title: Synthesis and biological evaluation of novel tyrosyl-DNA phosphodiesterase 1 inhibitors with a benzopentathiepine moiety.
abstract: Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a promising target for antitumor therapy based on Top1 poison-mediated DNA damage. Several novel benzopentathiepines were synthesized and tested as inhibitors of TDP1 using a new oligonucleotide-based fluorescence assay. The benzopentathiepines have IC₅₀ values in the range of 0.2-6.0 μM. According to the molecular modeling, the conformational flexibility of the dibutylamine group of the most effective inhibitor (3d) allows it to occupy an advantageous position for effective binding compared to its cyclic counterparts. The study of cytotoxicity of these compounds revealed that all compounds cause an apoptotic cell death in MCF-7 and Hep G2 cells. Therefore the new class of very effective inhibitors of TDP1 was elaborated.
authors.affiliation: Novosibirsk Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 8, Akademika Lavrentieva Ave., Novosibirsk 630090, Russian Federation.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zakharenko
authors.affiliation: N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9, Akademika Lavrentieva Ave., Novosibirsk 630090, Russian Federation; Novosibirsk State University, Pirogova 2, Novosibirsk 630090, Russian Federation.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Khomenko
authors.affiliation: Altai State University, 61, Lenina Ave., Barnaul 656049, Russian Federation.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Zhukova
authors.affiliation: Novosibirsk Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 8, Akademika Lavrentieva Ave., Novosibirsk 630090, Russian Federation; Novosibirsk State University, Pirogova 2, Novosibirsk 630090, Russian Federation.
authors.forename: Olga
authors.initials: O
authors.lastname: Koval
authors.affiliation: Novosibirsk Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 8, Akademika Lavrentieva Ave., Novosibirsk 630090, Russian Federation.
authors.forename: Olga
authors.initials: O
authors.lastname: Zakharova
authors.affiliation: Novosibirsk Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 8, Akademika Lavrentieva Ave., Novosibirsk 630090, Russian Federation; Novosibirsk State University, Pirogova 2, Novosibirsk 630090, Russian Federation.
authors.forename: Rashid
authors.initials: R
authors.lastname: Anarbaev
authors.affiliation: Novosibirsk Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 8, Akademika Lavrentieva Ave., Novosibirsk 630090, Russian Federation; Novosibirsk State University, Pirogova 2, Novosibirsk 630090, Russian Federation.
authors.forename: Natalya
authors.initials: N
authors.lastname: Lebedeva
authors.affiliation: N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9, Akademika Lavrentieva Ave., Novosibirsk 630090, Russian Federation.
authors.forename: Dina
authors.initials: D
authors.lastname: Korchagina
authors.affiliation: N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9, Akademika Lavrentieva Ave., Novosibirsk 630090, Russian Federation.
authors.forename: Nina
authors.initials: N
authors.lastname: Komarova
authors.affiliation: N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9, Akademika Lavrentieva Ave., Novosibirsk 630090, Russian Federation.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Vasiliev
authors.affiliation: School of Chemical Sciences, University of Auckland, New Zealand.
authors.forename: Jóhannes
authors.initials: J
authors.lastname: Reynisson
authors.affiliation: N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9, Akademika Lavrentieva Ave., Novosibirsk 630090, Russian Federation; Novosibirsk State University, Pirogova 2, Novosibirsk 630090, Russian Federation.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Volcho
authors.affiliation: N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9, Akademika Lavrentieva Ave., Novosibirsk 630090, Russian Federation; Novosibirsk State University, Pirogova 2, Novosibirsk 630090, Russian Federation. Electronic address: anvar@nioch.nsc.ru.
authors.forename: Nariman
authors.initials: N
authors.lastname: Salakhutdinov
authors.affiliation: Novosibirsk Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 8, Akademika Lavrentieva Ave., Novosibirsk 630090, Russian Federation; Novosibirsk State University, Pirogova 2, Novosibirsk 630090, Russian Federation. Electronic address: lavrik@niboch.nsc.ru.
authors.forename: Olga
authors.initials: O
authors.lastname: Lavrik
mesh_terms: D003988:Dibenzothiepins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D003988:Dibenzothiepins; D010726:Phosphodiesterase Inhibitors; D010727:Phosphoric Diester Hydrolases; C498508:TDP1 protein, human
keywords: Molecular modeling; Pentathiepine; TDP1; TDP1 inhibitor; Tyrosyl-DNA phosphodiesterase 1