Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Newcastle University, Newcastle upon Tyne, NE1 7RU, United Kingdom.
J Med Chem. 2013 Aug 22;56(16):6386-401. doi: 10.1021/jm400915j. Epub 2013 Aug 1.
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 ± 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 ± 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.
（二苯并[b，d]噻吩-4-基）-2-吗啉代-4H-色烯-4-酮（NU7441）类似物是一种有效的 DNA 依赖性蛋白激酶（DNA-PK；IC50=42±2nM）抑制剂，其在 1 位上引入了水溶性基团[NHCO（CH₂）nNR¹R²，其中 n=1 或 2，基团 R¹R²N 来源于伯胺和仲胺库，例如吗啉]。新合成的几种化合物对 DNA-PK 表现出高活性，并在体外将电离辐射（IR）的细胞毒性增强 10 倍或更多（例如，2-（4-乙基哌嗪-1-基）-N-（4-（2-吗啉代-4-氧代-4H-色烯-8-基）二苯并[b，d]噻吩-1-基）乙酰基）酰胺，39；DNA-PK IC₅₀=5.0±1nM，IR 剂量修饰比=13）。此外，39 不仅能增强体外的 IR，还能增强体外和体内的 DNA 诱导细胞毒性抗癌剂。针对磷酸肌醇 3-激酶（PI3K）相关激酶（PIKK）家族其他成员的反向筛选出人意料地发现，一些化合物是有效的 DNA-PK 和 PI3K 混合抑制剂。
