The search of new DNA repair enzymes inhibitors is a promising approach of modern pharmacology and one of the ways to increase cancer therapy effectiveness, especially for drug resistant tumors. At the same time the development of new compounds that effectively inhibit activity of various DNA repair enzymes is not an easy task. In the present work an attempt was made to synthesize dual or triple inhibitors of Tyrosyl-DNA-phosphodiesterase 1 and 2 (Tdp1 and 2) and Poly(ADP-ribose)polymerase 1 (PARP1).

The natural compound usnic acid 1 is a widespread secondary metabolite of lichens, the chemical transformation of which previously produced compounds with inhibitory activity against the DNA repair enzyme - Tdp1.

In this work, we have synthesized a number of usnic acid thioesters 2 that differ in the structure of the sulfur atom substituent and have studied their inhibitory activity to the repair enzymes Tdp1, Tdp2 and PARP1. Among the studied compounds, both compounds that are selective Tdp1 inhibitors, as well as dual (Tdp1 and PARP1) and triple inhibitors (Tdp1, Tdp2 and PARP1) were identified. The type of Tdp1 inhibition for the obtained compounds has been found to be uncompetitive.

This study was funded by Russian Foundation for Basic Research 19-415-540002