Disaccharide Pyrimidine Nucleosides and Their Derivatives: A Novel Group of Cell-Penetrating Inhibitors of Poly(ADP-Ribose) Polymerase 1

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.

Keywords:

• Disaccharide pyrimidine nucleosides
• poly(ADP-ribose) polymerase 1 inhibitors
• DNA repair
• cytotoxicity
• SKOV-3 human ovarian carcinoma cell line

Acknowledgments

This work was supported by the Program “Molecular and Cell Biology” of the Russian Academy of Sciences and by the Russian Foundation for Basic Research (grant nos. 10-04-01770, 11-04-12099, 11-04-01434, and 12-04-92601). The authors gratefully acknowledge the assistance of Artem A. Tikhomirov, PhD, in preparing the article.