Disaccharide Pyrimidine Nucleosides and Their Derivatives: A Novel Group of Cell-Penetrating Inhibitors of Poly(ADP-Ribose) Polymerase 1 |
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| Authors: | Anna S Efremova Alexandra L Zakharenko Stanislav I Shram Irina V Kulikova Mikhail S Drenichev Maria V Sukhanova |
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| Institution: | 1. Institute of Molecular Genetics , Russian Academy of Sciences , Moscow , Russia;2. Institute of Chemical Biology and Fundamental Medicine , Siberian Branch of the Russian Academy of Sciences , Novosibirsk , Russia;3. Engelhardt Institute of Molecular Biology , Russian Academy of Sciences , Moscow , Russia |
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| Abstract: | Nearly 30 synthetic nucleosides were tested with human recombinant poly(ADP-ribose) polymerase 1 as potential inhibitors of this enzyme. The most active compounds were some disaccharide analogues of thymidine: 3′-O-β-D-ribofuranosyl-5-iodo-dUrd (2d; IC50 = 45 μM), 3′-O-β-D-ribofuranosyl-2′-deoxythymidine (2e; IC50 = 38 μM), and 3′-O-β-D-ribofuranosyl-2′-deoxythymidine oxidized (4; IC50 = 25 μM). These compounds also reduced H2O2-induced synthesis of poly(ADP-ribose) in cultured human ovarian carcinoma (SKOV-3) cells in a dose-dependent manner. Furthermore, compounds 2d or 2e until a concentration of 1 mM did not affect growth of SKOV-3 cells, whereas dialdehyde compound 4, as well as thymidine, exhibited a significant cytotoxicity. |
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| Keywords: | Disaccharide pyrimidine nucleosides poly(ADP-ribose) polymerase 1 inhibitors DNA repair cytotoxicity SKOV-3 human ovarian carcinoma cell line |
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