2. Academic Validation
  3. 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

  • Int J Mol Sci. 2019 Dec 23;21(1):126. doi: 10.3390/ijms21010126.
Tatyana M Khomenko 1,  Alexandra L Zakharenko 2,  Arina A Chepanova 2,  Ekaterina S Ilina 2,  Olga D Zakharova 2,  Vasily I Kaledin 3,  Valeriy P Nikolin 3,  Nelly A Popova 3 4,  Dina V Korchagina 1,  Jóhannes Reynisson 5,  Raina Chand 6,  Daniel M Ayine-Tora 6,  Jinal Patel 6,  Ivanhoe K H Leung 6,  Konstantin P Volcho 1 4,  Nariman F Salakhutdinov 1 4,  Olga I Lavrik 2 4 7
Affiliations

Affiliations

  • 1 N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, 9 acad. Lavrentjev ave., 630090 Novosibirsk, Russia.
  • 2 Novosibirsk Institute of Chemical Biology and Fundamental Medicine, 8, acad. Lavrentjev ave., 630090 Novosibirsk, Russia.
  • 3 Institute of Cytology and Genetics, 10, acad. Lavrentjev Ave., 630090 Novosibirsk, Russia.
  • 4 Novosibirsk State University, V. Zelman Institute for Medicine and Psychology and Department of Natural Sciences, 2, Pirogova str., 630090 Novosibirsk, Russia.
  • 5 School of Pharmacy and Bioengineering, Keele University, Hornbeam Building, Staffordshire ST5 5BG, UK.
  • 6 School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
  • 7 Altai State University, Department of Physical and Chemical Biology and Biotechnology, 61, Lenina Ave., 656049 Barnaul, Russia.
PMID: 31878088 DOI: 10.3390/ijms21010126
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.

Keywords

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

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-161853
    99.69%, TDP1 Inhibitor