Design, Synthesis, and Biological Investigation of Novel Classes of 3-Carene-Derived Potent Inhibitors of TDP1.

Irina V Il’Ina,Konstantin P Volcho,Sergey P Medvedev,Nariman F Salakhutdinov,Anastasia A Malakhova,Alexander Yu Sidorenko,Alexandra L Zakharenko,Olga I Lavrik,Nikolay S Li-Zhulanov,Arina A Chepanova,Raina Chand,Nadezhda S Dyrkheeva,Jóhannes Reynisson,Ekaterina S Ilina,Daniel M Ayine-Tora,Dina V Korchagina,Suren M Zakian,Olga D Zakharova

doi:10.3390/molecules25153496

Abstract

Two novel structural types of tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitors with hexahydroisobenzofuran 11 and 3-oxabicyclo [3.3.1]nonane 12 scaffolds were discovered. These monoterpene-derived compounds were synthesized through preliminary isomerization of (+)-3-carene to (+)-2-carene followed by reaction with heteroaromatic aldehydes. All the compounds inhibit the TDP1 enzyme at micro- and submicromolar levels, with the most potent compound having an IC50 value of 0.65 μM. TDP1 is an important DNA repair enzyme and a promising target for the development of new chemosensitizing agents. A panel of isogenic clones of the HEK293FT cell line knockout for the TDP1 gene was created using the CRISPR-Cas9 system. Cytotoxic effects of topotecan (Tpc) and non-cytotoxic compounds of the new structures were investigated separately and jointly in the TDP1 gene knockout cells. For two TDP1 inhibitors, 11h and 12k, a synergistic effect was observed with Tpc in the HEK293FT cells but was not found in TDP1 −/− cells. Thus, it is likely that the synergistic effect is caused by inhibition of TDP1. Synergy was also found for 11h in other cancer cell lines. Thus, sensitizing cancer cells using a non-cytotoxic drug can enhance the efficacy of currently used pharmaceuticals and, concomitantly, reduce toxic side effects.

Highlights

It has been shown that carene can be successfully reacted with carbonyl compounds [23,24]
A new class of effective tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitors was discovered with activity in the low micromolar to nanomolar concentrations
All the tested derivatives exhibited low intrinsic cytotoxicity when tested in a panel of cancer cell lines

Summary

Introduction

There are a number of unresolved issues regarding chemotherapeutic treatment for oncological diseases, for example, low efficiency, resistance of malignant tumors, side effects, and high toxic load.The cytotoxic effect of chemotherapy is caused by DNA damage, and the ability of cancer cells to repairThere are a number of unresolved issues regarding chemotherapeutic treatment for oncologicalDNA lesionsfor results in resistance.theofdevelopment of DNA repair enzyme diseases, example, low efficiency, resistance malignant tumors, side effects, and high inhibitors toxic load. is a promising strategy to improve the efficacy of damaging agents in clinical use.The cytotoxic effect of chemotherapy is caused by DNA damage, and the ability of cancer cells to Tyrosyl-DNA-phosphodiesterase 1 (TDP1)is a DNAthe repair enzyme and a promising therapeutic repairDNA lesions results in resistance.development of DNA repair enzyme target to enhance established cancerTDP1 plays a key role in the removal of DNA inhibitors is a promising strategy to treatment improve the[1,2,3,4]. There are a number of unresolved issues regarding chemotherapeutic treatment for oncological diseases, for example, low efficiency, resistance of malignant tumors, side effects, and high toxic load. The cytotoxic effect of chemotherapy is caused by DNA damage, and the ability of cancer cells to repair. Theofdevelopment of DNA repair enzyme diseases, example, low efficiency, resistance malignant tumors, side effects, and high inhibitors toxic load. The cytotoxic effect of chemotherapy is caused by DNA damage, and the ability of cancer cells to Tyrosyl-DNA-phosphodiesterase 1 (TDP1). Development of DNA repair enzyme target to enhance established cancer. TDP1 plays a key role in the removal of DNA inhibitors is a promising strategy to treatment improve the[1,2,3,4]

Methods

Results

Conclusion