Novel Semisynthetic Derivatives of Bile Acids as Effective Tyrosyl-DNA Phosphodiesterase 1 Inhibitors.

Oksana Salomatina,Raina Chand,Olga Zakharova,Dmitriy Fadeev,Nariman Salakhutdinov,H Arabshahi,Nina Komarova,Irina Popadyuk,Jóhannes Reynisson,Alexandra Zakharenko,Konstantin Volcho,Olga Lavrik

doi:10.3390/molecules23030679

Abstract

An Important task in the treatment of oncological and neurodegenerative diseases is the search for new inhibitors of DNA repair system enzymes. Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is one of the DNA repair system enzymes involved in the removal of DNA damages caused by topoisomerase I inhibitors. Thus, reducing the activity of Tdp1 can increase the effectiveness of currently used anticancer drugs. We describe here a new class of semisynthetic small molecule Tdp1 inhibitors based on the bile acid scaffold that were originally identified by virtual screening. The influence of functional groups of bile acids (hydroxy and acetoxy groups in the steroid framework and amide fragment in the side chain) on inhibitory activity was investigated. In vitro studies demonstrate the ability of the semisynthetic derivatives to effectively inhibit Tdp1 with IC50 up to 0.29 µM. Furthermore, an excellent fit is realized for the ligands when docked into the active site of the Tdp1 enzyme.

Highlights

Systems that are responsible for repairing DNA damage play a crucial role in maintaining genome integrity
The GoldScore (GS), ChemScore (CS), Chem Piecewise Linear Potential (ChemPLP), and Astex Statistical Potential (ASP) scoring functions were used to assess the binding of the ligands
Analyzing the scheme of the tryptamides synthesis, we proposed that the commercial sample may contain impurities with protected hydroxyl groups.we

Summary

Introduction

Systems that are responsible for repairing DNA damage play a crucial role in maintaining genome integrity. The cytotoxic effects of chemo- and radiotherapy are often based on DNA damage and these methods are used in clinical practices that treat malignant tumors. The ability of tumor cells to recognize and repair DNA damage can lead to a resistance to certain anti-cancer medications. The inhibition of DNA repair enzymes can increase the effectiveness of several types of antitumor drugs that are in clinical use [4]. The search for inhibitors of the DNA repair system enzymes is one of the most crucial research areas in medical chemistry today [5,6,7]

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