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

• Published in: Molecules (Basel, Switzerland) Vol. 29; no. 3; p. 581
• Main Authors: Salomatina, Oksana V., Kornienko, Tatyana E., Zakharenko, Alexandra L., Komarova, Nina I., Achara, Chigozie, Reynisson, Jóhannes, Salakhutdinov, Nariman F., Lavrik, Olga I., Volcho, Konstantin P.
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.01.2024
• Subjects: Acids; Amino acids; cancer; Chromatography; Cytotoxicity; Deoxycholic acid; DNA; DNA damage; Enzymes; Etoposide; Ligands; oxirane; Radiotherapy; Steroids; TDP1 inhibitor; TDP2 inhibitor; thiols; Germany; Russia; oxirane; TDP1 inhibitor; TDP2 inhibitor; molecular modeling; tumor; cancer; deoxycholic acid; thiols
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules29030581

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 IC50 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.