Design, Synthesis, and Biological Evaluation of Pyrano[2,3-c]-pyrazole–Based RalA Inhibitors Against Hepatocellular Carcinoma

The activation of Ras small GTPases, including RalA and RalB, plays an important role in carcinogenesis, tumor progress, and metastasis. In the current study, we report the discovery of a series of 6-sulfonylamide-pyrano [2,3-c]-pyrazole derivatives as novel RalA inhibitors. ELISA-based biochemical...

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Autores principales:	Yuting Wang, Mingyao He, Xiang Li, Jinlong Chai, Qinglin Jiang, Cheng Peng, Gu He, Wei Huang
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	RalA inhibitors pyrano[2;3-c]-pyrazole hepatocellular carcinoma synthesis autophagy Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/53775f1024e345398dc94efc031c4ca8
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spelling	oai:doaj.org-article:53775f1024e345398dc94efc031c4ca82021-11-15T13:53:18ZDesign, Synthesis, and Biological Evaluation of Pyrano[2,3-c]-pyrazole–Based RalA Inhibitors Against Hepatocellular Carcinoma2296-264610.3389/fchem.2021.700956https://doaj.org/article/53775f1024e345398dc94efc031c4ca82021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fchem.2021.700956/fullhttps://doaj.org/toc/2296-2646The activation of Ras small GTPases, including RalA and RalB, plays an important role in carcinogenesis, tumor progress, and metastasis. In the current study, we report the discovery of a series of 6-sulfonylamide-pyrano [2,3-c]-pyrazole derivatives as novel RalA inhibitors. ELISA-based biochemical assay results indicated that compounds 4k–4r suppressed RalA/B binding capacities to their substrates. Cellular proliferation assays indicated that these RalA inhibitors potently inhibited the proliferation of HCC cell lines, including HepG2, SMMC-7721, Hep3B, and Huh-7 cells. Among the evaluated compounds, 4p displayed good inhibitory capacities on RalA (IC50 = 0.22 μM) and HepG2 cells (IC50 = 2.28 μM). Overall, our results suggested that a novel small-molecule RalA inhibitor with a 6-sulfonylamide-pyrano [2, 3-c]-pyrazole scaffold suppressed autophagy and cell proliferation in hepatocellular carcinoma, and that it has potential for HCC-targeted therapy.Yuting WangMingyao HeXiang LiXiang LiJinlong ChaiQinglin JiangCheng PengGu HeWei HuangFrontiers Media S.A.articleRalA inhibitorspyrano[2;3-c]-pyrazolehepatocellular carcinomasynthesisautophagyChemistryQD1-999ENFrontiers in Chemistry, Vol 9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	RalA inhibitors pyrano[2;3-c]-pyrazole hepatocellular carcinoma synthesis autophagy Chemistry QD1-999
spellingShingle	RalA inhibitors pyrano[2;3-c]-pyrazole hepatocellular carcinoma synthesis autophagy Chemistry QD1-999 Yuting Wang Mingyao He Xiang Li Xiang Li Jinlong Chai Qinglin Jiang Cheng Peng Gu He Wei Huang Design, Synthesis, and Biological Evaluation of Pyrano[2,3-c]-pyrazole–Based RalA Inhibitors Against Hepatocellular Carcinoma
description	The activation of Ras small GTPases, including RalA and RalB, plays an important role in carcinogenesis, tumor progress, and metastasis. In the current study, we report the discovery of a series of 6-sulfonylamide-pyrano [2,3-c]-pyrazole derivatives as novel RalA inhibitors. ELISA-based biochemical assay results indicated that compounds 4k–4r suppressed RalA/B binding capacities to their substrates. Cellular proliferation assays indicated that these RalA inhibitors potently inhibited the proliferation of HCC cell lines, including HepG2, SMMC-7721, Hep3B, and Huh-7 cells. Among the evaluated compounds, 4p displayed good inhibitory capacities on RalA (IC50 = 0.22 μM) and HepG2 cells (IC50 = 2.28 μM). Overall, our results suggested that a novel small-molecule RalA inhibitor with a 6-sulfonylamide-pyrano [2, 3-c]-pyrazole scaffold suppressed autophagy and cell proliferation in hepatocellular carcinoma, and that it has potential for HCC-targeted therapy.
format	article
author	Yuting Wang Mingyao He Xiang Li Xiang Li Jinlong Chai Qinglin Jiang Cheng Peng Gu He Wei Huang
author_facet	Yuting Wang Mingyao He Xiang Li Xiang Li Jinlong Chai Qinglin Jiang Cheng Peng Gu He Wei Huang
author_sort	Yuting Wang
title	Design, Synthesis, and Biological Evaluation of Pyrano[2,3-c]-pyrazole–Based RalA Inhibitors Against Hepatocellular Carcinoma
title_short	Design, Synthesis, and Biological Evaluation of Pyrano[2,3-c]-pyrazole–Based RalA Inhibitors Against Hepatocellular Carcinoma
title_full	Design, Synthesis, and Biological Evaluation of Pyrano[2,3-c]-pyrazole–Based RalA Inhibitors Against Hepatocellular Carcinoma
title_fullStr	Design, Synthesis, and Biological Evaluation of Pyrano[2,3-c]-pyrazole–Based RalA Inhibitors Against Hepatocellular Carcinoma
title_full_unstemmed	Design, Synthesis, and Biological Evaluation of Pyrano[2,3-c]-pyrazole–Based RalA Inhibitors Against Hepatocellular Carcinoma
title_sort	design, synthesis, and biological evaluation of pyrano[2,3-c]-pyrazole–based rala inhibitors against hepatocellular carcinoma
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/53775f1024e345398dc94efc031c4ca8
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Design, Synthesis, and Biological Evaluation of Pyrano[2,3-c]-pyrazole–Based RalA Inhibitors Against Hepatocellular Carcinoma

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