A diverse library of new ring system 12H-indazolo[2,1-a]cinnolin-12-ones have been synthesized efficiently via Ru (II) and Rh (III) catalyzed tandem CH alkylation/[4 + 2] annulation with diazo compounds in high to excellent yields. For the first time, we evaluated the biological activity of these compounds with this new skeleton and found some compounds exhibited high cytotoxic activity against human PC-3 and PANC-1 tumor cell lines with nanomolar IC50. Among them, the most potent compound 36 showed broad-spectrum cytotoxic activities against a series of human tumor cell lines derived from different organs (IC50 ~ 41 to 197 nM). Moreover, preliminary mechanistic studies indicated that 36 could inhibit the colony formation, cause cell cycle arrest and induce apoptosis of PC-3 cancer cells in a dose-dependent manner. Further intracellular mechanisms investigation found that 36 treatments could dose-dependently decrease the levels of caspase-3 and PARP and up-regulate the level of cleaved PARP. These results suggested that 36 is a novel compound with good potential in the treatment of human cancers and worthy of further investigation.

中文翻译：

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通过药物发现满足有机金属化学的需求：CH活化能够发现具有抗增殖活性的12H-吲哚并[2,1-a] cinnolin-12-环的新环系。

通过Ru（II）和Rh（III）催化的串联CH烷基化/ [4 + 2]与重氮化合物环合，有效地合成了各种新的环系统12H-吲唑并[2,1-a] cinnolin-12-。产量高至优异。我们首次用这种新骨架评估了这些化合物的生物活性，发现某些化合物对具有纳摩尔IC50的人PC-3和PANC-1肿瘤细胞系表现出高细胞毒活性。其中，最有效的化合物36对来自不同器官的一系列人类肿瘤细胞系（IC50〜41至197 nM）表现出广谱的细胞毒活性。此外，初步的机理研究表明，36能够以剂量依赖的方式抑制集落形成，引起细胞周期停滞并诱导PC-3癌细胞凋亡。进一步的细胞内机制研究发现36种治疗可以剂量依赖性地降低caspase-3和PARP的水平并上调裂解的PARP的水平。这些结果表明36是一种新型化合物，在治疗人类癌症方面具有良好的潜力，值得进一步研究。