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A series of Pulsatilla saponin D (PSD) and α-hederin derivatives bearing NO donors were designed, synthesized and evaluated for anticancer activities in vitro and in vivo. Among them, most of the target compounds exhibited strong antiproliferative activities against the tested cancer cell lines, and derivatives 5a, 5b and 5c exhibited high levels of NO release. Furthermore, compound 5c treated with a dose of 15 mg kg−1 showed a more potent tumor inhibitory effect than that of Taxol (27.44% vs. 23.26%). In addition, compound 5c blocked the cell cycle at the S phase and induced cancer cell apoptosis in a concentration-dependent manner. [ABSTRACT FROM AUTHOR]

Uveal melanoma (UM) has a high mortality rate due to liver metastasis. The insulin‐like growth factor‐1 receptor (IGF‐1R) is highly expressed in UM and has been shown to be associated with hepatic metastases. Targeting IGF signalling may be considered as a promising approach to inhibit the process of metastatic UM cells. Pristimerin (PRI) has been demonstrated to inhibit the growth of several cancer cells, but its role and underlying mechanisms in the IGF‐1‐induced UM cell proliferation are largely unknown. The present study examined the anti‐proliferative effect of PRI on UM cells and its possible role in IGF‐1R signalling transduction. MTT and clonogenic assays were used to determine the role of PRI in the proliferation of UM cells. Flow cytometry was performed to detect the effect of PRI on the cell cycle distribution of UM cells. Western blotting was carried out to assess the effects of PRI and IGF‐1 on the IGF‐1R phosphorylation and its downstream targets. The results indicated that IGF‐1 promoted the UM cell proliferation and improved the level of IGF‐1R phosphorylation, whereas PRI attenuated the effect of IGF‐1. Interestingly, PRI could not only induce the G1 phase accumulation and reduce the G2 phase induced by IGF‐1, but also could stimulate the expression of p21 and inhibit the expression of cyclin D1. Besides, PRI could attenuate the phosphorylations of Akt, mTOR and ERK1/2 induced by IGF‐1. Furthermore, the molecular docking study also demonstrated that PRI had potential inhibitory effects on IGF‐1R. Taken together, these results indicated that PRI could inhibit the proliferation of UM cells through down‐regulation of phosphorylated IGF‐1R and its downstream signalling. [ABSTRACT FROM AUTHOR]

A series of ester and amide derivatives of triterpenoid saponin Pulsatilla saponin D (PSD) were designed, synthesized, and evaluated for their antiproliferative activity. Compounds 1 and 6 displayed 1.7–8.3 times more potent cytotoxicity (IC50 = 1.2–4.7 and 1.7–4.5 μM, respectively) against five human tumor cell lines (SMMC-7721, MCF-7, NCI-H460, A549, and HCT-116) in vitro and lower acute toxicity to mice in vivo than did PSD. Furthermore, compound 6 was observed to show potent tumor growth inhibition against mice H22 hepatocellular cells (49.8% at 20 mg/kg) and induce cell cycle at G1 phase and apoptosis in HCT-116 cells. [ABSTRACT FROM AUTHOR]

A series of novel coumarin-based N -hydroxycinnamamide derivatives were designed and synthesized as histone deacetylase (HDAC) inhibitors. Most of the synthesized compounds showed potent HDAC inhibitory activity and significant antiproliferative activity against human cancer cell lines MCF-7, HepG2, HeLa and HCT-116. Among them, compound 14f displayed the most potent HDAC inhibition, especially against HDAC1 with IC 50 value of 0.19 μM, which was better than that of SAHA (IC 50 = 0.23 μM). It also showed the strongest antiproliferative activity towards HeLa cells and more than 26-fold selectivity for HDAC1 compared with HDAC6. Molecular docking studies revealed the possible binding modes of compound 14f into the two isoforms and provided a reasonable explanation for the selectivity. In addition, compound 14f could inhibit colony formation, upregulate the acetylation level of histone H3, and induce apoptosis and cell cycle arrest at G2/M phase in HeLa cells. Taken together, these results highlighted that compound 14f might be a promising HDAC inhibitor for cancer therapy. [ABSTRACT FROM AUTHOR]