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. 2024 Oct 5:276:116724.
doi: 10.1016/j.ejmech.2024.116724. Epub 2024 Jul 27.

Synthesis of furanotriterpenoids from betulin and evaluation of Tyrosyl-DNA phosphodiesterase 1 (Tdp1) inhibitory properties of new semi-synthetic triterpenoids

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Synthesis of furanotriterpenoids from betulin and evaluation of Tyrosyl-DNA phosphodiesterase 1 (Tdp1) inhibitory properties of new semi-synthetic triterpenoids

Irina Tolmacheva et al. Eur J Med Chem. .

Abstract

For the first time, a synthetic route for preparing lupane and oleanane derivatives with a hydrogenated furan ring as a cycle A of triterpene scaffold is described. Most of the synthesized compounds, furanoterpenoids and their synthetic intermediates, were non-toxic against the tested cancer and non-cancerous cell lines, and evinced significant inhibitory activity with IC50 1.0-9.0 μM in the tyrosyl-DNA phosphodiesterase 1 (Tdp1) inhibition test. Lupane derivatives - 1-oxime 7, 1,10-seco-hydroxynitrile 11 and furanoterpenoid 14 - were selected as those expected to be the most promising compounds. The results of molecular modeling evinced the strongest binding of compound 11 to the active site of Tdp1 compared to the reference drug. Simultaneously, only compound 11 at subtoxic concentration (10 μM) produced a synergetic effect on the topotecan activity against HeLa-V cells.

Keywords: Betulin; Furanoterpenoids; Heterocyclization; Molecular docking analysis; Synergetic effect; Tdp1 inhibitors; Topotecan.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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