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Promising New Inhibitors of Tyrosyl-DNA Phosphodiesterase I (Tdp 1) Combining 4-Arylcoumarin and Monoterpenoid Moieties as Components of Complex Antitumor Therapy.
Int J Mol Sci 2019; 21(1)IJ

Abstract

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 µM) 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.

Authors+Show Affiliations

N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, 9 acad. Lavrentjev ave., 630090 Novosibirsk, Russia.Novosibirsk Institute of Chemical Biology and Fundamental Medicine, 8, acad. Lavrentjev ave., 630090 Novosibirsk, Russia.Novosibirsk Institute of Chemical Biology and Fundamental Medicine, 8, acad. Lavrentjev ave., 630090 Novosibirsk, Russia.Novosibirsk Institute of Chemical Biology and Fundamental Medicine, 8, acad. Lavrentjev ave., 630090 Novosibirsk, Russia.Novosibirsk Institute of Chemical Biology and Fundamental Medicine, 8, acad. Lavrentjev ave., 630090 Novosibirsk, Russia.Institute of Cytology and Genetics, 10, acad. Lavrentjev Ave., 630090 Novosibirsk, Russia.Institute of Cytology and Genetics, 10, acad. Lavrentjev Ave., 630090 Novosibirsk, Russia.Institute of Cytology and Genetics, 10, acad. Lavrentjev Ave., 630090 Novosibirsk, Russia. Novosibirsk State University, V. Zelman Institute for Medicine and Psychology and Department of Natural Sciences, 2, Pirogova str., 630090 Novosibirsk, Russia.N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, 9 acad. Lavrentjev ave., 630090 Novosibirsk, Russia.School of Pharmacy and Bioengineering, Keele University, Hornbeam Building, Staffordshire ST5 5BG, UK.School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, 9 acad. Lavrentjev ave., 630090 Novosibirsk, Russia. Novosibirsk State University, V. Zelman Institute for Medicine and Psychology and Department of Natural Sciences, 2, Pirogova str., 630090 Novosibirsk, Russia.N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, 9 acad. Lavrentjev ave., 630090 Novosibirsk, Russia. Novosibirsk State University, V. Zelman Institute for Medicine and Psychology and Department of Natural Sciences, 2, Pirogova str., 630090 Novosibirsk, Russia.Novosibirsk Institute of Chemical Biology and Fundamental Medicine, 8, acad. Lavrentjev ave., 630090 Novosibirsk, Russia. Novosibirsk State University, V. Zelman Institute for Medicine and Psychology and Department of Natural Sciences, 2, Pirogova str., 630090 Novosibirsk, Russia. Altai State University, Department of Physical and Chemical Biology and Biotechnology, 61, Lenina Ave., 656049 Barnaul, Russia.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31878088

Citation

Khomenko, Tatyana M., et al. "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, vol. 21, no. 1, 2019.
Khomenko TM, Zakharenko AL, Chepanova AA, et al. Promising New Inhibitors of Tyrosyl-DNA Phosphodiesterase I (Tdp 1) Combining 4-Arylcoumarin and Monoterpenoid Moieties as Components of Complex Antitumor Therapy. Int J Mol Sci. 2019;21(1).
Khomenko, T. M., Zakharenko, A. L., Chepanova, A. A., Ilina, E. S., Zakharova, O. D., Kaledin, V. I., ... Lavrik, O. I. (2019). 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, 21(1), doi:10.3390/ijms21010126.
Khomenko TM, et al. Promising New Inhibitors of Tyrosyl-DNA Phosphodiesterase I (Tdp 1) Combining 4-Arylcoumarin and Monoterpenoid Moieties as Components of Complex Antitumor Therapy. Int J Mol Sci. 2019 Dec 23;21(1) PubMed PMID: 31878088.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Promising New Inhibitors of Tyrosyl-DNA Phosphodiesterase I (Tdp 1) Combining 4-Arylcoumarin and Monoterpenoid Moieties as Components of Complex Antitumor Therapy. AU - Khomenko,Tatyana M, AU - Zakharenko,Alexandra L, AU - Chepanova,Arina A, AU - Ilina,Ekaterina S, AU - Zakharova,Olga D, AU - Kaledin,Vasily I, AU - Nikolin,Valeriy P, AU - Popova,Nelly A, AU - Korchagina,Dina V, AU - Reynisson,Jóhannes, AU - Chand,Raina, AU - Ayine-Tora,Daniel M, AU - Patel,Jinal, AU - Leung,Ivanhoe K H, AU - Volcho,Konstantin P, AU - Salakhutdinov,Nariman F, AU - Lavrik,Olga I, Y1 - 2019/12/23/ PY - 2019/12/03/received PY - 2019/12/19/revised PY - 2019/12/20/accepted PY - 2019/12/28/entrez KW - DNA repair enzymes KW - Tdp1 inhibitor KW - cancer KW - chemical space KW - coumarin KW - molecular modeling KW - neoflavone KW - topoisomerase 1 inhibitors KW - topotecan KW - tumor JF - International journal of molecular sciences JO - Int J Mol Sci VL - 21 IS - 1 N2 - 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 µM) 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. SN - 1422-0067 UR - https://www.unboundmedicine.com/medline/citation/31878088/Promising_New_Inhibitors_of_Tyrosyl-DNA_Phosphodiesterase_I_(Tdp_1)_Combining_4-Arylcoumarin_and_Monoterpenoid_Moieties_as_Components_of_Complex_Antitumor_Therapy L2 - http://www.mdpi.com/resolver?pii=ijms21010126 DB - PRIME DP - Unbound Medicine ER -