Promising New Inhibitors of Tyrosyl-DNA Phosphodiesterase I (Tdp 1) Combining 4-Arylcoumarin and Monoterpenoid Moieties as Components of Complex Antitumor Therapy

Promising New Inhibitors of Tyrosyl-DNA Phosphodiesterase I (Tdp 1) Combining 4-Arylcoumarin and Monoterpenoid Moieties as Components of Complex Antitumor Therapy Full article

Journal

International Journal of Molecular Sciences
ISSN: 1661-6596

Output data

Year: 2020, Volume: 21, Number: 1, Article number : 126, Pages count : DOI: 10.3390/ijms21010126

Tags

coumarin; neoflavone; DNA repair enzymes; Tdp1 inhibitor; cancer; tumor; topotecan; topoisomerase 1 inhibitors; molecular modeling; chemical space

Authors

Khomenko Tatyana M. ¹ , Zakharenko Alexandra L. ² , Chepanova Arina A. ² , Ilina Ekaterina S. ² , Zakharova Olga D. ² , Kaledin Vasily I. ³ , Nikolin Valeriy P. ³ , Popova Nelly A. ^3,4,5 , Korchagina Dina V. ¹ , Reynisson Johannes ⁶ , Chand Raina ⁷ , Ayine-Tora Daniel M. ⁷ , Patel Jinal ⁷ , Leung Ivanhoe K.H. ⁷ , Volcho Konstantin P. ^1,4,5 , Salakhutdinov Nariman F. ^1,4,5 , Lavrik Olga I. ^2,4,5,8

Affiliations

1	(Данные Web of science) NN Vorozhtsov Novosibirsk Inst Organ Chem, 9 Acad Lavrentjev Ave, Novosibirsk 630090, Russia
2	(Данные Web of science) Novosibirsk Inst Chem Biol & Fundamental Med, 8,Acad Lavrentjev Ave, Novosibirsk 630090, Russia
3	(Данные Web of science) Inst Cytol & Genet, 10,Acad Lavrentjev Ave, Novosibirsk 630090, Russia
4	(Данные Web of science) Novosibirsk State Univ, V Zelman Inst Med & Psychol, 2,Pirogova Str, Novosibirsk 630090, Russia
5	(Данные Web of science) Novosibirsk State Univ, Dept Nat Sci, 2,Pirogova Str, Novosibirsk 630090, Russia
6	(Данные Web of science) Keele Univ, Sch Pharm & Bioengn, Hornbeam Bldg, Keele ST5 5BG, Staffs, England
7	(Данные Web of science) Univ Auckland, Sch Chem Sci, Private Bag 92019, Auckland 1142, New Zealand
8	(Данные Web of science) Altai State Univ, Dept Phys & Chem Biol & Biotechnol, 61,Lenina Ave, Barnaul 656049, Russia

Funding (1)

Российский Научный Фонд

19-13-00040

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is an important DNA repair enzyme in humans, and a current and promising inhibition target for the development of new chemosensitizing agents due to its ability to remove DNA damage caused by topoisomerase 1 (Top1) poisons such as topotecan and irinotecan. Herein, we report our work on the synthesis and characterization of new Tdp1 inhibitors that combine the arylcoumarin (neoflavonoid) and monoterpenoid moieties. Our results showed that they are potent Tdp1 inhibitors with IC50 values in the submicromolar range. In vivo experiments with mice revealed that compound 3ba (IC50 0.62 mu M) induced a significant increase in the antitumor effect of topotecan on the Krebs-2 ascites tumor model. Our results further strengthen the argument that Tdp1 is a druggable target with the potential to be developed into a clinically-potent adjunct therapy in conjunction with Top1 poisons.

Khomenko T.M. , Zakharenko A.L. , Chepanova A.A. , Ilina E.S. , Zakharova O.D. , Kaledin V.I. , Nikolin V.P. , Popova N.A. , Korchagina D.V. , Reynisson J. , Chand R. , Ayine-Tora D.M. , Patel J. , Leung I.K.H. , Volcho K.P. , Salakhutdinov N.F. , Lavrik O.I.
Promising New Inhibitors of Tyrosyl-DNA Phosphodiesterase I (Tdp 1) Combining 4-Arylcoumarin and Monoterpenoid Moieties as Components of Complex Antitumor Therapy

International Journal of Molecular Sciences. 2020. V.21. N1. 126 . DOI: 10.3390/ijms21010126 WOS Scopus РИНЦ

Full text from publisher

Published online:

Dec 23, 2019

Web of science	WOS:000515378000126
Scopus	2-s2.0-85077279055
Elibrary	43223484
OpenAlex	W2994678791