2,6-Disubstituted pyran-4-one and thiopyran-4-one inhibitors of DNA-Dependent protein kinase (DNA-PK)

• Published in: Bioorganic & medicinal chemistry letters 2003-09, Vol.13 (18), p.3083-3086
• Main Authors: Hollick, Jonathan J., Golding, Bernard T., Hardcastle, Ian R., Martin, Niall, Richardson, Caroline, Rigoreau, Laurent J.M., Smith, Graeme C.M., Griffin, Roger J.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Chromones - pharmacology; DNA-Activated Protein Kinase; DNA-Binding Proteins; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Humans; Inhibitory Concentration 50; Morpholines - pharmacology; Nuclear Proteins; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Pyrones - chemical synthesis; Pyrones - pharmacology; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(03)00652-8

6-Aryl-2-morpholin-4-yl-4 H-pyran-4-ones and 6-aryl-2-morpholin-4-yl-4 H-thiopyran-4-ones were synthesised and evaluated as potential inhibitors of the DNA repair enzyme DNA-dependent protein kinase (DNA-PK). Several compounds in each series exhibited superior activity to the chromenone LY294002, and were of comparable potency to the benzochromenone NU7026 (IC 50=0.23 μM). Importantly, members of both structural classes were found to be selective inhibitors of DNA-PK over related phosphatidylinositol 3-kinase-related kinase (PIKK) family members. A multiple-parallel synthesis approach, employing Suzuki cross-coupling methodology, was utilised to prepare libraries of thiopyran-4-ones with a range of aromatic groups at the 3′- and 4′-positions on the thiopyran-4-one 6-aryl ring. Screening of the libraries resulted in the identification of 6-aryl-2-morpholin-4-yl-4 H-thiopyran-4-ones bearing naphthyl or benzo[ b]thienyl substituents at the 4′-position, as potent DNA-PK inhibitors with IC 50 values in the 0.2–0.4 μM range. 6-Aryl-2-morpholin-4-yl-4 H-pyran-4-ones and 6-aryl-2-morpholin-4-yl-4 H-thiopyran-4-ones were synthesised and evaluated as potential inhibitors of the DNA repair enzyme DNA-dependent protein kinase (DNA-PK). Several compounds in each series exhibited superior activity to the chromenone LY294002, and were of comparable potency to the benzochromenone NU7026 (IC 50=0.23 μM). Importantly, members of both structural classes were found to be selective inhibitors of DNA-PK over related phosphatidylinositol 3-kinase-related kinase (PIKK) family members. A multiple-parallel synthesis approach, employing Suzuki cross-coupling methodology, was utilized to prepare libraries of thiopyran-4-ones with a range of aromatic groups at the 3′- and 4′-positions on the thiopyran-4-one 6-aryl ring. Screening of the libraries resulted in the identification of 6-aryl-2-morpholin-4-yl-4 H-thiopyran-4-ones bearing naphthyl or benzo[ b]thienyl substituents at the 4′-position, as potent DNA-PK inhibitors with IC 50 values in the 0.2–0.4 μM range.