351002-11-4Relevant articles and documents
SYNTHESIS OF 2-AMINO-SUBSTITUTED 4-OXO-4H-CHROMEN-8.YL-TRIFLUORO-METHANESULFONIC ACID ESTERS
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Page/Page column 33; 36, (2008/06/13)
A method of synthesising a compound of formula (I): wherein RN1 and RN2 are independently selected from hydrogen, an optionally substituted C1-7 alkyl group, C3-20 heterocyclyl group, or C5-20 aryl group, or may together form, along with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring having from 4 to 8 ring atoms; from a compound of formula (III): comprising the steps of: (a) removing the allyl group from the compound of formula (III) with appropriate reaction conditions to yield a compound of formula (II):; and (b) reacting the compound of formula (II) with a triflating agent to yield a compound of formula (I).
Discovery of potent chromen-4-one inhibitors of the DNA-dependent protein kinase (DNA-PK) using a small-molecule library approach
Hardcastle, Ian R.,Cockcroft, Xiaoling,Curtin, Nicola J.,El-Murr, Marine Desage,Leahy, Justin J. J.,Stockley, Martin,Golding, Bernard T.,Rigoreau, Laurent,Richardson, Caroline,Smith, Graeme C. M.,Griffin, Roger J.
, p. 7829 - 7846 (2007/10/03)
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 μM. The cytotoxicity of the topoisomerase II inhibitor etoposide was also potentiated.
Identification of a highly potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor (NU7441) by screening of chromenone libraries
Leahy, Justin J.J.,Golding, Bernard T.,Griffin, Roger J.,Hardcastle, Ian R.,Richardson, Caroline,Rigoreau, Laurent,Smith, Graeme C.M.
, p. 6083 - 6087 (2007/10/03)
A solution-phase multiple-parallel synthesis approach was employed for the preparation of 6-, 7- and 8-aryl-substituted chromenone libraries, which were screened as inhibitors of the DNA repair enzyme DNA-dependent protein kinase (DNA-PK). These studies r
