Synthesis of the New Derivatives of Usnic Acid and Study of Their Inhibiting Activity against Tyrosyl-DNA-Phosphodiesterases 1 and 2
A. S. FILIMONOV1, A. A. CHEPANOVA2, M. A. MIKHAILOVA2, O. A. LUZINA1, A. L. ZAKHARENKO2, N. S. SALAKHUTDINOV1, O. I. LAVRIK2
1Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
2Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
Keywords: usnic acid, usnic acid derivatives, Tdp1 and Tdp2 inhibitors, anti-tumour properties, topotecan
Pages: 698–706
Abstract
Tyrosyl-DNA phosphodiesterases 1 and 2 (Tdp1 and Tdp2) are DNA repair enzymes that are considered as potential targets for antitumour supporting therapy in combination with topoisomerase inhibitors. The most effective Tdp1 inhibitors were found among the derivatives of the lichen secondary metabolite usnic acid. The sensitising effect of these compounds in combination with the topoisomerase 1 inhibitor topotecan was confirmed in cell culture experiments and animal models. In the present work, we describe new derivatives of usnic acid synthesized on the basis of previously obtained Tdp1 inhibitors by introducing the pyrazole cycle annelated with the C ring in dibenzofuran backbone, which makes it possible to reduce the intrinsic toxicity of the obtained compounds. New dual Tdp1 and Tdp2 inhibitors in the micromolar range of concentrations are found.
DOI: 10.15372/CSD2023519
EDN: CVUPKZ
|
