Synthesis of 4-Tetrazolyl-Substituted 3,4-Dihydroquinazoline Derivatives with Anticancer Activity via a One-Pot Sequential Ugi-Azide/Palladium-Catalyzed Azide-Isocyanide Cross-Coupling/Cyclization Reaction.

A new one-pot preparation of 4-tetrazolyl-3,4-dihydroquinazolines has been reported. The Ugi-azide reactions of 2-azidobenzaldehydes, amines, trimethylsilyl azide, and isocyanides produced azide intermediates without separation, which were treated with isocyanides to give 4-tetrazolyl-3,4-dihydroquinazoline derivatives through a sequential Palladium-catalyzed azide-isocyanide cross-coupling/cyclization reaction in moderate to good yields. The biological evaluation demonstrated that compound 6c inhibited breast cancer cells well and displayed broad applications for synthesis and medicinal chemistry.

Effects of sand burial depth on Xanthium spinosum seed germination and seedling growth.

In desert habitats, sand burial is an important factor affecting germination of plant seeds and seedling growth. Xanthium spinosum has strong adaptability in arid desert areas, and is a common malignant invasive plant in Xinjiang, China. The effects of different sand burial depths on seed germination, seedling emergence, growth and biomass allocation were studied to provide a scientific basis for further control of X. spinosum. Six sand burial depths (1, 2, 3, 5, 7 and 9 cm) were established to explore the response of X. spinosum seed germination and seedling growth to sand burial. The first emergence time, peak emergence time, emergence rate, seedling growth height, biomass and biomass distribution of X. spinosum seeds was significantly different at sand burial depths (P < 0.05). The X. spinosum seeds had the highest emergence rate (71.5%) at 1 cm sand burial and the maximum seedling height (7.1 cm). As sand burial depth increased, the emergence rate and seedling height gradually decreased. Emergence rate (12.25%) and seedling height (2.9 cm) were lowest at 9 cm sand burial. The root length at 9 cm depth (13.6 cm) was significantly higher than that at other sand depths (P < 0.05). The sand burial depth affected the biomass accumulation and distribution of X. spinosum. As sand burial depth increased, the root biomass and rhizome ratio increased, and the most deeply buried seedlings allocated more biomass for root growth. The optimal sand burial depth for seed germination and seedling growth of X. spinosum was 1-3 cm, and high burial depth (5-9 cm) was not conducive to the germination and growth of X. spinosum seedlings. For prevention and control of X. spinosum, we suggest deeply ploughing crops before sowing to ensure X. spinosum seeds are ploughed into a deep soil layer.

Identification of novel 1,3-diaryl-1,2,4-triazole-capped histone deacetylase 6 inhibitors with potential anti-gastric cancer activity.

Histone deacetylase 6 (HDAC6) has emerged as a critical regulator of many cellular pathways in tumors due to its unique structure basis and abundant substrate types. Over the past few decades, the role played by HDAC6 inhibitors as anticancer agents has sparked great interest of biochemists worldwide. However, they were less reported for gastric cancer therapy. In this paper, with the help of bioisosteric replacement, in-house library screening, and lead optimization strategies, we designed, synthesized and verified a series of 1,3-diaryl-1,2,4-triazole-capped HDAC6 inhibitors with promising anti-gastric cancer activities. Amongst, compound 9r displayed the best inhibitory activity towards HDAC6 (IC50 = 30.6 nM), with 128-fold selectivity over HDAC1. Further BLI and CETSA assay proved the high affinity of 9r to HDAC6. In addition, 9r could dose-dependently upregulate the levels of acetylated α-tubulin, without significant effect on acetylated histone H3 in MGC803 cells. Besides, 9r exhibited potent antiproliferative effect on MGC803 cells, and promoted apoptosis and suppressed the metastasis without obvious toxicity, suggesting 9r would serve as a potential lead compound for the development of novel therapeutic agents of gastric cancer.

Thiosemicarbazone-based lead optimization to discover high-efficiency and low-toxicity anti-gastric cancer agents.

In this paper, a series of thiosemicarbazone derivatives containing different aromatic heterocyclic groups were synthesized and the tridentate donor system of the lead compound was optimized. Most of the target compounds showed improved antiproliferative activity against MGC803 cells. SAR studies revealed that compound 5d displayed significant advantages in inhibition effect with an IC50 value of 0.031 µM, and better selectivity between cancer and normal cells than 3-AP and DpC (about 15- and 5-fold improved respectively). Besides, compound 5d showed selective antiproliferative activity in not only other cancer cells but also different gastric cancer cell lines. In-depth mechanism studies showed that compound 5d could induce mitochondria-related apoptosis which might be related to the elevation of intracellular ROS level, and cause cell cycle arrest at S phase. Moreover, 5d could evidently suppress the cell migration and invasion by blocking the EMT (epithelial-mesenchymal transition) process. Consequently, our studies provided a lead optimization strategy of thiosemicarbazone derivatives which would contribute to discover high-efficiency and low-toxicity agents for the treatment of gastric cancer.