Azacarbazoles have attracted significant interest due to their valuable properties, such as anti-pathogenic and antitumor activity. In this study, a series of structurally related tricyclic benzo[4,5]- and tertacyclic naphtho[2',1':4,5]imidazo[1,2-c]pyrimidinone derivatives with one or two positively charged tethers were synthesized and evaluated for anti-proliferative activity. Lead tetracyclic derivative 5b with two amino-bearing arms inhibited the metabolic activity of A549 lung adenocarcinoma cells with a CC50 value of 3.6 μM, with remarkable selectivity (SI = 17.3) over VA13 immortalized fibroblasts. Cell-cycle assays revealed that 5b triggers G2/M arrest without signs of apoptosis. A study of its interaction with various DNA G4s and duplexes followed by dual luciferase and intercalator displacement assays suggests that intercalation, rather than the modulation of G4-regulated oncogene expression, might contribute to the observed activity. Finally, a water-soluble salt of 5b was shown to cause no acute toxic effects, changes in mice behavior, or any decrease in body weight after a 72 h treatment at concentrations up to 20 mg/kg. Thus, 5b is a promising candidate for studies in vivo; however, further investigations are needed to elucidate its molecular target(s).

中文翻译：

---

苯并[4,5]-和萘并[2',1':4,5]咪唑并[1,2-c]嘧啶酮衍生物的合成和生物学评价。


阿扎咔唑因其有价值的特性（例如抗病原体和抗肿瘤活性）而引起了人们的极大兴趣。在这项研究中，合成了一系列结构相关的三环苯并[4,5]-和四环萘并[2',1':4,5]咪唑并[1,2-c]嘧啶酮衍生物，具有一个或两个带正电荷的系链并评估抗增殖活性。具有两个氨基臂的铅四环衍生物 5b 抑制 A549 肺腺癌细胞的代谢活性，CC50 值为 3.6 μM，与 VA13 永生化成纤维细胞相比具有显着的选择性 (SI = 17.3)。细胞周期分析显示，5b 会触发 G2/M 期停滞，但没有细胞凋亡的迹象。对它与各种 DNA G4 和双链体相互作用的研究，随后进行双荧光素酶和嵌入剂置换测定，表明嵌入，而不是 G4 调节的癌基因表达的调节，可能有助于观察到的活性。最后，5b 的水溶性盐在浓度高达 20 mg/kg 的处理 72 小时后，不会引起急性毒性作用、小鼠行为变化或体重下降。因此，5b 是体内研究的有希望的候选者；然而，需要进一步研究来阐明其分子靶点。