881375-00-4Relevant articles and documents
1-substituted (dibenzo[ b,d ]thiophen-4-yl)-2-morpholino-4 h -chromen-4-ones endowed with dual DNA-PK/PI3-K inhibitory activity
Cano, Céline,Saravanan, Kappusamy,Bailey, Chris,Bardos, Julia,Curtin, Nicola J.,Frigerio, Mark,Golding, Bernard T.,Hardcastle, Ian R.,Hummersone, Marc G.,Menear, Keith A.,Newell, David R.,Richardson, Caroline J.,Shea,Smith, Graeme C. M.,Thommes, Pia,Ting, Attilla,Griffin, Roger J.
, p. 6386 - 6401 (2013/09/23)
Analogues of (dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (NU7441), a potent inhibitor of DNA-dependent protein kinase (DNA-PK; IC 50 = 42 ± 2 nM), have been synthesized in which water-solubilizing groups [NHCO(CH2)nNR1R 2, where n = 1 or 2 and the moiety R1R2N was derived from a library of primary and secondary amines, e.g., morpholine] were placed at the 1-position. Several of the newly synthesized compounds exhibited high potency against DNA-PK and potentiated the cytotoxicity of ionizing radiation (IR) in vitro 10-fold or more (e.g., 2-(4-ethylpiperazin-1-yl)-N-(4- (2-morpholino-4-oxo-4H-chromen-8-yl)dibenzo[b,d]thio-phen-1-yl)acetamide, 39; DNA-PK IC50 = 5.0 ± 1 nM, IR dose modification ratio = 13). Furthermore, 39 was shown to potentiate not only IR in vitro but also DNA-inducing cytotoxic anticancer agents, both in vitro and in vivo. Counter-screening against other members of the phosphatidylinositol 3-kinase (PI-3K) related kinase (PIKK) family unexpectedly revealed that some of the compounds were potent mixed DNA-PK and PI-3K inhibitors.