New Hybrid Compounds Combining Fragments of Usnic Acid and Thioether Are Inhibitors of Human Enzymes TDP1, TDP2 and PARP1

• Published in: International journal of molecular sciences Vol. 22; no. 21; p. 11336
• Main Authors: Dyrkheeva, Nadezhda S, Filimonov, Aleksandr S, Luzina, Olga A, Orlova, Kristina A, Chernyshova, Irina A, Kornienko, Tatyana E, Malakhova, Anastasia A, Medvedev, Sergey P, Zakharenko, Alexandra L, Ilina, Ekaterina S, Anarbaev, Rashid O, Naumenko, Konstantin N, Klabenkova, Kristina V, Burakova, Ekaterina A, Stetsenko, Dmitry A, Zakian, Suren M, Salakhutdinov, Nariman F, Lavrik, Olga I
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 20.10.2021; MDPI
• Subjects: Benzofurans - chemistry; Benzofurans - pharmacology; Cancer therapies; Cell Line; Cell Survival - drug effects; Chemotherapy; Cleavage; Clinical medicine; Cytotoxicity; Deoxyribonucleic acid; Dibenzofuran; DNA; DNA damage; DNA repair; DNA Topoisomerases, Type I - metabolism; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - metabolism; Drugs; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzymes; FDA approval; Human papillomavirus; Humans; inhibiting activity; Inhibitors; Ovaries; Phosphodiesterase; Phosphoric Diester Hydrolases - metabolism; Poly (ADP-Ribose) Polymerase-1 - antagonists & inhibitors; Poly (ADP-Ribose) Polymerase-1 - metabolism; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerases - metabolism; Proteins; Structure-Activity Relationship; Sulfides - chemistry; Sulfides - pharmacology; Sulfoxides; Sulfoxides - chemistry; Sulfoxides - pharmacology; TDP1 inhibitor; TDP2; thioether; Topoisomerase I Inhibitors - pharmacology; Topotecan; Topotecan - pharmacology; Tyrosine; tyrosyl-DNA phosphodiesterase 1; Usnic acid; inhibiting activity; TDP1 inhibitor; synergy; PARP1; TDP2; thioether; tyrosyl-DNA phosphodiesterase 1; HEK293 knockout cell line; usnic acid; topotecan
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms222111336

Tyrosyl-DNA phosphodiesterase 1 (TDP1) catalyzes the cleavage of the phosphodiester bond between the tyrosine residue of topoisomerase 1 (TOP1) and the 3' phosphate of DNA in the single-strand break generated by TOP1. TDP1 promotes the cleavage of the stable DNA-TOP1 complexes with the TOP1 inhibitor topotecan, which is a clinically used anticancer drug. This article reports the synthesis and study of usnic acid thioether and sulfoxide derivatives that efficiently suppress TDP1 activity, with IC values in the 1.4-25.2 μM range. The structure of the heterocyclic substituent introduced into the dibenzofuran core affects the TDP1 inhibitory efficiency of the compounds. A five-membered heterocyclic fragment was shown to be most pharmacophoric among the others. Sulfoxide derivatives were less cytotoxic than their thioester analogs. We observed an uncompetitive type of inhibition for the four most effective inhibitors of TDP1. The anticancer effect of TOP1 inhibitors can be enhanced by the simultaneous inhibition of PARP1, TDP1, and TDP2. Some of the compounds inhibited not only TDP1 but also TDP2 and/or PARP1, but at significantly higher concentration ranges than TDP1. Leader compound showed promising synergy on HeLa cells in conjunction with the TOP1 inhibitor topotecan.