Synthesis and Antiproliferative Activity of Ester Derivatives of Mogrol through JAK2/STAT3 Pathway.

In attempt to enhance the antiproliferative activity of mogrol, two series of ester derivatives modified at C ₃ -OH and C ₁₁ -OH were designed and synthesized. The activity against human cancer cells including A549, NCI-H460 and CNE1 was screened by Cell Counting Kit-8 (CCK8) assay. According to the results, modifications of the mogrol core through introduction of different ester scaffolds drastically improved the cytotoxicity, and some of the derivatives exhibited even higher activity than the positive drug. Among them, compound M2h exhibited nearly 4 times more cytotoxic than 5-Fu against CNE1 cells, derivative M6c showed ten times higher activity with the IC ₅₀ value of 10.59 μM than mogrol against NCI-H460 cells, and compound M6a which contained one 1,2,3-triazole motif showed the strongest activity with an three folds lower IC ₅₀ value than mogrol. Furthermore, the most potent compound M2h could lead to cell cycle arrest at G2 phase on CNE1 cell lines and M6a induced G1 phase arrest on A549 cell lines. It was noteworthy that both M2h and M6a regulated signal transducer and activator of transcription 3 (STAT3) signal pathway through inhibiting phosphorylation of Janus Kinase 2 (JAK2) and STAT3, and simultaneously increasing the protein level of downstream cyclin p21.
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