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

Kumpan, K., Nathubhai, Amit, Zhang, C., Wood, P.J., Lloyd, M.D., Thompson, A.S., Haikarainen, T., Lehtiö, L. and Threadgill, M.D. (2015) Structure-based design, synthesis and evaluation in vitro of arylnaphthyridinones, arylpyridopyrimidinones and their tetrahydro derivatives as inhibitors of the tankyrases. Bioorganic & Medicinal Chemistry, 23. pp. 3013-3032. ISSN 0968-0896

Item Type: Article


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 b-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.

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Depositing User: Amit Nathubhai


Item ID: 9790
Identification Number:
ISSN: 0968-0896
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Catalogue record

Date Deposited: 10 Aug 2018 09:08
Last Modified: 18 Dec 2019 16:07


Author: K. Kumpan
Author: Amit Nathubhai
Author: C. Zhang
Author: P.J. Wood
Author: M.D. Lloyd
Author: A.S. Thompson
Author: T. Haikarainen
Author: L. Lehtiö
Author: M.D. Threadgill

University Divisions

Faculty of Health Sciences and Wellbeing
Faculty of Health Sciences and Wellbeing > School of Pharmacy and Pharmaceutical Sciences


Sciences > Chemistry

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