Discovery of novel 1,2,4-triazine-chalcone hybrids as anti-gastric cancer agents via an axis of ROS-ERK-DR5 in vitro and in vivo |
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Institution: | 1. Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China;2. School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China;3. School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou 450001, China;4. Henan Institute of Advanced Technology, Zhengzhou University, Zhengzhou 450001, China;5. Department of Pharmacy, Liaocheng People''s Hospital, Liaocheng 252000, China |
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Abstract: | In this work, a series of novel 1,2,4-triazine-chalcone hybrids were designed through the molecular hybridization strategy, synthesized by two step chlorinations and further aldol condensation and evaluated their antiproliferative activity against MGC-803, HCT-116, PC-3, EC-109 and A549 cells. Compound 9l displayed significant antiproliferative activity against MGC-803, HCT-116, PC-3, EC-109 and A549 cell lines with IC50 values of 0.41, 0.43, 0.61, 0.78 and 0.52 μM, respectively. Subsequent mechanistic investigations suggested that compound 9l induced the generation of ROS and inhibited the activation of the ERK pathway. Compound 9l induced extrinsic cell apoptosis by up-regulating DR5 dependent on the generation of ROS, while up-regulation of DR5 caused by compound 9l relied on the inhibition of ERK. Thus, compound 9l inhibited the gastric cancer cells via an axis of ROS-ERK-DR5 in vitro. Compound 9l also showed potent activity on cell proliferation inhibition, and was effective in suppressing the growth of MGC-803 xenograft tumor in nude mice without obvious toxicity. Therefore, compound 9l is to be reported as anti-gastric cancer agent in vitro and in vivo via an axis of ROS-ERK-DR5. |
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Keywords: | 1 2 4-Triazine Chalcone Antiproliferative activity ROS ERK DR5 |
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