Quinone-carbohydrate nonglucoside conjugates as a new type of cytotoxic agents: synthesis and determination of in vitro activity

Eur J Med Chem. 2014 Apr 22:77:139-44. doi: 10.1016/j.ejmech.2014.03.006.

Dmitry N Pelageev ¹, Sergey A Dyshlovoy ², Nataly D Pokhilo ³, Vladimir A Denisenko ³, Ksenia L Borisova ³, Gunhild Keller-von Amsberg ⁴, Carsten Bokemeyer ⁴, Sergey N Fedorov ³, Friedemann Honecker ⁵, Victor Ph Anufriev ⁶

Affiliations

1 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.
2 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.
3 G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Russian Academy of Sciences, 690022 Vladivostok, Prospect 100 let Vladivostoku 159, Russia.
4 Department of Oncology, Haematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumorzentrum, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Martinistrasse 52, Germany.
5 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.
6 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.

PMID: 24631733 DOI: 10.1016/j.ejmech.2014.03.006

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.

Keywords

5(8)-Hydroxy-2-methoxynaphthalene-1,4-dione; 5,8-Dihydroxy-2-methoxynaphthalene-1,4-dione; Apoptosis; Cytotoxicity; Methyl-α-D-glucopyranoside.

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