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

TY - JOUR

T1 - Quinone-carbohydrate nonglucoside conjugates as a new type of cytotoxic agents: synthesis and determination of in vitro activity

AU - Pelageev, Dmitry

AU - Dyshlovoy, Sergey A

AU - Pokhilo, Nataly D

AU - Denisenko, Vladimir A

AU - Borisova, Ksenia L

AU - Amsberg, Gunhild

AU - Bokemeyer, Carsten

AU - Fedorov, Sergey N

AU - Honecker, Friedemann Ulrich

AU - Anufriev, Victor Ph

N1 - Copyright © 2014 Elsevier Masson SAS. All rights reserved.

PY - 2014/4/22

Y1 - 2014/4/22

N2 - 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.

AB - 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.

U2 - 10.1016/j.ejmech.2014.03.006

DO - 10.1016/j.ejmech.2014.03.006

M3 - SCORING: Journal article

C2 - 24631733

VL - 77

SP - 139

EP - 144

JO - EUR J MED CHEM

JF - EUR J MED CHEM

SN - 0223-5234

ER -