Yan Qi, Wang Yujie, Zhang Wei, Li Yingxia
School of Pharmacy, Fudan University, Shanghai 201203, China.
Mar Drugs. 2016 Apr 28;14(5):85. doi: 10.3390/md14050085.
A conformational restriction strategy was used to design and synthesize nine TZT-1027 analogues. 3-Aryl-azetidine moiety was used to replace phenylethyl group of TZT-1027 at the C-terminus. These analogues exhibited moderate to excellent antiproliferative activities, and the most potent compound 1a showed IC50 values of 2.2 nM against A549 and 2.1 nM against HCT116 cell lines, respectively. However, 1a could not achieve effective inhibition at all the dose levels in the A549 xenograft model (up to 5 mg/kg, injection, once a day), which is only 16%-35% inhibition at the end of the experiment.
采用构象限制策略设计并合成了9种TZT-1027类似物。在C端用3-芳基氮杂环丁烷部分取代TZT-1027的苯乙基。这些类似物表现出中等至优异的抗增殖活性，最有效的化合物1a对A549细胞系的IC50值为2.2 nM，对HCT116细胞系的IC50值为2.1 nM。然而，在A549异种移植模型中，1a在所有剂量水平下（高达5 mg/kg，注射，每天一次）均未实现有效抑制，在实验结束时仅为16%-35%的抑制率。
