ABSTRACT
Poly(ADP-ribose) polymerase-1 (PARP-1) is an important target in cancer therapy. We present the synthesis of novel disaccharide nucleoside analogues that resemble the central motif of poly(ADP-ribose) and test their inhibitory effects on human PARP-1. Some compounds show inhibition of enzymatic activity in vitro and thus might be interesting for further investigations.
Subject(s)
Poly (ADP-Ribose) Polymerase-1/antagonists & inhibitors , Poly Adenosine Diphosphate Ribose/analogs & derivatives , Poly Adenosine Diphosphate Ribose/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors/chemistry , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Chemistry Techniques, Synthetic , Disaccharides/chemical synthesis , Disaccharides/chemistry , Disaccharides/pharmacology , Drug Discovery , Humans , Poly (ADP-Ribose) Polymerase-1/metabolism , Poly Adenosine Diphosphate Ribose/chemical synthesis , Poly Adenosine Diphosphate Ribose/chemistry , Poly(ADP-ribose) Polymerase Inhibitors/chemical synthesisABSTRACT
Poly-adenosine diphosphate ribose (PAR) is a branched biopolymer that occurs as a result of post-translational modification of proteins. In 1981 Miwa et al. determined the structure of enzymatically prepared branched PAR. We present the first synthesis of the same branched PAR fragment and have shown by NMR that the structure proposed by Miwa is correct.
Subject(s)
Poly Adenosine Diphosphate Ribose/chemistry , Carbohydrate Conformation , Poly Adenosine Diphosphate Ribose/analogs & derivativesABSTRACT
Poly(ADP-ribose) is a biopolymer synthesized by poly(ADP-ribose) polymerases. Recent findings suggest the possibility for modulation of cellular functions including cell death and mitosis by poly(ADP-ribose). Derivatization of poly(ADP-ribose) may be useful for investigating the effects of poly(ADP-ribose) on various cellular processes. We prepared poly(etheno ADP-ribose) (poly(epsilonADP-ribose)) by converting the adenine moiety of poly(ADP-ribose) to 1-N(6)-etheno adenine residues. Poly(epsilonADP-ribose) is shown to be highly resistant to digestion by poly(ADP-ribose) glycohydrolase (Parg). On the other hand, poly(epsilonADP-ribose) could be readily digested by phosphodiesterase. Furthermore, poly(epsilonADP-ribose) inhibited Parg activity to hydrolyse ribose-ribose bonds of poly(ADP-ribose). This study suggests the possibility that poly(epsilonADP-ribose) might be a useful tool for studying the poly(ADP-ribose) dynamics and function of Parg. This study also implies that modification of the adenine moiety of poly(ADP-ribose) abrogates the susceptibility to digestion by Parg.
