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The abnormal biological functions of HDAC6 were closely related to the occurrence and development of various tumors, making HDAC6 gradually become promising therapeutic target for cancer treatment and inspiring researchers to explore and develop selective HDAC inhibitors. In this study, based on the classical pharmacophore model of HDAC inhibitors, 20 compounds were designed and synthesized by modifying the Cap group, and the biological activities of the target compounds were assessed through anti-proliferation and enzyme inhibition experiments. The title compounds exhibited varying degrees of inhibitory activities against the selected tumor cell lines, especially the compounds 9m, 9q, and 12c, which were further evaluated at the enzymatic level. The enzyme inhibition assay showed that compound 12c exerted broad-spectrum enzyme inhibitory activities and compounds 9m and 9q were more inclined to inhibit HDAC6, exhibiting certain selective inhibitory activities among the representative subtypes. Moreover, the binding modes of compounds 9q and 12c in HDAC16 were further explored via computational approaches to elucidate the molecular mechanisms underlying selective inhibitory activities, providing valuable hints for the discovery of novel HDAC6 inhibitors.

A series of glycyrrhetinic acid (GA, aglycone of glycyrrhizic acid) derivatives containing disulfide bond were synthesized and their anti-inflammatory and anti-fibrosis activities were evaluated in vivo and in vitro. Among them, compound 7 displayed the highest toxicity to all the tested cell lines including macrophages. Compounds 3 and 4 showed higher activities than GA in the cell and animal model. In the anti-inflammatory tests, compounds 3 and 4 down-regulated the expressions of several inflammatory factors, such as HMGB1, TLR4, IL-1β, TNF-α and TGF-β1 in LPS-treated RAW264.7 cells in a dose-dependent manner. Compounds 3 and 4 at 30 µM respectively reduced the levels of HMGB1 in the LPS group to 42.7% and 38.2%. In addition, the level of TLR4 decreased to close to that of control group when treated by compound 4 at the concentration of 30 µM. In the process of anti-fibrosis tests using TGF-β1-induced A549 cell line as the model, compounds 3 and 4 also decreased the expression levels of Col1 and α-SMA in a dose-dependent manner. Compound 3 and 4 at 30 µM respectively reduced the expression of α-SMA level by 2.2-fold and 2.6-fold compared to the TGF-β1-treated control group. Moreover, they influenced the ROS level and mitochondrial membrane potential (MMP) in A549 cells. In the paraquat-induced pulmonary fibrosis mice model, the symptoms of inflammation and fibrosis of mice were alleviated after administration of compound 3 or 4. The above results suggest that compounds 3 and 4 may be promising candidates for inflammation and lung fibrosis treatment.

Many tests have shown cyclooxygenase-2 (COX-2) was closely related to the activation of hepatic stellate cells (HSCs), which further promoting the onset and development of hepatic fibrosis. According to these research findings, a series of glycyrrhetinic acid derivatives were designed and synthesized. Meanwhile, their anti-hepaticfibrotic activities were evaluated in vitro and in vivo. Firstly, in the tests of the cell models, all the compounds displayed anti-proliferative effect on the HSC-T6 activated by (transforming growth factor beta) TGF-β1 (10 ng/mL). Among them, compounds 2 and 16 exhibited a stronger activity than the others, and their IC50 values were 17.6 µM and 30.3 µM, respectively; both of them were low toxicity to normal HSC-T6 cells and WI38 cells, and they inhibited the activated HSC-T6 cells proliferation by promoting apoptosis and resting them at the G0/G1 phase. Secondly, compounds 2 and 16 displayed strong inhibitory effect on activation of HSCs; they not only inhibited the expression of α-SMA and Col1 in the activated HSC-T6 cells, but also decreased the levels of COX-2, TGF-β1 and (reactive oxygen species) ROS in a concentration-dependent manner; they down-regulated the levels of three biomarkers in the process of test, but this decrease did not change linearly with the action time of compound. Thirdly, for the rats which induced with (carbon tetrachloride) CCl4, the symptoms of liver fibrosis in rats were significantly alleviated after successive administration the tested compound for 14d; the α-SMA level in liver tissue decreased in a concentration dependent manner; and the liver cell necrosis and the fat collagen fiber decreased significantly compared with the positive control group; furthermore, inflammatory infiltration was significantly lower than that of the control. This suggests the compounds possibly are candidates for hepatic fibrosis with promising application in clinic.