Design, Synthesis, and Molecular Docking Study of New Tyrosyl-DNA Phosphodiesterase 1 (TDP1) Inhibitors Combining Resin Acids and Adamantane Moieties.

Kseniya Kovaleva,Irina Chernyshova,Olga Yarovaya,Amirhossein Azimirad,Konstantin Ponomarev,Andrey Pokrovsky,Dmitry Nilov,Evgenii Suslov,Nariman Salakhutdinov,Olga Lavrik,Alexandra Zakharenko,Tatiana Khlebnikova,Vytas Švedas,Evgenii Mozhaytsev,Sergey Cheresiz,Vasily Konev

doi:10.3390/ph14050422

Abstract

In this paper, a series of novel abietyl and dehydroabietyl ureas, thioureas, amides, and thioamides bearing adamantane moieties were designed, synthesized, and evaluated for their inhibitory activities against tyrosil-DNA-phosphodiesterase 1 (TDP1). The synthesized compounds were able to inhibit TDP1 at micromolar concentrations (0.19–2.3 µM) and demonstrated low cytotoxicity in the T98G glioma cell line. The effect of the terpene fragment, the linker structure, and the adamantane residue on the biological properties of the new compounds was investigated. Based on molecular docking results, we suppose that adamantane derivatives of resin acids bind to the TDP1 covalent intermediate, forming a hydrogen bond with Ser463 and hydrophobic contacts with the Phe259 and Trp590 residues and the oligonucleotide fragment of the substrate.

Highlights

DNA in living organisms is constantly exposed to a variety of physical and chemical stresses, and damage occurs as a result
We have shown that dehydroabietylamine tyrosil-DNA-phosphodiesterase 1 (TDP1) inhibitors in combination with TMZ demonstrate a better cytotoxic effect on glioblastoma cells than TMZ alone, taken at the same concentration
Dehydroabietylamine niferous plants; for example, the high acid content is found in the resin of Picea obovata can be directly obtained from the resin by the reduction of dehydroabietyl nitrile

Summary

Introduction

DNA in living organisms is constantly exposed to a variety of physical and chemical stresses, and damage occurs as a result. Defects in the repair of DNA damage are implicated in a variety of diseases, many of which are typified by neurological dysfunction and/or increased genetic instability and cancer [1]. Traditional cancer chemotherapy is aimed at damaging the DNA of malignant cells, and the results depend on the effectiveness of their repair systems. Compounds that act as DNA repair inhibitors have been considered as potential drugs [2,3]. The enzyme tyrosil-DNA-phosphodiesterase 1 (TDP1) is one of the promising ones [4]. This enzyme is an important supplementary target for anticancer therapies based on topoisomerase

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Conclusion