Structure-based design, synthesis and evaluation in vitro of arylnaphthyridinones, arylpyridopyrimidinones and their tetrahydro derivatives as inhibitors of the tankyrases

Bioorg Med Chem. 2015 Jul 1;23(13):3013-32. doi: 10.1016/j.bmc.2015.05.005. Epub 2015 May 13.

Abstract

The tankyrases are members of the PARP superfamily; they poly(ADP-ribosyl)ate their target proteins using NAD(+) as a source of electrophilic ADP-ribosyl units. The three principal protein substrates of the tankyrases (TRF1, NuMA and axin) are involved in replication of cancer cells; thus inhibitors of the tankyrases may have anticancer activity. Using structure-based drug design and by analogy with known 3-arylisoquinolin-1-one and 2-arylquinazolin-4-one inhibitors, series of arylnaphthyridinones, arylpyridinopyrimidinones and their tetrahydro-derivatives were synthesised and evaluated in vitro. 7-Aryl-1,6-naphthyridin-5-ones, 3-aryl-2,6-naphthyridin-1-ones and 3-aryl-2,7-naphthyridin-1-ones were prepared by acid-catalysed cyclisation of the corresponding arylethynylpyridinenitriles or reaction of bromopyridinecarboxylic acids with β-diketones, followed by treatment with NH3. The 7-aryl-1,6-naphthyridin-5-ones were methylated at 1-N and reduced to 7-aryl-1-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-5-ones. Cu-catalysed reaction of benzamidines with bromopyridinecarboxylic acids furnished 2-arylpyrido[2,3-d]pyrimidin-4-ones. Condensation of benzamidines with methyl 1-benzyl-4-oxopiperidine-3-carboxylate and deprotection gave 2-aryl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ones, aza analogues of the known inhibitor XAV939. Introduction of the ring-N in the arylnaphthyridinones and the arylpyridopyrimidinones caused >1000-fold loss in activity, compared with their carbocyclic isoquinolinone and quinazolinone analogues. However, the 7-aryl-1-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-5-ones showed excellent inhibition of the tankyrases, with some examples having IC50=2nM. One compound (7-(4-bromophenyl)-1-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-5-one) showed 70-fold selectivity for inhibition of tankyrase-2 versus tankyrase-1. The mode of binding was explored through crystal structures of inhibitors in complex with tankyrase-2.

Keywords: 7-Aryl-1-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-5-one; Crystal structure; Naphthyridinone; TNKS; Tankyrase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ammonia / chemistry
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Aza Compounds / chemistry
  • Benzamidines / chemistry
  • Carboxylic Acids / chemistry
  • Crystallography, X-Ray
  • Cyclization
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Heterocyclic Compounds, 3-Ring / chemistry
  • Humans
  • Ketones / chemistry
  • Molecular Docking Simulation
  • Naphthyridines / chemical synthesis*
  • Naphthyridines / chemistry
  • Nitriles / chemistry
  • Pyrimidinones / chemical synthesis*
  • Pyrimidinones / chemistry
  • Structure-Activity Relationship
  • Tankyrases / antagonists & inhibitors*
  • Tankyrases / chemistry

Substances

  • Antineoplastic Agents
  • Aza Compounds
  • Benzamidines
  • Carboxylic Acids
  • Enzyme Inhibitors
  • Heterocyclic Compounds, 3-Ring
  • Ketones
  • Naphthyridines
  • Nitriles
  • Pyrimidinones
  • XAV939
  • Ammonia
  • TNKS2 protein, human
  • Tankyrases
  • TNKS protein, human