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

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

Journal

Letters in Drug Design and Discovery
ISSN: 1570-1808 , E-ISSN: 1875-628X

Output data

Year: 2019, Volume: 16, Number: 5, Pages: 597-605 Pages count : DOI: 10.2174/1570180816666181220121042

Tags

Anilines; secondary amines; myrtenal; perillyl aldehyde; terpenes; cancer; molecular modeling; chemical space

Authors

Mozhaitsev Evgenii ¹ , Suslov Evgenii ¹ , Demidova Yuliya ^3,4 , Korchagina Dina ¹ , Volcho Konstantin ^1,4 , Zakharenko Alexandra ² , Vasil'eva Inna ² , Kupryushkin Maksim ² , Chepanova Arina ² , Ayine-Tora Daniel Moscoh ⁵ , Reynisson Johannes ⁵ , Salakhutdinov Nariman ¹ , Lavrik Olga ^2,4

Affiliations

1	(Данные Web of science) Russian Acad Sci, Siberian Branch, NN Vorozhtsov Novosibirsk Inst Organ Chem, 9 Lavrentjev Ave, Novosibirsk 630090, Russia
2	(Данные Web of science) Russian Acad Sci, Siberian Branch, Inst Chem Biol & Fundamental Med, Novosibirsk, Russia
3	(Данные Web of science) Russian Acad Sci, Siberian Branch, Boreskov Inst Catalysis, Novosibirsk 630090, Russia
4	(Данные Web of science) Novosibirsk State Univ, Novosibirsk 630090, Russia
5	(Данные Web of science) Univ Auckland, Sch Chem Sci, Auckland 1142, New Zealand

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 arc 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 H-1 and C-13 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 mu M. 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.

Mozhaitsev E. , Suslov E. , Demidova Y. , Korchagina D. , Volcho K. , Zakharenko A. , Vasil'eva I. , Kupryushkin M. , Chepanova A. , Ayine-Tora D.M. , Reynisson J. , Salakhutdinov N. , Lavrik O.
The Development of Tyrosyl-DNA Phosphodyesterase 1 (TDP1) Inhibitors Based on the Amines Combining Aromatic/Heteroaromatic and Monoterpenoid Moieties
Letters in Drug Design and Discovery. 2019. V.16. N5. P.597-605. DOI: 10.2174/1570180816666181220121042 WOS Scopus РИНЦ

Published print:

Apr 15, 2019

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