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：

---

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


(二苯并[ b , d ]噻吩-4-基)-2-吗啉代-4 H -chromen-4-one (NU7441) 类似物，DNA 依赖性蛋白激酶 (DNA-PK；IC ₅₀ = 42) 的有效抑制剂± 2 nM)，其中水溶性基团 [NHCO(CH ₂ ) _n NR ¹ R ² ，其中n = 1 或 2，且 R ¹ R ² N 部分源自伯胺和仲胺库，例如吗啉]被置于1位。几种新合成的化合物对 DNA-PK 表现出高效能，并将体外电离辐射 (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-4 H-铬-8-基)二苯并[ b , d ]噻吩-1-基)乙酰胺， 39 ；DNA-PK IC ₅₀ = 5.0 ± 1 nM，IR 剂量调整比率 = 13)。此外， 39不仅在体外增强IR，而且在体外和体内增强DNA诱导的细胞毒性抗癌剂。针对磷脂酰肌醇 3 激酶 (PI-3K) 相关激酶 (PIKK) 家族其他成员的反筛选意外地发现，其中一些化合物是有效的 DNA-PK 和 PI-3K 混合抑制剂。