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

•2-methoxy-1,4-naphthoquinones easy interact only with primary alcohols.•The synthesis of three quinone–carbohydrate nonglucoside conjugates is described.•The synthesized conjugates exhibit cytotoxic activity.•The structure–activity relationships of the conjugates are investigated.•The compounds investigated are able to inhibit the transcriptional activity of p53.

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.

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