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Letters in Drug Design & Discovery


ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

General Research Article

The Development of Tyrosyl-DNA Phosphodyesterase 1 (TDP1) Inhibitors Based on the Amines Combining Aromatic/Heteroaromatic and Monoterpenoid Moieties

Author(s): Evgenii Mozhaitsev, Evgenii Suslov*, Yuliya Demidova, Dina Korchagina, Konstantin Volcho, Alexandra Zakharenko, Inna Vasil'eva, Maksim Kupryushkin, Arina Chepanova, Daniel Moscoh Ayine-Tora, Jóhannes Reynisson, Nariman Salakhutdinov and Olga Lavrik

Volume 16, Issue 5, 2019

Page: [597 - 605] Pages: 9

DOI: 10.2174/1570180816666181220121042

Price: $65


Background: Inhibition of the DNA repair enzyme, tyrosyl-DNA phosphodiesterase 1 (TDP1), may increase the efficacy of cancer drugs that cause damage to tumor cell DNA. Among the known TDP1 inhibitors, there are compounds containing moieties of natural substances, e.g., monoterpenoids. In this work, we synthesized several compounds containing aromatic/ heteroaromatic amines and monoterpenoid groups and assessed their TDP1 inhibition potential.

Methods: Structures of all the synthesized compounds were confirmed by 1H and 13C NMR as well as HRMS. The TDP1 inhibitory activity of the amines was determined by real-time fluorescence oligonucleotide biosensor.

Results: The synthesized secondary amines had TDP1 inhibitory activity IC50 in the range of 0.79-9.2 µM. The highest activity was found for (–)-myrtenal derivatives containing p-bromoaniline or m-(trifluoromethyl)aniline residue.

Conclusion: We synthesized 22 secondary amines; of these, 17 amines are novel chemical structures. Many of the amines inhibit TDP1 activity in the low micromolar range. Therefore, these compounds are promising for further study of their antiproliferative activity in conjunction with DNA damaging drugs.

Keywords: Anilines, secondary amines, myrtenal, perillyl aldehyde, terpenes, cancer, molecular modeling, chemical space.

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