53918-44-8

Upstream product

• 624-65-7 2-propynyl chloride 
• 118025-46-0 3-amino-1H-1,2,4-triazole-5-thiol 
• 16691-43-3 5-amino-3-mercapto-4H-[1,2,4]triazole 

Relevant academic research and scientific papers

Discovery of the Triazolo[1,5- a]Pyrimidine-Based Derivative WS-898 as a Highly Efficacious and Orally Bioavailable ABCB1 Inhibitor Capable of Overcoming Multidrug Resistance

Targeting P-glycoprotein (ABCB1 or P-gp) has been recognized as a promising strategy to overcome multidrug resistance. Here, we reported our medicinal chemistry efforts that led to the discovery of the triazolo[1,5-a]pyrimidine derivative WS-898 as a highly effective ABCB1 inhibitor capable of reversing paclitaxel (PTX) resistance in drug-resistant SW620/Ad300, KB-C2, and HEK293/ABCB1 cells (IC50 = 5.0, 3.67, and 3.68 nM, respectively), more potent than verapamil and zosuquidar. WS-898 inhibited the efflux function of ABCB1, thus leading to decreased efflux and increased intracellular PTX concentration in SW620/Ad300 cells. The cellular thermal shift assay indicated direct engagement of WS-898 to ABCB1. Furthermore, WS-898 stimulated the ATPase activity of ABCB1 but had minimal effects on cytochrome P450 3A4 (CYP3A4). Importantly, WS-898 increased PTX sensitization in vivo without obvious toxicity. The results suggest that WS-898 is a highly effective triazolo[1,5-a]pyrimidine-based ABCB1 inhibitor and shows promise in reversing ABCB1-mediated PTX resistance.

Discovery of [1,2,4]triazolo[1,5-a]pyrimidine derivatives as new bromodomain-containing protein 4 (BRD4) inhibitors

Targeting bromodomain-containing protein 4 (BRD4) has been proved to be an effective strategy for cancer therapy. To date, numerous BRD4 inhibitors and degraders have been identified, some of which have advanced into clinical trials. In this work, a focused library of new [1,2,4]triazolo[1,5-a]pyrimidine derivatives were discovered to be able to inhibit BRD4. WS-722 inactivated BRD4 (BD1/BD2), BRD2 (BD1/BD2) and BRD3 (BD1/BD2) broadly with the IC50 values less than 5 μmol/L. Besides, WS-722 inhibited growth of THP-1 cells with an IC50 value of 3.86 μmol/L. Like (+)-JQ1, WS-722 inhibited BRD4 in a reversible manner and enhanced protein stability. Docking studies showed that WS-722 occupied the central acetyl-lysine (Kac) binding cavity and formed a hydrogen bond with Asn140. In THP-1 cells, WS-722 showed target engagement to BRD4. Cellular effects of WS-722 on THP-1 cells were also examined, showing that WS-722 could block c-MYC expression, induce G0/G1 phase arrest and p21 up-regulation, and promote differentiation of THP-1 cells. BRD4 inhibition by WS-722 resulted in cell apoptosis and up-regulated expression of cleaved caspased-3/7 and PARP in THP-1 cell lines. The [1,2,4]triazolo[1,5-a]pyrimidine is a new template for the development of new BRD4 inhibitors.

Discovery of tofacitinib derivatives as orally active antitumor agents based on the scaffold hybridization strategy

In this work, a novel series of tofacitinib analogs were designed and synthesized based on the scaffold hybridization strategy and then evaluated for their antiproliferative activity toward three gastric cancer cell lines, leading to the identification of compound C18 which exhibited potent inhibitory activity against MGC-803 cell lines with an IC50 value of 2.68 μM. Compound C18 could effectively inhibit the colony formation, suppress the cell migration and induce apoptosis of MGC-803 cells through activating the p38 and JNK signaling pathways, while C18 showed no obvious effect on the cell cycle distribution in MGC-803 cells. In addition, C18 could initiate mitochondrial dysfunction of MGC-803 cells. Besides, in vivo antitumor studies indicated that C18 could inhibit gastric cancer tumor growth in vivo without obvious global toxicity.

Discovery of new [1,2,4] Triazolo[1,5-a]Pyrimidine derivatives that Kill gastric cancer cells via the mitochondria pathway

Mitochondria are known as “powerhouse of cells” and play the role of a bridge in redox balance, cell apoptosis, and autophagy. ROS accumulation can cause mitochondria damage, while the injured mitochondria will further enhance ROS levels reciprocally. Herein, we synthesized a novel series of [1,2,4]triazolo[1,5-a]pyrimidine-based compounds 4a-4v and tested their anti-proliferation efficacy against gastric cancer cell line MGC-803. Among them, compounds 4o and 4p inhibited gastric cancer cells at micromolar level. Compound 4o caused G2/M arrest and induced mitochondria-dependent apoptosis in MGC-803 and SGC-7901. However, inhibiting apoptosis pathway cannot prevent the inhibitory activity of compound 4o against gastric cancer cell. To our surprising, ROS level was increased by compound 4o and elevation of ROS could be rescued by NAC. In accordance with that, NAC absolutely prevented the anti-proliferation efficacy of compound 4o. We further found that autophagy inhibitor CQ rather than 3-MA partially reversed inhibitory activity of compound 4o in MGC-803 cells. Taken together, compound 4o exhibited its anti-proliferative activity via increasing ROS level and inducing autophagy, thus leading to apoptosis of gastric cancer cells. Therefore, compound 4o may support further development of lead compounds for gastric cancer therapy via mitochondria pathway.

Structure-Based Design, Synthesis, and Biological Evaluation of New Triazolo[1,5- a]Pyrimidine Derivatives as Highly Potent and Orally Active ABCB1 Modulators

ABCB1 is a promising therapeutic target for overcoming multidrug resistance (MDR). In this work, we reported the structure-based design of triazolo[1,5-a]pyrimidines as new ABCB1 modulators, of which WS-691 significantly increased sensitization of ABCB1-overexpressed SW620/Ad300 cells to paclitaxel (PTX) (IC50 = 22.02 nM). Mechanistic studies indicated that WS-691 significantly increased the intracellular concentration of PTX and [3H]-PTX while decreasing the efflux of [3H]-PTX in SW620/Ad300 cells by inhibiting the efflux function of ABCB1. The cellular thermal shift assay suggested that WS-691 could stabilize ABCB1 by directly binding to ABCB1. WS-691 could stimulate the activity of ABCB1 ATPase but had almost no inhibitory activity against CYP3A4. Importantly, WS-691 increased the sensitivity of SW620/Ad300 cells to PTX in vivo without observed toxicity. Collectively, WS-691 is a highly potent and orally active ABCB1 modulator capable of overcoming MDR. The triazolo[1,5-a]pyrimidine may be a promising scaffold for developing more potent ABCB1 modulators.

Development of Highly Potent, Selective, and Cellular Active Triazolo[1,5- a]pyrimidine-Based Inhibitors Targeting the DCN1-UBC12 Protein-Protein Interaction

The cullin-RING ubiquitin ligases (CRLs) are responsible for about 20% of cellular protein degradation and regulate diverse cellular processes, and the dysfunction of CRLs is implicated in human diseases. Targeting the CRLs has become an emerging strategy for the treatment of human diseases. Herein, we describe the discovery of a hit compound from our in-house library and further structure-based optimizations, which have enabled the identification of new triazolo[1,5-a]pyrimidine-based inhibitors targeting the DCN1-UBC12 interaction. Compound WS-383 blocks the DCN1-UBC12 interaction (IC50 = 11 nM) reversibly and shows selectivity over selected kinases. WS-383 exhibits cellular target engagement to DCN1 in MGC-803 cells. WS-383 inhibits Cul3/1 neddylation selectively over other cullins and also induces accumulation of p21, p27, and NRF2. Collectively, targeting the DCN1-UBC12 interaction would be a viable strategy for selective neddylation inhibition of Cul3/1 and may be of therapeutic potential for disease treatment in which Cul3/1 is dysregulated.

Experience-based discovery (EBD) of aryl hydrazines as new scaffolds for the development of LSD1/KDM1A inhibitors

Phenelzine was first employed to design new aryl hydrazine-based LSD1 inhibitors based on the experience-based discovery (EBD) strategy. Among these compounds, D8 potently inhibited LSD1 (IC50 = 882.30 nM) in a reversible manner. Compound D8 was selective to LSD1 over MAO-A/B and showed H3K4me2 competitive binding to LSD1. The interaction between H3K4me2 and LSD1 was also confirmed by the Co-IP assay. In LSD1 overexpressed A549 cells, compound D8 dose-dependently induced accumulation of LSD1 substrates H3K4me1/2 and H3K9me1/2, showed cellular target engagement to LSD1 and significantly inhibited cell migration of A549 cells. Docking studies suggested that compound D8 occupied the peptide binding region and therefore blocked the access of the peptide substrate to the FAD, finally leading to the demethylase activity inhibition of LSD1. The findings indicate that aryl hydrazines are new scaffolds for the design of LSD1 inhibitors, the identification of D8 provides further evidence for our previously proposed general principle that fused heterocycles with an amine group are potentially active toward LSD1 by competitive binding to LSD1 with H3 peptide substrates.

Synthesis, structure-activity relationship studies and biological characterization of new [1,2,4]triazolo[1,5-a]pyrimidine-based LSD1/KDM1A inhibitors

The histone lysine specific demethylase 1 (LSD1/KDM1A) is implicated in the development of cancers, targeting LSD1 has been recognized as a promising strategy for cancer therapy. To date, some small-molecule inhibitors are currently being investigated in clinical trials. Herein we report the design, synthesis and biochemical characterization of [1,2,4]triazolo[1,5-a]pyrimidine derivatives as new LSD1 inhibitors. Of these compounds, compound C26 inhibited LSD1 in a reversible manner (IC50 = 1.72 μM) and showed selectivity to LSD1 over MAO-A/B. Besides, compound C26 displayed FAD-competitive binding to LSD1. Interestingly, C26 did not inhibit horseradish peroxidase (HRP) and quench H2O2, thus excluding the possibility that LSD1 inhibition by C26 was due to the HRP inhibition and consumption of H2O2. In LSD1 overexpressed A549 cells, compound C26 concentration-dependently induced accumulation of H3K4me1/me2 and H3K9me2 and showed cellular target engagement to LSD1. Additionally, compound C26 significantly inhibited migration of A549 cells in a concentration-dependent manner, further western blot analysis showed that C26 increased expression levels of epithelial cell markers E-Cadherin and Claudin-1, down-regulated mesenchymal cell marker N-Cadherin and the upstream transcription factors Snail and Slug. Docking studies were also performed to rationalize the potency of C26 toward LSD1. To conclude, the [1,2,4]triazolo[1,5-a]pyrimidine could serve as a promising scaffold for the development of new LSD1 inhibitors.