title: 1-substituted (Dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-ones endowed with dual DNA-PK/PI3-K inhibitory activity.
abstract: Analogues of (dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (NU7441), a potent inhibitor of DNA-dependent protein kinase (DNA-PK; IC50 = 42 ± 2 nM), have been synthesized in which water-solubilizing groups [NHCO(CH₂)nNR¹R², where n = 1 or 2 and the moiety R¹R²N was derived from a library of primary and secondary amines, e.g., morpholine] were placed at the 1-position. Several of the newly synthesized compounds exhibited high potency against DNA-PK and potentiated the cytotoxicity of ionizing radiation (IR) in vitro 10-fold or more (e.g., 2-(4-ethylpiperazin-1-yl)-N-(4-(2-morpholino-4-oxo-4H-chromen-8-yl)dibenzo[b,d]thio-phen-1-yl)acetamide, 39; DNA-PK IC₅₀ = 5.0 ± 1 nM, IR dose modification ratio = 13). Furthermore, 39 was shown to potentiate not only IR in vitro but also DNA-inducing cytotoxic anticancer agents, both in vitro and in vivo. Counter-screening against other members of the phosphatidylinositol 3-kinase (PI-3K) related kinase (PIKK) family unexpectedly revealed that some of the compounds were potent mixed DNA-PK and PI-3K inhibitors.
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Newcastle University, Newcastle upon Tyne, NE1 7RU, United Kingdom. celine.cano@ncl.ac.uk
authors.forename: Céline
authors.initials: C
authors.lastname: Cano
authors.forename: Kappusamy
authors.initials: K
authors.lastname: Saravanan
authors.forename: Chris
authors.initials: C
authors.lastname: Bailey
authors.forename: Julia
authors.initials: J
authors.lastname: Bardos
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Curtin
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: 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: K
authors.initials: K
authors.lastname: Shea
authors.forename: Graeme C M
authors.initials: GC
authors.lastname: Smith
authors.forename: Pia
authors.initials: P
authors.lastname: Thommes
authors.forename: Attilla
authors.initials: A
authors.lastname: Ting
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Griffin
mesh_terms: D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors*; D006367:HeLa Cells; D006801:Humans; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*
chemical_list: D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051747:DNA-Activated Protein Kinase