title: Discovery of potent chromen-4-one inhibitors of the DNA-dependent protein kinase (DNA-PK) using a small-molecule library approach.
abstract: Structure-activity relationships for inhibition of DNA-dependent protein kinase (DNA-PK) have been defined for substituted chromen-4-ones. For the 2-amino-substituted benzo[h]chromen-4-ones, a morpholine substituent at this position was essential for activity. Small libraries of 6- and 7-alkoxy-substituted chromen-4-ones showed that a number of 7-alkoxy-substituted chromenones displayed improved activity. Focused libraries incorporating 6-, 7-, and 8-aryl and heteroaryl substituents were prepared. In these cases, 6- and 7-substitution was disfavored, whereas 8-substitution was largely tolerated. Surprisingly, two compounds, 2-N-morpholino-8-dibenzofuranyl-chromen-4-one (NU7427, 32{38}) and the 2-N-morpholino-8-dibenzothiophenyl-chromen-4-one (NU7441, 32{26}) were excellent inhibitors (IC50 vs DNA-PK = 40 and 13 nM, respectively). The ring-saturated analogue 2-N-morpholino-8-(6',7',8',9'-tetrahydrodibenzothiophene)chromen-4-one, 36, retained potent activity (IC50 vs DNA-PK = 23 nM). The dibenzothiophene 32{38} sensitized HeLa cells to ionizing radiation in vitro, with dose modification factors of 2.5 at 10% survival being observed at 0.5 microM. The cytotoxicity of the topoisomerase II inhibitor etoposide was also potentiated.
authors.affiliation: Northern Institute for Cancer Research, School of Natural Sciences--Chemistry, Bedson Building, Newcastle upon Tyne NE1 7RU, UK. I.R.Hardcastle@ncl.ac.uk
authors.forename: Ian R
authors.initials: IR
authors.lastname: Hardcastle
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Cockcroft
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Curtin
authors.forename: Marine Desage
authors.initials: MD
authors.lastname: El-Murr
authors.forename: Justin J J
authors.initials: JJ
authors.lastname: Leahy
authors.forename: Martin
authors.initials: M
authors.lastname: Stockley
authors.forename: Bernard T
authors.initials: BT
authors.lastname: Golding
authors.forename: Laurent
authors.initials: L
authors.lastname: Rigoreau
authors.forename: Caroline
authors.initials: C
authors.lastname: Richardson
authors.forename: Graeme C M
authors.initials: GC
authors.lastname: Smith
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Griffin
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002867:Chromones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020650:Combinatorial Chemistry Techniques; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004357:Drug Synergism; D005047:Etoposide / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D009025:Morpholines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C507724:2-N-morpholino-8-dibenzofuranylchromen-4-one; C499693:8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one; D000970:Antineoplastic Agents; D001578:Benzopyrans; D002867:Chromones; D009025:Morpholines; D011838:Radiation-Sensitizing Agents; D013876:Thiophenes; D005047:Etoposide; D000255:Adenosine Triphosphate; D051747:DNA-Activated Protein Kinase