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Considerable progress has been made in the development of anticancer agents over the past few decades, and a lot of new anticancer agents from natural and synthetic sources have been produced. Among heterocyclic compounds, pyrimidine-fused bicyclic heterocycles possess a variety of biological activities such as anticancer, antiviral, etc. To date, 147 pyrimidine-fused bicyclic heterocycles have been approved for clinical assessment or are currently being used in clinic, 57 of which have been approved by FDA for clinical treatment of various diseases, and 22 of them are being used in the clinic for the treatment of different cancers. As the potentially privileged scaffolds, pyrimidine-fused bicyclic heterocycles may be used to discover new drugs with similar biological targets and improved therapeutic efficacy. This review aims to provide an overview of the anticancer applications and synthetic routes of 22 approved pyrimidine-fused bicyclic heterocyclic drugs in clinic. Image 1 • 22 pyrimidine-fused bicyclic heterocyclic drugs have been approved for the treatment of cancers. • Pyrimidine-fused bicyclic heterocycles could be used as privileged structures for further development of new drugs. • The synthetic routes of 22 drugs and their anticancer applications are summarized. [ABSTRACT FROM AUTHOR]

In this work, we reported the discovery of compound 6i with potent antiproliferative activity against MGC-803. Among these compounds, the most potent compound 6i could effectively inhibit MGC-803 (IC 50 = 0.96 μM), being around 38-fold selectivity over GES-1. Further underlying mechanism studies indicated that 6i inhibited the colony formation, migration of MGC-803, and exerted anti-proliferative effect by inducing G0/G1 phase arrest in MGC-803 cells. Cell apoptosis was induced by 6i through activating mitochondria-mediated intrinsic pathway and the death receptor-mediated extrinsic pathway. 6i induced cell apoptosis by elevating the level of ROS. Also, 6i up-regulated pro-apoptotic Bax and p53 level, while down-regulating anti-apoptotic Bcl-2 protein expression. Furthermore, acute toxicity experiment indicated 6i exhibited good safety in vivo. Therefore, 6i may be a template for future development of [1,2,4]triazolo [1,5- a pyrimidine-based anti-cancer agents. Image 1 • The antiproliferative efficacy of [1,2,4]triazolo [1,5-a]pyrimidine derivatives were discovered and further optimized. • 6i effectively inhibited growth of MGC-803 (IC 50 = 0.96 μM), being around 38-fold selectivity over GES-1. • 6i induced cell apoptosis and G0/G1 phase arrest of MGC-803 cells. • 6i exhibited good safety in vivo. [ABSTRACT FROM AUTHOR]

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. Image 1 • New [1,2,4]triazolo[1,5-a]pyrimidines 4a-4v were designed and synthesized. • Compound 4o significantly and irreversibly inhibited proliferation of gastric cancer cells. • Compound 4o reduced the G2/M phase arrest. • Compound 4o induced ROS accumulation and activation of autophagy. [ABSTRACT FROM AUTHOR]

Abstract 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 (IC 50 = 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 H 2 O 2 , thus excluding the possibility that LSD1 inhibition by C26 was due to the HRP inhibition and consumption of H 2 O 2. 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. Graphical abstract Image 1 Highlights • A new series of [1,2,4]triazolo[1,5- a ]pyrimidine derivatives were designed as new LSD1 inhibitors. • C26 inhibited LSD1 reversibly and showed selectivity to LSD1 over MAO-A/B. • C26 concentration-dependently induced accumulation of H3K4/9 substrates and showed cellular target engagement to LSD1 in A549 cells. • C26 significantly inhibited migration of A549 cells in a concentration-dependent manner. • The [1,2,4]triazolo[1,5- a ]pyrimidine could serve as a promising scaffold for the development of new LSD1 inhibitors. [ABSTRACT FROM AUTHOR]

Abstract 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 (IC 50 = 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. Graphical abstract Image 1 Highlights • Phenelzine was first employed to design new aryl hydrazine-based LSD1 inhibitors. • D8 reversibly inhibited LSD1 (IC 50 = 882.30 nM) and showed H3K4me2 competitive binding to LSD1. • In A549 cells, D8 induced accumulation of H3K4me1/2 and H3K9me1/2. • D8 was cellularly engaged to LSD1 and inhibited migration of A549 cells. • The aryl hydrazines are new scaffolds for the design of LSD1 inhibitors. [ABSTRACT FROM AUTHOR]

Various kinds of bioactive compounds contribute to versatile health-promoting properties of Eucommia ulmoides Oliver (E. ulmoides). In present study, we developed a UPLC-QqQ-MS/MS method for simultaneous quantification of fourteen characteristic active compounds, including 3 lignans, 4 iridoids, 3 flavonoids and 4 phenolics in E. ulmoides and its tea product for the first time. The running time of the method is 6.5 min. It has good linearity, sensitivity, precision, accuracy, and stability. Using this high-throughput method, the distributions of fourteen characteristic active compounds in E. ulmoides and its tea product were clarified. Also, it was found that E. ulmoides tea exhibited superiority in contents of chlorogenic acid as compared with natural resources. Overall, the study provided a rapid, reliable, and efficient analysis method, which could be applied for the quality evaluation of E. ulmoides natural resources and their relative products in the field of food and medicine. [ABSTRACT FROM AUTHOR]

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 IC 50 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. Image 1 • New tofacitinib analogs were designed based on the scaffold hybridization strategy. • C18 effectively inhibits colony formation and cell migration of MGC-803 cells. • C18 induces apoptosis of MGC-803 cells through activation of the p38 and JNK signaling pathways. • C18 induces mitochondrial dysfunction of MGC-803 cells. • C18 effectively inhibits tumor growth of xenograft model bearing MGC-803 cells. [ABSTRACT FROM AUTHOR]

Drug repurposing plays a vital role in the discovery of undescribed bioactivities in clinical drugs. Based on drug repurposing strategy, we for the first time reported a novel series of troxipide analogs and then evaluated their antiproliferative activity against MCF-7, PC3, MGC-803, and PC9 cancer cell lines and WPMY-1, most of which showed obvious selectivity toward PC-3 over the other three cancer cell lines and WPMY-1. Compound 5q , especially, could effectively inhibit PC3 with an IC 50 value of 0.91 μM, which exhibited around 53-fold selectivity toward WPMY-1. Data indicated that 5q effectively inhibited the colony formation, suppressed the cell migration, and induced G1/S phase arrest in PC3 cells. Also, compound 5q induced cell apoptosis by activating the two apoptotic signaling pathways in PC3 cells: death receptor-mediated extrinsic pathway and mitochondria-mediated intrinsic pathway. Compound 5q up-regulated the expression of both pro-apoptotic Bax and P53, while down-regulated anti-apoptotic Bcl-2 expression. Besides, compound 5q significantly increased the expression of cleaved caspase 3/9 and cleaved PARP. Therefore, the successful discovery of compound 5q may further validate the feasibility of this theory, which will encourage researchers to reveal undescribed bioactivities in traditional drugs. Image 1 • A novel series of troxipide analogs were designed using drug repurposing strategy. • 5q effectively inhibited PC3 (IC 50 = 0.91 μM), being around 53-fold selectivity toward WPMY-1. • 5q effectively inhibited the colony formation, suppressed the cell migration, and induced G1/S phase arrest in PC3. • 5q induced apoptosis by activating death receptor-mediated extrinsic and mitochondria-mediated intrinsic pathways in PC3. [ABSTRACT FROM AUTHOR]