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Synthesis and DNase I Inhibitory Properties of New Squaramides.

ABSTRACT: Three new monosquaramides (3a-c) were synthesized, characterized by IR, NMR and X-ray, and evaluated for inhibitory activity against deoxyribonuclease I (DNase I) and xanthine oxidase (XO) in vitro. The target compounds inhibited DNase I with IC₅₀ values below 100 μM, being at the same time more potent DNase I inhibitors than crystal violet, used as a positive control. 3-Ethoxy-4-((1-(pyridin-3-yl)propan-2-yl)amino)cyclobut-3-ene-1,2-dione (3c) stood out as the most potent compound, exhibiting a slightly better IC₅₀ value (48.04 ± 7.98 μM) compared to the other two compounds. In order to analyze potential binding sites for the studied compounds with DNase I, a molecular docking study was performed. Compounds 3a-c are among the most potent small organic DNase I inhibitors tested to date.

SUBMITTER: Ruseva N

PROVIDER: S-EPMC9863136 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Synthesis and DNase I Inhibitory Properties of New Squaramides.

Ruseva Nina N Sbirkova-Dimitrova Hristina H Atanasova Mariyana M Marković Ana A Šmelcerović Žaklina Ž Šmelcerović Andrija A Bakalova Adriana A Cherneva Emiliya E

Molecules (Basel, Switzerland) 20230105 2

Three new monosquaramides (3a-c) were synthesized, characterized by IR, NMR and X-ray, and evaluated for inhibitory activity against deoxyribonuclease I (DNase I) and xanthine oxidase (XO) in vitro. The target compounds inhibited DNase I with IC50 values below 100 μM, being at the same time more potent DNase I inhibitors than crystal violet, used as a positive control. 3-Ethoxy-4-((1-(pyridin-3-yl)propan-2-yl)amino)cyclobut-3-ene-1,2-dione (3c) stood out as the mo ...[more]

PMID: 36677597

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Project description:BackgroundGlycosidases are involved in several metabolic pathways and the development of inhibitors is an important challenge towards the treatment of diseases, such as diabetes, cancer and viral infections including AIDS. Thus, inhibition of intestinal alpha-glucosidases can be used to treat diabetes through the lowering of blood glucose levels, and alpha-glucosidase inhibitors are being marketed against type 2 (non-insulinodependent mellitus) diabetes (i.e.: Glyset or Diastabol, Basen and Glucor or Precose).ResultsIn that context, new C8-carbasugars and related aminocyclitols have been targeted in order to study the effect of the enhanced flexibility and of the new spatial distribution displayed by these structures on their adaptability in the active site of the enzymes. The synthesis of these new C8-glycomimetics is described from enantiomerically pure C2-symmetrical polyhydroxylated cyclooctenes. Their obtention notably involved a syn-dihydroxylation, and more extended functionalization through formation of a cis-cyclic sulfate followed by amination and subsequent reductive amination. This strategy involving the nucleophilic opening of a cis-cyclic sulfate by sodium azide is to our knowledge the first example in C8-series. It revealead to be an efficient alternative to the nucleoplilic opening of an epoxide moiety which proved unsuccessful in this particular case, due to the hindered conformation of such epoxides as demonstrated by X-ray cristallographic analysis.ConclusionThe biological activity of the synthesized glycomimetics has been evaluated towards 24 commercially available glycosidases. The weak observed activities can probably be related to the spatial disposition of the hydroxy and amino groups which depart too much from that realized in glycomimetics such as valiolamine, voglibose and valienamine. Nevertheless, the synthetic strategy described here is efficient and general, and could be extended to increase the diversity of the glycosidase inhibitors obtained since this diversity is introduced in an ultimate step of the synthesis.

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Synthesis and DNase I Inhibitory Properties of New Squaramides.

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Synthesis and DNase I Inhibitory Properties of New Squaramides.

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