Tetrazanbigen (TNBG) is a novel sterol isoquinoline derivative with poor water solubility and moderate inhibitory effects on human cancer cell lines via lipoapoptosis induction. Herein, we developed a series of novel TNBG analogues with improved water solubility and antiproliferative activities. The CCK-8 assay enabled us to identify a novel compound, 14g, which strongly inhibited HepG2 and A549 cell growth with IC₅₀ values of 0.54 and 0.47 μM, respectively. The anticancer effects might be explained by the partial activation and upregulation of PPARγ expression, as indicated by the transactivation assay and western blotting evaluation. Furthermore, the in vitro antiproliferative activity was verified in an in vivo xenograft model in which 14g strongly reduced tumor growth at a dose of 10 mg/kg. In line with these positive observations, 14g exhibited an excellent water solubility of 31.4 mg/mL, which was more than 1000-fold higher than that of TNBG (4 μg/mL). Together, these results suggest that 14g is a promising anticancer therapeutic that deserves further investigation.

中文翻译：

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Tetrazanbigen衍生物作为过氧化物酶体增殖物激活受体γ（PPARγ）部分激动剂：设计，合成，结构-活性关系和抗癌活性。

Tetrazanbigen（TNBG）是一种新型的固醇异喹啉衍生物，其水溶性差，并且通过脂质凋亡诱导对人癌细胞系具有中等抑制作用。本文中，我们开发了一系列具有改善的水溶性和抗增殖活性的新型TNBG类似物。CCK-8分析使我们能够鉴定出一种新型化合物14g，该化合物强烈抑制HepG2和A549细胞的生长，IC ₅₀值分别为0.54和0.47μM。如反式激活分析和蛋白质印迹评估所示，抗癌作用可以通过PPARγ表达的部分激活和上调来解释。此外，体外在体内异种移植模型中验证了抗增殖活性，其中14g以10 mg / kg的剂量强烈降低了肿瘤的生长。与这些积极的观察一致，14g的水溶性极好，为31.4 mg / mL，比TNBG（4μg / mL）高出1000倍以上。总之，这些结果表明14g是一种有前途的抗癌治疗药物，值得进一步研究。