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

作者：Pelageev Dmitry N; Dyshlovoy Sergey A; Pokhilo Nataly D; Denisenko Vladimir A; Borisova Ksenia L; Keller von Am**erg Gunhild; Bokemeyer Carsten; Fedorov Sergey N; Honecker Friedemann; Anufriev Victor Ph^*

来源：European Journal of Medicinal Chemistry, 2014, 77(2): 139-144.

DOI：10.1016/j.ejmech.2014.03.006

• 5(8)-Hydroxy-2-methoxynaphthalene-1,4-dione
• 5,8-Dihydroxy-2-methoxynaphthalene-1,4-dione
• Methyl-alpha-D-glucopyranoside
• Cytotoxicity
• Apoptosis

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)-alpha-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.

• 出版日期2014-4