Atropisomeric 8-arylchromen-4-ones exhibit enantioselective inhibition of the DNA-dependent protein kinase (DNA-PK).
Substitution at the 3-position of the dibenzothiophen-4-yl ring of 8-(dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one NU7441, a potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor, with propyl, allyl or methyl enabled the separation by chiral HPLC of atropisomers. This is a consequence of restricted rotation about the dibenzothiophene-chromenone bond. Biological evaluation against DNA-PK of the pairs of atropisomers showed a marked difference in potency, with only one enantiomer being biologically active.
Cano
Céline
C
Northern Institute for Cancer Research, School of Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne, United KingdomNE1 7RU. celine.cano@ncl.ac.uk
Golding
Bernard T
BT
Haggerty
Karen
K
Hardcastle
Ian R
IR
Peacock
Marcus
M
Griffin
Roger J
RJ
D002851:Chromatography, High Pressure Liquid; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D007536:Isomerism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D047428:Protein Kinase Inhibitors; D013876:Thiophenes; D051747:DNA-Activated Protein Kinase; C016366:dibenzothiophene