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

Katerina Kumpan, Amit Nathubhai, Chenlu Zhang, Pauline J Wood, Matthew D Lloyd, Andrew S Thompson, Teemu Haikarainen, Lari Lehtiö, Michael D Threadgill

Research output: Contribution to JournalArticlepeer-review


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 = 2 nM. 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.
Original languageEnglish
Pages (from-to)3013-3032
Number of pages20
JournalBioorganic and Medicinal Chemistry
Issue number13
Early online date12 May 2015
Publication statusPublished - 1 Jul 2015

Bibliographical note

Copyright © 2015 Elsevier Ltd. All rights reserved.


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


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