New Dual Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 and 2 Based on Deoxycholic Acid: Design, Synthesis, Cytotoxicity, and Molecular Modeling.

Autor: Salomatina OV; N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, SB RAS, 9, Lavrent'ev Ave., Novosibirsk 630090, Russia., Kornienko TE; Institute of Chemical Biology and Fundamental Medicine, SB RAS, 8, Lavrent'ev Ave., Novosibirsk 630090, Russia., Zakharenko AL; Institute of Chemical Biology and Fundamental Medicine, SB RAS, 8, Lavrent'ev Ave., Novosibirsk 630090, Russia., Komarova NI; N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, SB RAS, 9, Lavrent'ev Ave., Novosibirsk 630090, Russia., Achara C; School of Pharmacy and Bioengineering, Keele University, Hornbeam Building, Newcastle-under-Lyme, Staffordshire ST5 5BG, UK., Reynisson J; School of Pharmacy and Bioengineering, Keele University, Hornbeam Building, Newcastle-under-Lyme, Staffordshire ST5 5BG, UK., Salakhutdinov NF; N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, SB RAS, 9, Lavrent'ev Ave., Novosibirsk 630090, Russia., Lavrik OI; Institute of Chemical Biology and Fundamental Medicine, SB RAS, 8, Lavrent'ev Ave., Novosibirsk 630090, Russia., Volcho KP; N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, SB RAS, 9, Lavrent'ev Ave., Novosibirsk 630090, Russia.
Jazyk: angličtina
Zdroj: Molecules (Basel, Switzerland) [Molecules] 2024 Jan 24; Vol. 29 (3). Date of Electronic Publication: 2024 Jan 24.
DOI: 10.3390/molecules29030581
Abstrakt: Deoxycholic acid derivatives containing various heterocyclic functional groups at C-3 on the steroid scaffold were designed and synthesized as promising dual tyrosyl-DNA phosphodiesterase 1 and 2 (TDP1 and TDP2) inhibitors, which are potential targets to potentiate topoisomerase poison antitumor therapy. The methyl esters of DCA derivatives with benzothiazole or benzimidazole moieties at C-3 demonstrated promising inhibitory activity in vitro against TDP1 with IC 50 values in the submicromolar range. Furthermore, methyl esters 4d - e , as well as their acid counterparts 3d - e , inhibited the phosphodiesterase activity of both TDP1 and TDP2. The combinations of compounds 3d - e and 4d - e with low-toxic concentrations of antitumor drugs topotecan and etoposide showed significantly greater cytotoxicity than the compounds alone. The docking of the derivatives into the binding sites of TDP1 and TDP2 predicted plausible binding modes of the DCA derivatives.
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje