Journal
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY
Volume 45, Issue 6, Pages 647-655Publisher
MAIK NAUKA/INTERPERIODICA/SPRINGER
DOI: 10.1134/S1068162019060104
Keywords
tyrosyl-DNA phosphodiesterase 1 inhibitors; topotecan; octahydro-2H-chromene; cytotoxicity
Funding
- Russian Foundation for Basic Research [19-44-543001 r_mol_a]
- Program of Fundamental Scientific Research of State Academies of Sciences [VI.57.1.2, 0309-2016-0001]
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Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is one of the important DNA repair enzymes responsible for the repair of DNA damage caused by anticancer drugs, such as topotecan. In this regard, enzyme activity is one of the possible causes of tumor resistance to chemotherapy, and the use of inhibitors of this enzyme is considered as a promising adjuvant therapy. We have obtained a number of new isomeric naphthyl derivatives of thiophenyl octahydro-2H-chromene, the structure of one of which is confirmed by X-ray structural analysis. Based on molecular modeling data, the structure of the ligand-Tdp1 complex has been proposed. All compounds obtained inhibit Tdp1 at a concentration of about 2 mu M. Low toxicity of three compounds was shown, which makes them promising candidates for the development of accompanying cancer therapy.
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