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.

Poly(ADP-Ribose)—A Unique Natural Polymer Structural Features, Biological Role and Approaches to the Chemical Synthesis

“…Disaccharide nucleosides seem to be advantageous class of PARP-1 inhibitors due to their cell penetrability and low cytotoxicity. [37] It has been shown, that many of PARP-1 inhibitors, even the drugs for clinical trials, possess cross-binding affinity to more than one member of PARP family, thus demonstrating polypharmacology in PARP-inhibition. [29] To better understand the results of biochemical and clinical studies and also to avoid the risks, associated with broad-range PARP-inhibition, novel selective PARP inhibitors are required.…”

Poly(ADP-ribose): From chemical synthesis to drug design

“…50,53 Natural nucleosides and nucleotides show low biological activity towards PARP-1, but disaccharide nucleosides seem to be an advantageous class of PARP-1 inhibitors due to their cell penetrability and low cytotoxicity. 55 Inhibition of PARG may be essential for studying the poly(ADPribose) dynamics and metabolism. Among known PARG inhibitors are poly(etheno-ADP-ribose) 56 , pargamicin, adenosine diphosphate hydroxymethylpyrrolidinediol (APD-HPD) and its derivatives, tannins, oxofluorenyl derivatives and some others.…”

Design, Synthesis and Molecular Modeling Study of Conjugates of ADP and Morpholino Nucleosides as A Novel Class of Inhibitors of PARP-1, PARP-2 and PARP-3

“…Natural and modified nucleosides and their phosphorylated derivatives are indispensable tools in searching new anticancer, antiviral and antibacterial drugs [26,27]. However, a small number of studies on nucleoside derivatives as PARPi have been reported in the literature, although some of them exhibit moderate PARP-1 inhibition activity [28]. It has been shown that some thymidine derivatives modified at the 5-and/or 5 -position inhibited PARP-1 more efficiently than 3-aminobenzamide, which is the first generation of the PARP-1 inhibitors and the closest structural analog of nicotinamide [29].…”