Potent enantioselective inhibition of DNA-dependent protein kinase (DNA-PK) by atropisomeric chromenone derivatives.
Substitution at the 7-position of the chromen-4-one pharmacophore 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 allyl, n-propyl or methyl enabled the resolution by chiral HPLC of atropisomers. Biological evaluation against DNA-PK of each pair of atropisomers showed a marked difference in potency, with biological activity residing exclusively in the laevorotatory enantiomer.
Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Newcastle University, Newcastle upon Tyne, UK.
Kate M
KM
Clapham
Tommy
T
Rennison
Gavin
G
Jones
Faye
F
Craven
Julia
J
Bardos
Bernard T
BT
Golding
Roger J
RJ
Griffin
Karen
K
Haggerty
Ian R
IR
Hardcastle
Pia
P
Thommes
Attilla
A
Ting
Céline
C
Cano
D000818:Animals; D001665:Binding Sites; D002867:Chromones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009025:Morpholines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013552:Swine
C499693:8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one; D002867:Chromones; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D051747:DNA-Activated Protein Kinase