title: Quinone-carbohydrate nonglucoside conjugates as a new type of cytotoxic agents: synthesis and determination of in vitro activity.
abstract: We have found that 2-methoxy-1,4-naphthoquinones easily react with primary alcohols to produce the corresponding 2-alkoxyderivatives. Using this reaction, we synthesized methyl-6-O-(naphthalene-1,4-dione-2-yl)-α-D-glucopyranosides, a new type of water soluble quinone-carbohydrate nonglucoside conjugates. The resulting conjugates induced apoptosis in human cancer HeLa and normal mouse JB6 P(+) Cl41 cells with simultaneous inhibition of p53-dependant transcriptional activity, suggesting that the observed cell death was p53-independent. Furthermore, we analyzed structure-activity relationship and bioactivity of 2-hydroxy- and 2-methoxy-1,4-naphthoquinones as well as carbohydrate nonglucoside conjugates. All compounds containing a quinone moiety were able to inhibit p53-dependant transcriptional activity and exerted moderate inhibitory effects on HeLa cell colony formation. Investigations of structure-activity relationships revealed that cytotoxicity depended on the type of substituent at C-2 of the quinone moiety, decreasing in the following order: methoxyderivatives > carbohydrate nonglucoside conjugates > hydroxyderivatives. Furthermore, cytotoxicity depended on the position of the hydroxy substituent in the quinone moiety in all derivatives and decreased in the following order: 8- > 5- > 5,8-derivatives. In conclusion, this is the first report on synthesis and biological structure-activity relationships of the new class of quinone-carbohydrate nonglucoside conjugates.
authors.affiliation: G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Russian Academy of Sciences, 690022 Vladivostok, Prospect 100 let Vladivostoku 159, Russia; School of Natural Sciences, Far East Federal University, 690950 Vladivostok, Sukhanova St. 8, Russia.
authors.forename: Dmitry N
authors.initials: DN
authors.lastname: Pelageev
authors.affiliation: G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Russian Academy of Sciences, 690022 Vladivostok, Prospect 100 let Vladivostoku 159, Russia; School of Natural Sciences, Far East Federal University, 690950 Vladivostok, Sukhanova St. 8, Russia; Department of Oncology, Haematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumorzentrum, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Martinistrasse 52, Germany.
authors.forename: Sergey A
authors.initials: SA
authors.lastname: Dyshlovoy
authors.affiliation: G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Russian Academy of Sciences, 690022 Vladivostok, Prospect 100 let Vladivostoku 159, Russia.
authors.forename: Nataly D
authors.initials: ND
authors.lastname: Pokhilo
authors.affiliation: G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Russian Academy of Sciences, 690022 Vladivostok, Prospect 100 let Vladivostoku 159, Russia.
authors.forename: Vladimir A
authors.initials: VA
authors.lastname: Denisenko
authors.affiliation: G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Russian Academy of Sciences, 690022 Vladivostok, Prospect 100 let Vladivostoku 159, Russia.
authors.forename: Ksenia L
authors.initials: KL
authors.lastname: Borisova
authors.affiliation: Department of Oncology, Haematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumorzentrum, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Martinistrasse 52, Germany.
authors.forename: Gunhild
authors.initials: G
authors.lastname: Keller-von Amsberg
authors.affiliation: Department of Oncology, Haematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumorzentrum, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Martinistrasse 52, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Bokemeyer
authors.affiliation: G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Russian Academy of Sciences, 690022 Vladivostok, Prospect 100 let Vladivostoku 159, Russia.
authors.forename: Sergey N
authors.initials: SN
authors.lastname: Fedorov
authors.affiliation: Department of Oncology, Haematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumorzentrum, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Martinistrasse 52, Germany; Tumor and Breast Center ZeTuP, 9006 St. Gallen, Rorschacher Strasse 150, Switzerland.
authors.forename: Friedemann
authors.initials: F
authors.lastname: Honecker
authors.affiliation: G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Russian Academy of Sciences, 690022 Vladivostok, Prospect 100 let Vladivostoku 159, Russia. Electronic address: anufriev@piboc.dvo.ru.
authors.forename: Victor Ph
authors.initials: VP
authors.lastname: Anufriev
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D002241:Carbohydrates / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005960:Glucosides / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D002241:Carbohydrates; D005960:Glucosides; C004532:quinone
keywords: 5(8)-Hydroxy-2-methoxynaphthalene-1,4-dione; 5,8-Dihydroxy-2-methoxynaphthalene-1,4-dione; Apoptosis; Cytotoxicity; Methyl-α-D-glucopyranoside