New Deoxycholic Acid Derived Tyrosyl-DNA Phosphodiesterase 1 Inhibitors Also Inhibit Tyrosyl-DNA Phosphodiesterase 2.

Oksana V Salomatina,Konstantin P Volcho,Olga I Lavrik,Ekaterina S Ilina,Alexandra L Zakharenko,Nina I Komarova,Nadezhda S Dyrkheeva,Irina I Popadyuk,Jóhannes Reynisson,Nariman F Salakhutdinov

doi:10.3390/molecules27010072

Abstract

A series of deoxycholic acid (DCA) amides containing benzyl ether groups on the steroid core were tested against the tyrosyl-DNA phosphodiesterase 1 (TDP1) and 2 (TDP2) enzymes. In addition, 1,2,4- and 1,3,4-oxadiazole derivatives were synthesized to study the linker influence between a para-bromophenyl moiety and the steroid scaffold. The DCA derivatives demonstrated promising inhibitory activity against TDP1 with IC50 in the submicromolar range. Furthermore, the amides and the 1,3,4-oxadiazole derivatives inhibited the TDP2 enzyme but at substantially higher concentration. Tryptamide 5 and para-bromoanilide 8 derivatives containing benzyloxy substituent at the C-3 position and non-substituted hydroxy group at C-12 on the DCA scaffold inhibited both TDP1 and TDP2 as well as enhanced the cytotoxicity of topotecan in non-toxic concentration in vitro. According to molecular modeling, ligand 5 is anchored into the catalytic pocket of TDP1 by one hydrogen bond to the backbone of Gly458 as well as by π–π stacking between the indolyl rings of the ligand and Tyr590, resulting in excellent activity. It can therefore be concluded that these derivatives contribute to the development of specific TDP1 and TDP2 inhibitors for adjuvant therapy against cancer in combination with topoisomerase poisons.

Highlights

Traditional chemo- and radiotherapy of oncological diseases are aimed at damaging DNA in malignant cells
We synthesized a set of tryptamides (4–6) and para-bromoanilides (7–9) of deoxycholic acid (DCA) with the benzyloxy-group at C-3 and benzyloxy, hydroxy, and oxo-groups at C-12 on the steroid core (Scheme 1)
We modified the steroid framework by attaching the benzyloxygroup using DCA as the starting material for the synthesis. 3,12-Bis-benzyloxy derivative 1 was obtained by the reaction of DCA (1 mol eq.) with benzyl bromide (4.5 mol eq.) in THF under reflux with 73% yield. 3-Benzyloxy derivative 2 was obtained in a similar condition using 3-fold excess of benzyl bromide in THF under reflux with 68% yield after purification by column chromatography. 3-Benzyloxy-12-oxo derivative 3 was obtained by Jones oxidation of 12-hydroxy group in compound 2 with 94% yield

Summary

Introduction

Traditional chemo- and radiotherapy of oncological diseases are aimed at damaging DNA in malignant cells. An effective DNA repair system can lead to resistance to therapeutic agents of cancer cells, making DNA repair enzymes promising targets for adjunct anti-cancer drugs [1]. Topoisomerase inhibitors (TOP1: topotecan and irinotecan, TOP2: etoposide and doxorubicin) stabilize covalent topoisomerase/DNA complexes, resulting in the accumulation of DNA breaks and cell death. DNA reparation of such covalent complexes is aided by tyrosyl-DNA phosphodiesterases 1 and 2 (TDP1 and TDP2), which play a significant role in the development of drug resistance [2]. TDP1 and TDP2 are considered as potential targets for adjunct therapy in combination with topoisomerase inhibitors. The discovery of dual inhibitors of TDP1 and TDP2 is a promising strategy to be pursued

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Conclusion