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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)

1 Российский Научный Фонд 19-13-00040

Abstract: 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.
Cite: 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
Files: Full text from publisher
Dates:
Published online: Jul 31, 2020
Identifiers:
Web of science WOS:000558986700001
Scopus 2-s2.0-85089133050
Elibrary 45422791
OpenAlex W3046641740
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