Abstract

This study describes the synthesis and vacuole-inducing activity of 5-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)-1H-indole-2-carbohydrazide derivatives, including five potent derivatives 12c, 12 g, 12i, 12n, and 12A that exhibit excellent vacuole-inducing activity. Remarkably, 12A effectively induces methuosis in tested cancer cells but not human normal cells. In addition, 12A exhibits high pan-cytotoxicity against different cancer cell lines but is hardly toxic to normal cells. It is found that the 12A-induced vacuoles are derived from macropinosomes but not autophagosomes. The 12A-induced cytoplasmic vacuoles may originate from the endoplasmic reticulum (ER) and be accompanied by ER stress. The MAPK/JNK signalling pathway is involved in the 12A-induced methuotic cell death. Moreover, 12A exhibits significant inhibition of tumour growth in the MDA-MB-231 xenograft mouse model. The excellent potency and selectivity of 12A prompt us to select it as a good lead compound for further development of methuosis inducers and investigation of the molecular and cellular mechanisms underlying methuosis.

摘要

本研究描述了 5-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)-1 H -indole-2-carbohydrazide 衍生物的合成和液泡诱导活性，包括五种有效的衍生物12c , 12 g、12i、12n和12A表现出优异的液泡诱导活性。值得注意的是，12A在测试的癌细胞中有效地诱导了灭活，而不是在人类正常细胞中。此外，12A对不同癌细胞系表现出高泛细胞毒性，但对正常细胞几乎没有毒性。发现12A诱导的液泡来源于巨松质体而不是自噬体。在12A诱导的细胞质液泡可能起源于内质网（ER）并伴有内质网应激。MAPK/JNK 信号通路参与12A诱导的甲基化细胞死亡。此外，12A在 MDA-MB-231 异种移植小鼠模型中表现出对肿瘤生长的显着抑制。12A的优异效力和选择性促使我们将其选为一种良好的先导化合物，用于进一步开发 Methosis 诱导剂和研究 Methosis 的分子和细胞机制。