Design, synthesis, and biological evaluation of 5-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)-1-Indole-2-Carbohydrazide derivatives: the methuosis inducer 12A as a Novel and selective anticancer agent.

This study describes the synthesis and vacuole-inducing activity of 5-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)-1-indole-2-carbohydrazide derivatives, including five potent derivatives , , , , and that exhibit excellent vacuole-inducing activity. Remarkably, effectively induces methuosis in tested cancer cells but not human normal cells. In addition, exhibits high pan-cytotoxicity against different cancer cell lines but is hardly toxic to normal cells. It is found that the -induced vacuoles are derived from macropinosomes but not autophagosomes. The -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 -induced methuotic cell death. Moreover, exhibits significant inhibition of tumour growth in the MDA-MB-231 xenograft mouse model. The excellent potency and selectivity of 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.