Xue-Qi Liu

Discovery of [1,2,3]Triazolo[4,5-d]pyrimidine Derivatives as Novel LSD1 Inhibitors

Lysine specific demethylase 1 (LSD1) plays a pivotal role in regulating the lysine methylation. The aberrant overexpression of LSD1 has been reported to be involved in the progression of certain human malignant tumors. Abrogation of LSD1 with RNAi or small molecule inhibitors may lead to the inhibition of cancer proliferation and migration. Herein, a series of [1,2,3]triazolo[4,5-d]pyrimidine derivatives were synthesized and evaluated for their LSD1 inhibitory effects. The structure-activity relationship studies (SARs) were conducted by exploring three regions of this scaffold, leading to the discovery of compound 27 as potent LSD1 inhibitor (IC50 = 0.564 μM). Compound 27 was identified as a reversible LSD1 inhibitor and showed certain selectivity to LSD1 over monoamine oxidase A/B (MAO-A/B). When MGC-803 cells were treated with compound 27, the activity of LSD1 can be significantly inhibited, and the cell migration ability was also suppressed. Docking studies indicated that the hydrogen interaction between the nitrogen atom in the pyridine ring and Met332 could be responsible for the improved activity of 2-thiopyridine series. The [1,2,3]triazolo[4,5-d]pyrimidine scaffold can be used as the template for designing new LSD1 inhibitors.

Baicalin, a natural LSD1 inhibitor.

Baicalin is one of the active ingredients in the skullcap, with a variety of pharmacological effects, such as blood pressure reduction, sedation, liver-protection, gallbladder-protection, anti-bacteria, and anti-inflammation. In our study, baicalin was first characterized as a LSD1 inhibitor with an IC50 of 3.01μM and showed strong LSD1 inhibitory effect in cells. Baicalin may serve as a template for designing flavone-based LSD1 inhibitors.

1,2,3-Triazole-Dithiocarbamate Hybrids, a Group of Novel Cell Active SIRT1 Inhibitors

Background/Aims: Human SIRT1 is reported to be involved in tumorgenesis, mainly due to its modulating effect on p53 by deacetylation on lysine382. A large quantity of SIRT1 inhibitors was applied in chemotherapeutic study, but few of them were applied into clinical trials. Methods and Results: In the current study, a novel series of compounds with 1,4-bispiperazinecarbodithioic acid methyl esters scaffold were characterized to have inhibitory potency to SIRT1 by molecular docking and biochemical evaluation. Further cell level study revealed that one of the most potent SIRT1 inhibitors, compound 3a, is cell active. It can upregulate the amount of p53 by accumulating the K382 acetylation of p53, which lead to the stabilization of p53 in human gastric cancer cell line MGC-803 cells. Meanwhile, we also found compound 3a can inactivate SIRT2 in cells, which suggests the compound as a non-selective SIRT inhibitor. Conclusion: All these findings indicate that compound 3a is a potent, reversible and cell active SIRT1 inhibitor and deserves further investigation as an anticancer agent or a biological tool.

Design, synthesis and preliminary antiproliferative activity studies of new diheteroaryl thioether derivatives

A series of structurally new diheteroaryl thioether analogs was designed, prepared and screened toward MGC-803, MKN-45, EC-109 and H1650. Most of the target compounds displayed moderate to potent antiproliferative activities. Among them, compound 5 showed the best antiproliferative activity against the tested cell lines with the half maximal inhibitory concentration (IC50) values below 10μM. In addition, flow cytometry analysis showed that compound 5 increased Bax expression, down-regulated expression of Bcl-2, cleaved caspases-3/9, finally inducing apoptosis of MKN-45 cells as well asarrested the cell cycle at G2/M phase. This study suggests that the diheteroaryl thioethers are a class of emerging chemotypes for developing antitumor agents or biological probes, and compound 5 could serve as a good starting point to design new apoptosis inducers.

Design, synthesis and in vitro biological evaluation of novel [1,2,3]triazolo[4,5-d]pyrimidine derivatives containing a thiosemicarbazide moiety.

A series of hybrid molecules containing [1,2,3]triazolo[4,5-d]pyrimidine and thiosemicarbazide moieties were designed, synthesized and evaluated for their antiproliferative activities against MGC-803, NCI-H1650 and PC-3 human cancer cells. Some of the synthesized compounds showed moderate to good activity against three selected cancer cell lines. Among these compounds, compound 29 displayed the most potent antiproliferative activity as well as good selectivity between cancer cells and normal cells. Further mechanism studies revealed that compound 29 could obviously inhibit the colony formation and migration of MGC-803 as well as induced apoptosis.