophores has been synthesized and its sensing behavior toward several metal cations has been investigated by UV/Vis, fluorescence,

Cited by 19 publications

References 45 publications

The dimer-monomer equilibrium of SARS-CoV-2 main protease is affected by small molecule inhibitors

The dimer-monomer equilibrium of SARS-CoV-2 main protease is affected by small molecule inhibitors

Toward a Rationale for the PTC124 (Ataluren) Promoted Readthrough of Premature Stop Codons: A Computational Approach and GFP-Reporter Cell-Based Assay

3-(3-Methylphenyl)-5-(quinolin-8-ylmethoxy)-1,2,4-oxadiazole monohydrate

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Product

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Fluorescent Hg²⁺ Sensors: Synthesis and Evaluation of a Tren‐Based Starburst Molecule Containing Fluorinated 1,2,4‐Oxadiazoles