Rutin as Deoxyribonuclease I Inhibitor

Kolarević, Ana; Pavlović, Aleksandra; Djordjevic, Aleksandra; Lazarević, Jelena; Savić, Saša; Kocić, Gordana; Anderluh, Marko; Šmelcerović, Andrija

doi:10.1002/cbdv.201900069

Cited by 21 publications

(14 citation statements)

References 45 publications

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“…In addition, active compounds 2 , 15 , 18 , and 22 exhibited, respectively 2.70‐, 2.45‐, 2.43‐ and 2.44‐times better inhibitory activity in comparison to crystal violet used as a positive control. Observed DNase I inhibitory potential of active 1,2,3,4‐tetrahydroisoquinolines is in line with a multitude of other small organic DNase I inhibitors, whose IC 50 mainly range between 70 and 150 μM, [28–34] whereas the most potent small natural products inhibitors of DNase I are cyclocariol F and schisanlactone E with IC 50 s of 12.5±2 μM and 30±3 μM, respectively [35] …”

Section: Resultssupporting

confidence: 59%

1,2,3,4‐Tetrahydroisoquinoline Derivatives as a Novel Deoxyribonuclease I Inhibitors

Gajić

Ilić

Bondžić

et al. 2021

Chemistry & Biodiversity

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Herein we report an assessment of 24 1,2,3,4‐tetrahydroisoquinoline derivatives for potential DNase I (deoxyribonuclease I) inhibitory properties in vitro. Four of them inhibited DNase I with IC50 values below 200 μM. The most potent was 1‐(6,7‐dimethoxy‐1,2,3,4‐tetrahydroisoquinolin‐1‐yl)propan‐2‐one (2) (IC50=134.35±11.38 μM) exhibiting slightly better IC50 value compared to three other active compounds, 2‐[2‐(4‐fluorophenyl)‐1,2,3,4‐tetrahydroisoquinolin‐1‐yl]‐1‐phenylethan‐1‐one (15) (IC50=147.51±14.87 μM), 2‐[2‐(4‐fluorophenyl)‐1,2,3,4‐tetrahydroisoquinolin‐1‐yl]cyclohexan‐1‐one (18) (IC50=149.07±2.98 μM) and 2‐[6,7‐dimethoxy‐2‐(p‐tolyl)‐1,2,3,4‐tetrahydroisoquinolin‐1‐yl]cyclohexan‐1‐one (22) (IC50=148.31±2.96 μM). Cytotoxicity assessment of the active DNase I inhibitors revealed a lack of toxic effects on the healthy cell lines MRC‐5. Molecular docking and molecular dynamics simulations suggest that interactions with Glu 39, His 134, Asn 170, Tyr 211, Asp 251 and His 252 are an important factor for inhibitors affinity toward the DNase I. Observed interactions would be beneficial for the discovery of new active 1,2,3,4‐tetrahydroisoquinoline‐based inhibitors of DNase I, but might also encourage researchers to further explore and utilize potential therapeutic application of DNase I inhibitors, based on a versatile role of DNase I during apoptotic cell death.

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Section: Resultssupporting

confidence: 59%

1,2,3,4‐Tetrahydroisoquinoline Derivatives as a Novel Deoxyribonuclease I Inhibitors

Gajić

Ilić

Bondžić

et al. 2021

Chemistry & Biodiversity

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“…Sixteen identified DNase I inhibitors with IC 50 values below 80 μM ( 7 – 9 , 11 , 12 , 14 – 24 ), exceeded the inhibitory activity of all previously reported small‐molecule DNase I inhibitors [8,19,21–29] . To the best of our knowledge, compounds 8 and 22 are among the most potent synthetic non‐peptide DNase I inhibitors reported to date, with the natural product cyclocariol F inhibiting DNase I with a lower IC 50 value (IC 50 =12.5±2 μM) [30] .…”

Section: Resultsmentioning

confidence: 82%

Repurposing of 8‐Hydroxyquinoline‐Based Butyrylcholinesterase and Cathepsin B Ligands as Potent Nonpeptidic Deoxyribonuclease I Inhibitors

et al. 2022

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A library of 31 butyrylcholinesterase (BChE) and cathepsin B (CatB) inhibitors was screened in vitro for inhibition of deoxyribonuclease I (DNase I). Compounds 22, 8 and 7 are among the most potent synthetic non‐peptide DNase I inhibitors reported to date. Three 8‐hydroxyquinoline analogues inhibited both DNase I and BChE with IC50 values below 35 μM and 50 nM, respectively, while two nitroxoline derivatives inhibited DNase I and Cat B endopeptidase activity with IC50 values below 60 and 20 μM. Selected derivatives were screened for various co‐target binding affinities at dopamine D2 and D3, histamine H3 and H4 receptors and inhibition of 5‐lipoxygenase. Compound 8 bound to the H3 receptor and is highlighted as the most promising multifunctional ligand with a favorable pharmacokinetic profile and one of the most potent non‐peptide DNase I inhibitors. The present study demonstrates that 8‐hydroxyquinoline is a structural fragment critical for DNase I inhibition in the presented series of compounds.

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“…According to the obtained results, tested compounds 1 and 2 posses 1.89‐ and 2.73‐times better DNase I inhibitory properties (respectively) compared to crystal violet (IC 50 ±SD=362.45±35.55 μM) used as a positive control, given the general lack of ‘golden standard’ in DNase I assays. In addition, the activity of tested 1‐(pyrrolidin‐2‐yl)propan‐2‐one derivatives against DNase I is comparable to the majority of known small organic DNase I inhibitors [9–15] …”

Section: Resultsmentioning

confidence: 86%

Deoxyribonuclease I Inhibitory Properties, Molecular Docking and Molecular Dynamics Simulations of 1‐(Pyrrolidin‐2‐yl)propan‐2‐one Derivatives

Ilić

Gajić

Bondžić

et al. 2021

Chemistry & Biodiversity

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Deoxyribonuclease I (DNase I) inhibitory properties of two 1‐(pyrrolidin‐2‐yl)propan‐2‐one derivatives were examined in vitro. Determined IC50 values of 1‐[1‐(4‐methoxyphenyl)pyrrolidin‐2‐yl]propan‐2‐one (1) (192.13±16.95 μM) and 1‐[1‐(3,4,5‐trimethoxyphenyl)pyrrolidin‐2‐yl]propan‐2‐one (2) (132.62±9.92 μM) exceed IC50 value of crystal violet, used as a positive control, 1.89‐ and 2.73‐times, respectively. Compounds are predicted to be nontoxic and to have favorable pharmacokinetic profiles, with high gastrointestinal absorption and blood‐brain barrier permeability. Molecular docking and molecular dynamics simulations suggest that interactions with Glu 39, Glu 78, Arg 111, Pro 137, Asp 251 and His 252 are an important factor for inhibitors affinity toward the DNase I. Determined inhibitory properties along with predicted ADMET profiles and observed interactions would be beneficial for the discovery of new active 1‐(pyrrolidin‐2‐yl)propan‐2‐one‐based inhibitors of DNase I.

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Rutin as Deoxyribonuclease I Inhibitor

Cited by 21 publications

References 45 publications

1,2,3,4‐Tetrahydroisoquinoline Derivatives as a Novel Deoxyribonuclease I Inhibitors

1,2,3,4‐Tetrahydroisoquinoline Derivatives as a Novel Deoxyribonuclease I Inhibitors

Repurposing of 8‐Hydroxyquinoline‐Based Butyrylcholinesterase and Cathepsin B Ligands as Potent Nonpeptidic Deoxyribonuclease I Inhibitors

Deoxyribonuclease I Inhibitory Properties, Molecular Docking and Molecular Dynamics Simulations of 1‐(Pyrrolidin‐2‐yl)propan‐2‐one Derivatives

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