title: DNA-dependent protein kinase (DNA-PK) inhibitors. Synthesis and biological activity of quinolin-4-one and pyridopyrimidin-4-one surrogates for the chromen-4-one chemotype.
abstract: Following the discovery of dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (NU7441) ( Leahy , J. J. J. ; Golding , B. T. ; Griffin , R. J. ; Hardcastle , I. R. ; Richardson , C. ; Rigoreau , L. ; Smith , G. C. M. Bioorg. Med. Chem. Lett. 2004 , 14 , 6083 - 6087) as a potent inhibitor (IC₅₀ = 30 nM) of DNA-dependent protein kinase (DNA-PK), we have investigated analogues in which the chromen-4-one core template has been replaced by aza-heterocyclic systems: 9-substituted 2-morpholin-4-ylpyrido[1,2-a]pyrimidin-4-ones and 8-substituted 2-morpholin-4-yl-1H-quinolin-4-ones. The 8- and 9-substituents were either dibenzothiophen-4-yl or dibenzofuran-4-yl, which were each further substituted at the 1-position with water-solubilizing groups [NHCO(CH₂)(n)NR¹R², where n = 1 or 2 and the moiety R¹R²N was derived from a library of primary and secondary amines (e.g., morpholine)]. The inhibitors were synthesized by employing a multiple-parallel approach in which the two heterocyclic components were assembled by Suzuki-Miyaura cross-coupling. Potent DNA-PK inhibitory activity was generally observed across the compound series, with structure-activity studies indicating that optimal potency resided in pyridopyrimidin-4-ones bearing a substituted dibenzothiophen-4-yl group. Several of the newly synthesized compounds (e.g., 2-morpholin-4-yl-N-[4-(2-morpholin-4-yl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)dibenzothiophen-1-yl]acetamide) combined high potency against the target enzyme (DNA-PK IC₅₀ = 8 nM) with promising activity as potentiators of ionizing radiation-induced cytotoxicity in vitro.
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne, UK. celine.cano@ncl.ac.uk
authors.forename: Céline
authors.initials: C
authors.lastname: Cano
authors.forename: Olivier R
authors.initials: OR
authors.lastname: Barbeau
authors.forename: Christine
authors.initials: C
authors.lastname: Bailey
authors.forename: Xiao-Ling
authors.initials: XL
authors.lastname: Cockcroft
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Curtin
authors.forename: Heather
authors.initials: H
authors.lastname: Duggan
authors.forename: Mark
authors.initials: M
authors.lastname: Frigerio
authors.forename: Bernard T
authors.initials: BT
authors.lastname: Golding
authors.forename: Ian R
authors.initials: IR
authors.lastname: Hardcastle
authors.forename: Marc G
authors.initials: MG
authors.lastname: Hummersone
authors.forename: Charlotte
authors.initials: C
authors.lastname: Knights
authors.forename: Keith A
authors.initials: KA
authors.lastname: Menear
authors.forename: David R
authors.initials: DR
authors.lastname: Newell
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Richardson
authors.forename: Graeme C M
authors.initials: GC
authors.lastname: Smith
authors.forename: Ben
authors.initials: B
authors.lastname: Spittle
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Griffin
mesh_terms: D001578:Benzopyrans / Q000737:chemistry*; D002463:Cell Membrane Permeability; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors*; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D001578:Benzopyrans; D005663:Furans; D011725:Pyridines; D011744:Pyrimidinones; D015363:Quinolones; D054852:Small Molecule Libraries; D013876:Thiophenes; D051747:DNA-Activated Protein Kinase