Identification of a highly potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor (NU7441) by screening of chromenone libraries

Bioorganic and Medicinal Chemistry Letters

Volumn 14, Issue 24, 2004, Pages 6083-6087

  Leahy, Justin J J ^a   Golding, Bernard T ^a   Griffin, Roger J ^a   Hardcastle, Ian R ^a   Richardson, Caroline ^b   Rigoreau, Laurent ^b   Smith, Graeme C M ^b  

^a NEWCASTLE UNIVERSITY   (United Kingdom)

^b KuDOS Pharmaceuticals Ltd   (United Kingdom)

Author keywords

Chromenones; DNA repair; DNA PK; Inhibitors

Indexed keywords

8 DIBENZOTHIOPHEN 4 YL 2 MORPHOLIN 4 YLCHROMEN 4 ONE; ADENOSINE TRIPHOSPHATE; DNA DEPENDENT PROTEIN KINASE; ENZYME INHIBITOR; NU 7441; NU7441; PROTEIN KINASE; UNCLASSIFIED DRUG;

ARTICLE; COMPETITIVE INHIBITION; DNA LIBRARY; DNA REPAIR; IC 50; INHIBITION KINETICS; SCREENING; STRUCTURE ACTIVITY RELATION; SUBSTITUTION REACTION; SYNTHESIS;

CHROMONES; DNA-ACTIVATED PROTEIN KINASE; DNA-BINDING PROTEINS; ENZYME INHIBITORS; MOLECULAR STRUCTURE; MORPHOLINES; PROTEIN-SERINE-THREONINE KINASES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 8844254050     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2004.09.060     Document Type: Article

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17. A general procedure for the MPS of aryl-substituted chromen-4-ones is as follows: a mixture of the bromochromenone (11) or chromenone triflate (19, 20) (20 mg, 0.053 mmol), the appropriate arylboronic acid (0.06 mmol), and powdered potassium carbonate (14.6 mg, 0.106 mmol) was purged with nitrogen, and dioxane (0.5 mL, degassed by sonication-purging with nitrogen) was added. A solution of tetrakis(triphenylphosphine)palladium(0) (3.1 mg) in degassed dioxane (0.3 mL) was added, and the mixture was stirred under nitrogen for 18 h at 90°C. The reaction mixture was cooled, and filtered through silica (isolute Si 0.5 g cartridge) eluting with DCM-MeOH (7:3 v/v, 8 mL). Confirmation of product formation and approximate purity was determined by LC-MS/UV analysis, and further purification was achieved by semi-preparative HPLC, furnishing the required chromenones in 10-30% yields
18. 50 values generated from these results. See Ref. 10 for full details of the assay
19. 1H NMR, IR, UV) and analytical (elemental analysis and LC-MS) data fully consistent with the assigned structure
20. Smith, G. C. M., et al., unpublished results