Synthesis of different thio-scaffolds bearing sulfonamide with subnanomolar carbonic anhydrase II and IX inhibitory properties and X-ray investigations for their inhibitory mechanism

Tanini, Damiano; Capperucci, Antonella; Malevolti, Gianni; Turco, Francesca; Angeli, Andrea; Supuran, Claudiu T.

doi:10.1016/j.bioorg.2018.09.028

Cited by 36 publications

(17 citation statements)

References 27 publications

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“…Inhibitor and enzyme solutions were preincubated together for 15 min at room temperature prior to assay, in order to allow for the formation of the E−I complex. The inhibition constants were obtained by nonlinear least‐squares methods using PRISM 3 and the Cheng‐Prusoff equation, as reported earlier, [40–42] and represent the mean from at least three different determinations. All CA isofoms were recombinant ones obtained in‐house as reported earlier [40–42] …”

Section: Methodsmentioning

confidence: 99%

Synthesis, Computational Studies and Assessment of in Vitro Activity of Squalene Derivatives as Carbonic Anhydrase Inhibitors

Clima¹,

Craciun²,

Angeli

et al. 2020

ChemMedChem

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We report novel molecules incorporating the nontoxic squalene scaffold and different carbonic anhydrase inhibitors (CAIs). Potent inhibitory action, in the low‐nanomolar range, was detected against isoforms hCA II for sulfonamide derivatives, which proved to be selective against this isoform over the tumor‐associate hCA IX and XII isoforms. On the other hand, coumarin derivatives showed weak potency but high selectivity against the tumor‐associated isoform CA IX. These compounds are interesting candidates for preclinical evaluation in glaucoma or various tumors in which the two enzymes are involved. In addition, an in silico study of inhibitor‐bound hCA II revealed extensive interactions with the hydrophobic pocket of the active site and provided molecular insights into the binding properties of these new inhibitors.

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Section: Methodsmentioning

confidence: 99%

Synthesis, Computational Studies and Assessment of in Vitro Activity of Squalene Derivatives as Carbonic Anhydrase Inhibitors

Clima¹,

Craciun²,

Angeli

et al. 2020

ChemMedChem

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“…Errors were in the range of ± 5À10% of the reported K I values. Human CA isoforms were recombinant enzymes obtained in-house as reported earlier [50][51][52] . The enzyme concentrations in the assay system were as follows: hCA I, 13.2 nM; hCA II, 8.4 nM; hCA IX, 7.9 nM; hCA XII, 15.2 nM.…”

Section: Ca Inhibition Screening Assaymentioning

confidence: 99%

Novel insights on saccharin- and acesulfame-based carbonic anhydrase inhibitors: design, synthesis, modelling investigations and biological activity evaluation

Guglielmi

Rotondi

Secci

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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A large library of saccharin and acesulfame derivatives has been synthesised and evaluated against four isoforms of human carbonic anhydrase, the two off-targets hCA I/II and the tumour related isoforms hCA IX/XII. Different strategies of scaffold modification have been attempted on both saccharin as well as acesulfame core leading to the obtainment of 60 compounds. Some of them exhibited inhibitory activity in the nanomolar range, albeit some of the performed changes led to either micromolar activity or to its absence, against hCA IX/XII. Molecular modelling studies focused the attention on the binding mode of these compounds to the enzyme. The proposed inhibition mechanism is the anchoring to zinc-bound water molecule. Docking studies along with molecular dynamics also underlined the importance of the compounds flexibility (e.g. achieved through the insertion of methylene group) which favoured potent and selective hCA inhibition.

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“…A large number of sulfurated moieties are present in many organic compounds, which possess a variety of different properties. Together with their wide use in organic synthesis, sulfurated molecules find application in different fields, as pharmaceutical [1][2][3][4][5], agrochemical [6], food [7][8][9], materials and polymer chemistry [10,11]. Despite the high variety of linear and cyclic sulfurated structures, the methods for their synthesis are often limited by the availability of sulfur reagents and by the harsh conditions.…”

Section: Introductionmentioning

confidence: 99%

1,3,5-Trithianes and sulfur monochloride/sodium sulfide: an alternative route to 3,5-disubstituted 1,2,4-trithiolanes

Tanini

Trapani

Capperucci

2020

Journal of Sulfur Chemistry

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Synthesis of different thio-scaffolds bearing sulfonamide with subnanomolar carbonic anhydrase II and IX inhibitory properties and X-ray investigations for their inhibitory mechanism

Cited by 36 publications

References 27 publications

Synthesis, Computational Studies and Assessment of in Vitro Activity of Squalene Derivatives as Carbonic Anhydrase Inhibitors

Synthesis, Computational Studies and Assessment of in Vitro Activity of Squalene Derivatives as Carbonic Anhydrase Inhibitors

Novel insights on saccharin- and acesulfame-based carbonic anhydrase inhibitors: design, synthesis, modelling investigations and biological activity evaluation

1,3,5-Trithianes and sulfur monochloride/sodium sulfide: an alternative route to 3,5-disubstituted 1,2,4-trithiolanes

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