Toggle Main Menu Toggle Search

Open Access padlockePrints

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

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


Full text for this publication is not currently held within this repository. Alternative links are provided below where available.


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


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

PubMed id: 12941339


Altmetrics provided by Altmetric