Novel Tdp1 Inhibitors Based on Adamantane Connected with Monoterpene Moieties via Heterocyclic Fragments.

Aldar A Munkuev,Dina V Korchagina,Evgenii S Mozhaitsev,Nariman F Salakhutdinov,Arina A Chepanova,Jóhannes Reynisson,Ekaterina S Ilina,Olga D Zakharova,Olga I Lavrik,Konstantin P Volcho,Evgeniy V Suslov,Alexandra L Zakharenko,Nadezhda S Dyrkheeva

doi:10.3390/molecules26113128

Abstract

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a promising target for anticancer therapy due to its ability to counter the effects topoisomerase 1 (Top1) poison, such as topotecan, thus, decreasing their efficacy. Compounds containing adamantane and monoterpenoid residues connected via 1,2,4-triazole or 1,3,4-thiadiazole linkers were synthesized and tested against Tdp1. All the derivatives exhibited inhibition at low micromolar or nanomolar concentrations with the most potent inhibitors having IC50 values in the 0.35–0.57 µM range. The cytotoxicity was determined in the HeLa, HCT-116 and SW837 cancer cell lines; moderate CC50 (µM) values were seen from the mid-teens to no effect at 100 µM. Furthermore, citral derivative 20c, α-pinene-derived compounds 20f, 20g and 25c, and the citronellic acid derivative 25b were found to have a sensitizing effect in conjunction with topotecan in the HeLa cervical cancer and colon adenocarcinoma HCT-116 cell lines. The ligands are predicted to bind in the catalytic pocket of Tdp1 and have favorable physicochemical properties for further development as a potential adjunct therapy with Top1 poisons.

Highlights

IntroductionThe camptothecin derivatives irinotecan and topotecan are frontline cancer drugs used for the treatment of breast, small-cell lung, lymphomas, cervical, colorectal and ovarian cancers [2,3,4,5]
Synthesis of 1,2,4-triazole 16 was performed by the cyclocondensation of compound 15 in an aqueous solution of sodium hydroxide under refluxing conditions with 80% yield, as described previously [30]. 2-Amino-1,3,4-thiadiazole 17 was synthesized with a 71% yield after recrystallization from EtOH following a procedure previously described [31], which involved the treatment of starting compound 15 with concentrated sulfuric acid at room temperature
New hybrid molecules consisting of adamantane, monoterpene and heterocyclic fragments were synthesized and tested for their Tyrosyl-DNA phosphodiesterase 1 (Tdp1)-inhibitory properties

Summary

Introduction

The camptothecin derivatives irinotecan and topotecan are frontline cancer drugs used for the treatment of breast, small-cell lung, lymphomas, cervical, colorectal and ovarian cancers [2,3,4,5]. Their target is Topoisomerase 1 (Top1), an enzyme that catalyzes the process of relieving the torsional DNA strain during replication, transcription and chromatin remodeling [6] by generating a reversible single-stranded break and covalently attaching to the 30 -end, followed by religation and releasing of DNA. One of the DNA repair enzymes is tyrosyl-DNA-phosphodiesterase 1 (Tdp1), which

Methods

Results

Conclusion