The Development of Tyrosyl-DNA Phosphodyesterase 1 (TDP1) Inhibitors Based on the Amines Combining Aromatic/Heteroaromatic and Monoterpenoid Moieties
Full article
| Общее |
Language:
Английский,
Genre:
Full article,
Status:
Published,
Source type:
Original
|
| 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
: 9
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 Jóhannes
5
,
Salakhutdinov Nariman
1,4
,
Lavrik Olga
2,4
|
| Affiliations |
| 1 |
N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry Siberian Branch of the Russian Academy of Sciences,
Novosibirsk, 630090, Russia
|
| 2 |
Institute of Chemical Biology and Fundamental Medicine Siberian Branch of the Russian
Academy of Sciences
|
| 3 |
Boreskov Institute of Catalysis Siberian Branch of the Russian Academy of Sciences,
Novosibirsk, 630090, Russia
|
| 4 |
Novosibirsk State University, Novosibirsk, 630090, Russia
|
| 5 |
School of Chemical Sciences,
The University of Auckland, Auckland, 1142, New Zealand
|
|
Funding (3)
|
1
|
Russian Foundation for Basic Research
|
16-33-60028
|
|
2
|
Russian Foundation for Basic Research
|
18-44-540023
|
|
3
|
Federal Agency for Scientific Organizations
|
0309-2016-0001 (VI.57.1.2), (АААА-А17-117020210022-4)
|
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.