Tao-Qian Zhao

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.

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.

Novel 3-(2,6,9-trisubstituted-9H-purine)-8-chalcone derivatives as potent anti-gastric cancer agents: Design, synthesis and structural optimization

To explore anti-gastric cancer agents with high efficacy and selectivity, we report the design, synthesis and optimization of a novel series of 3-(2,6,9-trisubstituted-9H-purine)-8-chalcone derivatives starting from the compound PCA-15 reported by us previously. Most of the target compounds demonstrated significant antiproliferative effects on MGC803 cancer cell line, and more potent than the positive control (PCA-15 and 5-Fu). Among them, compound 6o was identified to be the most active compound against MGC803 cell line with an IC50 value of 0.84 μM. Additionally, high selectivity was also observed between cancer and normal cells (23.35 μM against GES-1). Further mechanism studies confirmed that compound 6o could inhibit colony formation and migration, induce the apoptosis of MGC803 cells through both the mitochondrial-mediated intrinsic pathway and death receptor-mediated extrinsic pathway, which were evidenced by the up-regulation of Bax, cleaved-caspase 9/3/8, cleaved PARP and down-regulation of Bcl-2. Our systematic studies implied a new scaffold targeting gastric cancer cells for further development of small-molecule compounds with improved potency and selectivity.

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.

Discovery of 6-chloro-2-(propylthio)-8,9-dihydro-7H-purines containing a carboxamide moiety as potential selective anti-lung cancer agents

A new series of 6-chloro-2-(propylthio)-8,9-dihydro-7H-purine-8-caboxamide derivatives were designed, synthesized, and further evaluated for their antiproliferative activities on four human cancer cell lines (A549, MGC803, PC-3 and TE-1). The structure-activity relationships (SARs) studies were conducted through the variation in the two regions, which including position 8 and 9, of purine core. One of the compounds, 8, containing a terminal piperazine appendage with a carboxamide moiety at position 8 and phenyl group at position 9 of 6-chloro-8,9-dihydro-7H-purine core, showed the most potent antiproliferative activity and good selectivity between cancer and normal cells (IC50 values of 2.80 μM against A549 and 303.03 μM against GES-1, respectively). In addition, compound 8 could inhibit the colony formation and migration of A549 cells in a concentration-dependent manner, as well as induce the apoptosis possibly through the intrinsic pathway.