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.
Keywords:
1H-indole-2-carbohydrazide derivatives; Anticancer agent; MDA-MB-231 cells; Methuosis.
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Dose-Response Relationship, Drug
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Drug Design*
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Drug Screening Assays, Antitumor
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Endoplasmic Reticulum / drug effects
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Endoplasmic Reticulum / metabolism
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Humans
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Hydrazines / chemical synthesis
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Hydrazines / chemistry
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Hydrazines / pharmacology*
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Mammary Neoplasms, Experimental / drug therapy
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Mammary Neoplasms, Experimental / metabolism
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Mammary Neoplasms, Experimental / pathology
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Mice
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Models, Molecular
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Molecular Structure
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Structure-Activity Relationship
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Tumor Cells, Cultured
Substances
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Antineoplastic Agents
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Hydrazines
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carbohydrazide
Grants and funding
The research was supported in part by grants from the Fundamental Research Funds for the Central Universities of China [No. 20720180051], the National Key R&D Program of China [2018YFA0107303], the National Natural Science Foundation of China [No. 81672955], the Fujian Provincial Natural Science Foundation [No. 2018J01132], the Jinhua Science and Technology Plan Project of China [2020–4-088], and the Health Commission of Zhejiang Province of China [2020KY628].