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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Line, Tumor / drug effects
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Disaccharides / chemical synthesis*
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Disaccharides / chemistry
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Disaccharides / pharmacology
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Humans
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Hydrogen Peroxide / metabolism
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Poly (ADP-Ribose) Polymerase-1
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Poly(ADP-ribose) Polymerase Inhibitors*
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Poly(ADP-ribose) Polymerases / metabolism
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Pyrimidine Nucleosides / chemical synthesis*
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Pyrimidine Nucleosides / chemistry
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Pyrimidine Nucleosides / pharmacology
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Structure-Activity Relationship
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Thymidine / analogs & derivatives
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Thymidine / chemical synthesis*
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Thymidine / chemistry
Substances
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Disaccharides
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Enzyme Inhibitors
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Poly(ADP-ribose) Polymerase Inhibitors
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Pyrimidine Nucleosides
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Hydrogen Peroxide
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PARP1 protein, human
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Poly (ADP-Ribose) Polymerase-1
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Poly(ADP-ribose) Polymerases
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Thymidine