A versatile strategy for the design and synthesis of novel ADP conjugates and their evaluation as potential poly(ADP-ribose) polymerase 1 inhibitors

Mol Divers. 2017 Feb;21(1):101-113. doi: 10.1007/s11030-016-9703-x. Epub 2016 Sep 27.

Abstract

A versatile strategy for the synthesis of [Formula: see text] mimetics was developed, involving an efficient pyrophosphate linkage formation in key conjugates containing a functional amino group which acts as useful reactive anchor for further derivatization. These [Formula: see text] mimetics consist of ADP conjugated through a diphosphate chain to an extended aliphatic linker bearing an aromatic acid residue. A number of conjugates containing aromatic carboxylic acids were found to inhibit poly(ADP-ribose) synthesis catalyzed by poly(ADP-ribose) polymerase-1 (PARP-1). A new class of potential PARP-1 inhibitors mimicking [Formula: see text], a substrate in the PARP-1 catalyzed reaction, was proposed.

Keywords: PARP inhibitors; PARP-1; Pyrophosphate synthesis; analogues.

MeSH terms

  • Adenosine Diphosphate / chemistry*
  • Biomimetic Materials / chemical synthesis*
  • Biomimetic Materials / chemistry
  • Biomimetic Materials / pharmacology*
  • Chemistry Techniques, Synthetic
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • NAD / chemistry
  • Poly (ADP-Ribose) Polymerase-1 / antagonists & inhibitors*

Substances

  • Enzyme Inhibitors
  • NAD
  • Adenosine Diphosphate
  • Poly (ADP-Ribose) Polymerase-1