Design, Synthesis, and Biological Investigation of Novel Classes of 3-Carene-Derived Potent Inhibitors of TDP1

Design, Synthesis, and Biological Investigation of Novel Classes of 3-Carene-Derived Potent Inhibitors of TDP1 Full article

Journal

Molecules
, E-ISSN: 1420-3049

Output data

Year: 2020, Volume: 25, Number: 15, Article number : 3496, Pages count : DOI: 10.3390/molecules25153496

Tags

monoterpene; carene; topotecan; tyrosyl-DNA phosphodiesterase 1; synergy; TDP1gene knockout cells; inhibitor

Authors

Il'ina Irina, V ¹ , Dyrkheeva Nadezhda S. ² , Zakharenko Alexandra L. ² , Sidorenko Alexander Yu. ³ , Li-Zhulanov Nikolay S. ^1,4 , Korchagina Dina, V ¹ , Chand Raina ⁵ , Ayine-Tora Daniel M. ⁵ , Chepanova Arina A. ² , Zakharova Olga D. ² , Ilina Ekaterina S. ² , Reynisson Johannes ⁶ , Malakhova Anastasia A. ^2,7 , Medvedev Sergey P. ^7,8 , Zakian Suren M. ^4,7 , Volcho Konstantin P. ^1,4 , Salakhutdinov Nariman F. ^1,4 , Lavrik Olga, I ^2,4

Affiliations

1	N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9, Lavrentiev Ave., 630090 Novosibirsk, Russia
2	Institute of Chemica Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 8, Lavrentiev Ave., 630090 Novosibirsk, Russia
3	Institute of Chemistry of New Materials of National Academy of Sciences of Belarus, Skaryna Str, 36, 220141 Minsk, Belarus
4	(Данные Web of science) Novosibirsk State Univ, Russian Acad Sci, Nstitute Cytol & Genet, Siberian Div, 2 Pirogova Str, Novosibirsk 630090, Russia
5	(Данные Web of science) Univ Auckland, Sch Chem Sci, Private Bag 92019,Victoria St West, Auckland 1142, New Zealand
6	(Данные Web of science) Keele Univ, Sch Pharm & Bioengn, Hornbeam Bldg, Keele ST5 5BG, Staffs, England
7	(Данные Web of science) Russian Acad Sci, Siberian Branch, Fed Res Ctr, Inst Cytol & Genet, 10 Lavrentiev Ave, Novosibirsk 630090, Russia
8	E.Meshalkin National medical research center of the Ministry of Health of the Russian Federation, 15 Rechkunovskaya Str., 630055 Novosibirsk, Russia

Funding (1)

Российский Научный Фонд

19-13-00040

Two novel structural types of tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitors with hexahydroisobenzofuran11and 3-oxabicyclo [3.3.1]nonane12scaffolds were discovered. These monoterpene-derived compounds were synthesized through preliminary isomerization of (+)-3-carene to (+)-2-carene followed by reaction with heteroaromatic aldehydes. All the compounds inhibit the TDP1 enzyme at micro- and submicromolar levels, with the most potent compound having an IC(50)value of 0.65 mu M. TDP1 is an important DNA repair enzyme and a promising target for the development of new chemosensitizing agents. A panel of isogenic clones of the HEK293FT cell line knockout for theTDP1gene was created using the CRISPR-Cas9 system. Cytotoxic effects of topotecan (Tpc) and non-cytotoxic compounds of the new structures were investigated separately and jointly in theTDP1gene knockout cells. For two TDP1 inhibitors,11hand12k, a synergistic effect was observed with Tpc in the HEK293FT cells but was not found in TDP1 -/- cells. Thus, it is likely that the synergistic effect is caused by inhibition of TDP1. Synergy was also found for11hin other cancer cell lines. Thus, sensitizing cancer cells using a non-cytotoxic drug can enhance the efficacy of currently used pharmaceuticals and, concomitantly, reduce toxic side effects.

Il'ina I.V. , Dyrkheeva N.S. , Zakharenko A.L. , Sidorenko A.Y. , Li-Zhulanov N.S. , Korchagina D.V. , Chand R. , Ayine-Tora D.M. , Chepanova A.A. , Zakharova O.D. , Ilina E.S. , Reynisson J. , Malakhova A.A. , Medvedev S.P. , Zakian S.M. , Volcho K.P. , Salakhutdinov N.F. , Lavrik O.I.
Design, Synthesis, and Biological Investigation of Novel Classes of 3-Carene-Derived Potent Inhibitors of TDP1

Molecules. 2020. V.25. N15. 3496 . DOI: 10.3390/molecules25153496 WOS Scopus РИНЦ OpenAlex

Full text from publisher

Published online:

Jul 31, 2020

Web of science:	WOS:000558986700001
Scopus:	2-s2.0-85089133050
Elibrary:	45422791
OpenAlex:	W3046641740

DB	Citing
Web of science	29
Scopus	28
Elibrary	30
OpenAlex	30