Design, synthesis and biological evaluation of 4-aniline-thieno[2,3-d]pyrimidine derivatives as MNK1 inhibitors against renal cell carcinoma and nasopharyngeal carcinoma.

MAP Kinase Interacting Serine/Threonine Kinase 1 (MNK1) play important roles in the signaling transduction of MAPK pathways. It is significantly overexpressed in renal clear cell carcinoma and head-neck squamous cell carcinoma tissues in both mRNA and protein levels. Based on the crystallographic structure of MNK1 protein and binding modes analysis of known MNK inhibitors, we have designed and synthesized a series of 4-aniline-thieno[2,3-d]pyrimidine derivatives as potential MNK1 inhibitors. These synthetic compounds are tested in biochemical and cell proliferation assays, and six of them display potent inhibitory capacity against MNK1 kinase and cancer cell lines. Compound 12dj with strongest inhibitory capacity is transferred to molecular mechanism studies, and the results indicated that 12dj remarkably suppresses the phosphorylation of EIF4E, a substrate of MNK1. And the expression levels of MNK1, ERK1/2 and pERK1/2 are not affected by compound 12dj incubation in SUNE-1 and 786-O cells. In summary, our works suggested that these novel 4-aniline-thieno[2,3-d]pyrimidine based MNK1 inhibitors might be attractive lead compounds for targeted therapy of renal cell carcinoma and nasopharyngeal carcinoma.

Design, Synthesis, and Biological Evaluation of Pyrano[2,3-c]-pyrazole-Based RalA Inhibitors Against Hepatocellular Carcinoma.

The activation of Ras small GTPases, including RalA and RalB, plays an important role in carcinogenesis, tumor progress, and metastasis. In the current study, we report the discovery of a series of 6-sulfonylamide-pyrano [2,3-c]-pyrazole derivatives as novel RalA inhibitors. ELISA-based biochemical assay results indicated that compounds 4k-4r suppressed RalA/B binding capacities to their substrates. Cellular proliferation assays indicated that these RalA inhibitors potently inhibited the proliferation of HCC cell lines, including HepG2, SMMC-7721, Hep3B, and Huh-7 cells. Among the evaluated compounds, 4p displayed good inhibitory capacities on RalA (IC50 = 0.22 µM) and HepG2 cells (IC50 = 2.28 µM). Overall, our results suggested that a novel small-molecule RalA inhibitor with a 6-sulfonylamide-pyrano [2, 3-c]-pyrazole scaffold suppressed autophagy and cell proliferation in hepatocellular carcinoma, and that it has potential for HCC-targeted therapy.

Turntable Paper-Based Device to Detect Escherichia coli.

Escherichia coli has been known to cause a variety of infectious diseases. The conventional enzyme-linked immunosorbent assay (ELISA) is a well-known method widely used to diagnose a variety of infectious diseases. This method is expensive and requires considerable time and effort to conduct and complete multiple integral steps. We previously proposed the use of paper-based ELISA to rapidly detect the presence of E. coli. This approach has demonstrated utility for point-of-care (POC) urinary tract infection diagnoses. Paper-based ELISA, while advantageous, still requires the execution of several procedural steps. Here, we discuss the design and experimental implementation of a turntable paper-based device to simplify the paper-based ELISA protocols for the detection of E. coli. In this process, antibodies or reagents are preloaded onto zones of a paper-based device and allowed to dry before use. We successfully used this device to detect E. coli with a detection limit of 105 colony-forming units (colony-forming unit [CFU])/mL.