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

Lookup NU author(s): Jonathan Hollick, Professor Bernard Golding, Dr Ian Hardcastle, Dr Laurent Rigoreau, Professor Roger Griffin

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Abstract

6-Aryl-2-morpholin-4-yl-4H-pyran-4-ones and 6-aryl-2-morpholin-4-yl-4H-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 (IC50=0.23 muM). 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-4H-thiopyran-4-ones bearing naphthyl or benzo[b]thienyl substituents at the 4'-position, as potent DNA-PK inhibitors with IC50 values in the 0.2-0.4 muM range. (C) 2003 Elsevier Ltd. All rights reserved.


Publication metadata

Author(s): Hollick JJ, Golding BT, Hardcastle IR, Martin N, Richardson C, Rigoreau LJM, Smith GCM, Griffin RJ

Publication type: Article

Publication status: Published

Journal: Bioorganic & Medicinal Chemistry Letters

Year: 2003

Volume: 13

Issue: 18

Pages: 3083-3086

ISSN (print): 0960-894X

ISSN (electronic): 1464-3405

URL: http://dx.doi.org/10.1016/S0960-894X(03)00652-8

DOI: 10.1016/S0960-894X(03)00652-8

PubMed id: 12941339


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