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

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