title: Antioxidant and antitumor activity of trolox, trolox succinate, and α-tocopheryl succinate conjugates with nitroxides.
abstract: A possible ability of twelve new derivatives of known antioxidants trolox (TroH), trolox succinate (TroS), α-tocopheryl succinate (α-TOS) containing nitroxyl radicals (1-12) to protect bacterial cells from spontaneous and peroxide-induced mutagenesis and their cytotoxicity against six different tumor cells as well as two normal cells were investigated and compared with that for TroH, TroS, α-TOH, and α-TOS for the first time. In contrast to TroH and TroS, all nitroxide derivatives 1-12 demonstrated not only antioxidant properties, but also suppress the growth of human tumor cells: myeloma, mammary adenocarcinoma, hepatocarcinoma, T cells leukemia, histiocytic lymphoma, and T-cellular leucosis. The IC50 values (24 - ≥ 300 μM) depend significantly on the compounds and type of tumor cells. Some compounds were capable to inhibit the growth of normal mouse (LMTK) and hamster (AG17) fibroblast cells and demonstrate very different ratios in inhibition of various tumor and normal cell lines. Some nitroxide conjugates showed pronounced selectivity in suppressing the growth of several cancer cells. Overall, several compounds may be promising in parallel as antioxidants and as specific inhibitors of some tumor cells growth. Among considered spin labeled conjugates the most perspective derivatives as antioxidants and as antitumor agents are the compounds containing pyrrolidine nitroxides. In contrast to spin labeled TroH, TroS and α-TOS conjugates 1-12 succinyl derivatives 13-15 were inactive in inhibiting the growth of any tumor cells. It means that for suppressing the cancer cells the compounds should contain in their structures fragments of TroH, TroS or α-TOS.
authors.affiliation: Institute of Chemical Biology and Fundamental Medicine, Siberian Division of Russian Academy of Sciences, 8 Lavrentiev Ave., 630090 Novosibirsk, Russia.
authors.forename: Ol'ga D
authors.initials: OD
authors.lastname: Zakharova
authors.affiliation: N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Division of Russian Academy of Sciences, 9 Lavrentiev Ave., 630090 Novosibirsk, Russia; Novosibirsk State University, 2 Pirogova St., 630090 Novosibirsk, Russia; Institute of Cytology and Genetics, Siberian Division of Russian Academy of Sciences, 10 Lavrentiev Ave., 630090 Novosibirsk, Russia.
authors.forename: Tat'yana S
authors.initials: TS
authors.lastname: Frolova
authors.affiliation: N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Division of Russian Academy of Sciences, 9 Lavrentiev Ave., 630090 Novosibirsk, Russia.
authors.forename: Yuliya V
authors.initials: YV
authors.lastname: Yushkova
authors.affiliation: N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Division of Russian Academy of Sciences, 9 Lavrentiev Ave., 630090 Novosibirsk, Russia. Electronic address: chernyak@nioch.nsc.ru.
authors.forename: Elena I
authors.initials: EI
authors.lastname: Chernyak
authors.affiliation: Novosibirsk State University, 2 Pirogova St., 630090 Novosibirsk, Russia.
authors.forename: Andrei G
authors.initials: AG
authors.lastname: Pokrovsky
authors.affiliation: Novosibirsk State University, 2 Pirogova St., 630090 Novosibirsk, Russia.
authors.forename: Mikhail A
authors.initials: MA
authors.lastname: Pokrovsky
authors.affiliation: N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Division of Russian Academy of Sciences, 9 Lavrentiev Ave., 630090 Novosibirsk, Russia; Novosibirsk State University, 2 Pirogova St., 630090 Novosibirsk, Russia.
authors.forename: Sergei V
authors.initials: SV
authors.lastname: Morozov
authors.affiliation: Institute of Cytology and Genetics, Siberian Division of Russian Academy of Sciences, 10 Lavrentiev Ave., 630090 Novosibirsk, Russia.
authors.forename: Ol'ga I
authors.initials: OI
authors.lastname: Sinitsina
authors.affiliation: N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Division of Russian Academy of Sciences, 9 Lavrentiev Ave., 630090 Novosibirsk, Russia; Academician E.N. Meshalkin State Research Institute of Circulation Pathology, 15, Rechkunovskaya St., 630055, Novosibirsk, Russia. Electronic address: grig@nioch.nsc.ru.
authors.forename: Igor A
authors.initials: IA
authors.lastname: Grigor'ev
authors.affiliation: Institute of Chemical Biology and Fundamental Medicine, Siberian Division of Russian Academy of Sciences, 8 Lavrentiev Ave., 630090 Novosibirsk, Russia; Novosibirsk State University, 2 Pirogova St., 630090 Novosibirsk, Russia. Electronic address: nevinsky@niboch.nsc.ru.
authors.forename: Georgy A
authors.initials: GA
authors.lastname: Nevinsky
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002839:Chromans / Q000737:chemistry* / Q000494:pharmacology*; D006224:Cricetinae; D006801:Humans; D051379:Mice; D009589:Nitrogen Oxides / Q000737:chemistry*; D019802:Succinic Acid / Q000737:chemistry*; D024502:alpha-Tocopherol / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D002839:Chromans; D009589:Nitrogen Oxides; D019802:Succinic Acid; C039900:nitroxyl; D024502:alpha-Tocopherol; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid
keywords: Antioxidants; Antitumor activity; Nitroxides; Trolox; α-tocopheryl succinate