title: New inhibitors of tyrosyl-DNA phosphodiesterase I (Tdp 1) combining 7-hydroxycoumarin and monoterpenoid moieties.
abstract: A number of derivatives of 7-hydroxycoumarins containing aromatic or monoterpene substituents at hydroxy-group were synthesized based on a hit compound from a virtual screen. The ability of these compounds to inhibit tyrosyl-DNA phosphodiesterase I (Tdp 1), important target for anti-cancer therapy, was studied for the first time. It was found that the 7-hydroxycoumarin derivatives with monoterpene pinene moiety are effective inhibitors of Tdp 1 with the most active derivative (+)-25c with IC50value of 0.675μM. This compound has low cytotoxicity (CC50>100μM) when tested against human cancer cells which is crucial for presupposed application in combination with clinically established anticancer drugs. The ability of the new compounds to enhance the cytotoxicity of camptothecin, an established topoisomerase 1 poison, was demonstrated.
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: 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: Odarchenko
authors.affiliation: School of Chemical Sciences, University of Auckland, New Zealand.
authors.forename: Homayon John
authors.initials: HJ
authors.lastname: Arabshahi
authors.affiliation: Novosibirsk State University, Pirogova 2, Novosibirsk 630090, Russian Federation.
authors.forename: Victoriya
authors.initials: V
authors.lastname: Sannikova
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: 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: 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.
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: D004305:Dose-Response Relationship, Drug; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D039821:Monoterpenes / Q000737:chemistry / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014468:Umbelliferones / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D039821:Monoterpenes; D010726:Phosphodiesterase Inhibitors; D014468:Umbelliferones; C031477:7-hydroxycoumarin; D010727:Phosphoric Diester Hydrolases; C498508:TDP1 protein, human
keywords: Coumarin; Molecular modeling; Monoterpene; Tyrosyl-DNA Phosphodiesterase I inhibitor