New Deoxycholic Acid Derived Tyrosyl-DNA Phosphodiesterase 1 Inhibitors Also Inhibit Tyrosyl-DNA Phosphodiesterase 2

• Published in: Molecules (Basel, Switzerland) Vol. 27; no. 1; p. 72
• Main Authors: Salomatina, Oksana V., Dyrkheeva, Nadezhda S., Popadyuk, Irina I., Zakharenko, Alexandra L., Ilina, Ekaterina S., Komarova, Nina I., Reynisson, Jóhannes, Salakhutdinov, Nariman F., Lavrik, Olga I., Volcho, Konstantin P.
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 23.12.2021; MDPI
• Subjects: Acids; amide; Apoptosis; Binding Sites; cancer; Cancer therapies; Cell Line; Chemical Phenomena; Chemistry Techniques, Synthetic; Chromatography; Cytotoxicity; deoxycholic acid; Deoxycholic Acid - analogs & derivatives; Deoxycholic Acid - chemistry; Deoxycholic Acid - pharmacology; DNA repair; Enzyme Activation - drug effects; Enzymes; Humans; Models, Molecular; Molecular Conformation; Molecular Structure; Organic chemicals; oxadiazoles; Peptides; Phosphodiesterase Inhibitors - chemical synthesis; Phosphodiesterase Inhibitors - chemistry; Phosphodiesterase Inhibitors - pharmacology; Phosphoric Diester Hydrolases - chemistry; Phosphoric Diester Hydrolases - metabolism; Protein Binding; Recombinant Proteins - chemistry; Steroids; Structure-Activity Relationship; TDP1 inhibitor; TDP2 inhibitor; TDP1 inhibitor; TDP2 inhibitor; amide; molecular modeling; tumor; oxadiazoles; cancer; deoxycholic acid
• DOI: 10.3390/molecules27010072
• ISSN: 1420-3049

A series of deoxycholic acid (DCA) amides containing benzyl ether groups on the steroid core were tested against the tyrosyl-DNA phosphodiesterase 1 (TDP1) and 2 (TDP2) enzymes. In addition, 1,2,4- and 1,3,4-oxadiazole derivatives were synthesized to study the linker influence between a para-bromophenyl moiety and the steroid scaffold. The DCA derivatives demonstrated promising inhibitory activity against TDP1 with IC50 in the submicromolar range. Furthermore, the amides and the 1,3,4-oxadiazole derivatives inhibited the TDP2 enzyme but at substantially higher concentration. Tryptamide 5 and para-bromoanilide 8 derivatives containing benzyloxy substituent at the C-3 position and non-substituted hydroxy group at C-12 on the DCA scaffold inhibited both TDP1 and TDP2 as well as enhanced the cytotoxicity of topotecan in non-toxic concentration in vitro. According to molecular modeling, ligand 5 is anchored into the catalytic pocket of TDP1 by one hydrogen bond to the backbone of Gly458 as well as by π–π stacking between the indolyl rings of the ligand and Tyr590, resulting in excellent activity. It can therefore be concluded that these derivatives contribute to the development of specific TDP1 and TDP2 inhibitors for adjuvant therapy against cancer in combination with topoisomerase poisons.