Structure-based design, synthesis and evaluation in vitro of arylnaphthyridinones, arylpyridopyrimidinones and their tetrahydro derivatives as inhibitors of the tankyrases. Issue 13 (1st July 2015)

• Record Type: Journal Article
• Authors: Kumpan, Katerina; Nathubhai, Amit; Zhang, Chenlu; Wood, Pauline J.; Lloyd, Matthew D.; Thompson, Andrew S.; Haikarainen, Teemu; Lehtiö, Lari; Threadgill, Michael D.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 13(2015)
• Page Start: 3013
• Page End: 3032
• Publication Date: 2015-07-01
• Subjects: Tankyrase -- TNKS -- Naphthyridinone -- 7-Aryl-1-methyl-1, 2, 3, 4-tetrahydro-1, 6-naphthyridin-5-one -- Crystal structure; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.05.005
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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 = 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.