1-Substituted (Dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-ones Endowed with Dual DNA-PK/PI3-K Inhibitory Activity

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• 作者：C茅line Cano ; Kappusamy Saravanan ; Chris Bailey ; Julia Bardos ; Nicola J. Curtin ; Mark Frigerio ; Bernard T. Golding ; Ian R. Hardcastle ; Marc G. Hummersone ; Keith A. Menear ; David R. Newell ; Caroline J. Richardson ; K. Shea ; Graeme C. M. Smith ; Pia Thommes ; Attilla Ting ; Roger J. Griffin
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：August 22, 2013
• 年：2013
• 卷：56
• 期：16
• 页码：6386-6401
• 全文大小：622K
• 年卷期：v.56,no.16(August 22, 2013)
• ISSN：1520-4804

文摘

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; IC₅₀ = 42 卤 2 nM), have been synthesized in which water-solubilizing groups [NHCO(CH₂)_nNR¹R², 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 卤 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.