Design, synthesis, and biological evaluation of 5-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)-1<i>H</i>-Indole-2-Carbohydrazide derivatives: the methuosis inducer 12A as a Novel and selective anticancer agent
Jun Wu, Hongyu Hu, Mingtao Ao, Zhenzhen Cui, Xiaoping Zhou, Jingbo Qin, Yafei Guo, Jingwei Chen, Yuhua Xue, Meijuan Fang
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.