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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