The Development of Tyrosyl-DNA Phosphodiesterase 1 Inhibitors. Combination of Monoterpene and Adamantine Moieties via Amide or Thioamide Bridges

The Development of Tyrosyl-DNA Phosphodiesterase 1 Inhibitors. Combination of Monoterpene and Adamantine Moieties via Amide or Thioamide Bridges Full article

Journal

Applied Sciences
ISSN: 2076-3417

Output data

Year: 2019, Volume: 9, Number: 13, Article number : 2767, Pages count : DOI: 10.3390/app9132767

Tags

topotecan; A-549 lung adenocarcinoma cell line l; Topoisomerase 1; molecular modelling; chemical space; synergy; thermal shift assay; intrinsic tryptophan fluorescence binding assay; fluorescence biosensor assay

Authors

Chepanova Arina A. ¹ , Mozhaitsev Evgenii S. ² , Munkuev Aldar A. ^2,3 , Suslov Evgeniy V. ² , Korchagina Dina V. ² , Zakharova Olga D. ¹ , Zakharenko Alexandra L. ¹ , Patel Jinal ⁴ , Ayine-Tora Daniel M. ⁴ , Reynisson Johannes ⁵ , Leung Ivanhoe K.H. ^4,6 , Volcho Konstantin P. ^2,3 , Salakhutdinov Nariman F. ^2,3 , Lavrik Olga I. ^1,3

Affiliations

1	(Данные Web of science) Russian Acad Sci, Siberian Branch, Inst Chem Biol & Fundamental Med, 8 Lavrentiev Ave, Novosibirsk 630090, Russia
2	(Данные Web of science) Russian Acad Sci, Siberian Branch, NN Vorozhtsov Novosibirsk Inst Organ Chem, 9 Lavrentiev Ave, Novosibirsk 630090, Russia
3	(Данные Web of science) Novosibirsk State Univ, 2 Pirogova Str, Novosibirsk 630090, Russia
4	(Данные Web of science) Univ Auckland, Sch Chem Sci, Private Bag 92019,Victoria St West, Auckland 1142, New Zealand
5	(Данные Web of science) Keele Univ, Sch Pharm, Hornbeam Bldg, Keele ST5 5BG, Staffs, England
6	(Данные Web of science) Univ Auckland, Maurice Wilkins Ctr Mol Biodiscovery, Private Bag 92019,Victoria St West, Auckland 1142, New Zealand

Funding (1)

Российский Научный Фонд

19-13-00040

Eleven amide and thioamide derivatives with monoterpene and adamantine substituents were synthesised. They were tested for their activity against the tyrosyl-DNA phosphodiesterase 1 DNA (Tdp1) repair enzyme with the most potent compound 47a, having an IC50 value of 0.64 mu M. When tested in the A-549 lung adenocarcinoma cell line, no or very limited cytotoxic effect was observed for the ligands. However, in conjunction with topotecan, a well-established Topoisomerase 1 (Top1) poison in clinical use against cancer, derivative 46a was very cytotoxic at 5 mu M concentration, displaying strong synergism. This effect was only seen for 46a (IC50-3.3 mu M) albeit some other ligands had better IC50 values. Molecular modelling into the catalytic site of Tdp1 predicted plausible binding mode of 46a, effectively blocking access to the catalytic site.

Chepanova A.A. , Mozhaitsev E.S. , Munkuev A.A. , Suslov E.V. , Korchagina D.V. , Zakharova O.D. , Zakharenko A.L. , Patel J. , Ayine-Tora D.M. , Reynisson J. , Leung I.K.H. , Volcho K.P. , Salakhutdinov N.F. , Lavrik O.I.
The Development of Tyrosyl-DNA Phosphodiesterase 1 Inhibitors. Combination of Monoterpene and Adamantine Moieties via Amide or Thioamide Bridges

Applied Sciences. 2019. V.9. N13. 2767 . DOI: 10.3390/app9132767 WOS Scopus РИНЦ

Full text from publisher

Published online:

Jul 9, 2019

Web of science	WOS:000477031900186
Scopus	2-s2.0-85073695940
Elibrary	41711691
OpenAlex	W2961313069