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.

中文翻译：

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具有双重DNA-PK / PI3-K抑制活性的1-取代的（二苯并[ b，d ]噻吩-4-基）-2-吗啉代-4 H-色氨酸-4-酮

（二苯并[ b，d ]噻吩-4-基）-2-吗啉代-4 H-铬4-4-酮（NU7441）的类似物，一种有效的DNA依赖性蛋白激酶抑制剂（DNA-PK; IC ₅₀ = 42合成了±2 nM）的水溶性基团[NHCO（CH ₂）_n NR ¹ R ²，其中n = 1或2，且部分R ¹ R ²N来自伯胺和仲胺库，例如吗啉]置于1位。几种新合成的化合物对DNA-PK表现出高效力，并在体外将电离辐射（IR）的细胞毒性增强了10倍或更多（例如2-（4-乙基哌嗪-1-基）-N-（4- （2-morpholino-4-oxo-4 H -chromen-8-yl）dibenzo [ b，d ] thio-phen-1-yl）乙酰胺，39 ; DNA-PK IC ₅₀ = 5.0±1 nM，IR剂量修改比= 13）。此外，39已显示不仅在体外能增强IR，而且在体外和体内都能增强DNA诱导的细胞毒性抗癌剂。对磷脂酰肌醇3激酶（PI-3K）相关激酶（PIKK）家族的其他成员进行反筛选出乎意料地表明，某些化合物是有效的DNA-PK和PI-3K混合抑制剂。