摘要：A new series of isatin semicarbazide derivatives（7a-7j） were synthesized and characterized by spectroscopic means and elemental *** and anti-inflammatory screening was performed using tail-flick technique and the carrageenan-induced foot paw edema test *** ulcerogenicity was also determined for all the *** of the compounds showed moderate enhancement of the *** the synthesized derivatives,compound 7d showed higher analgesic, antiinflammatory and one-third of ulcer index of the reference drug.

摘要：Cell-derived microvesicles(MVs) are secreted from almost all kinds of mammalian cells into the extracellular space, and play crucial roles in intercellular communication and transporting biomolecules between cells. However, there is a great challenge for visualizing and monitoring of MVs’ bio-behaviors due to the limitations of existing labeling methods. Herein, we report the first paradigm of designer cell-self-implemented labeling of MVs secreted from living mammalian MCF-7 cells in situ using the intracellular-synthesized fluorescent quantum dots(QDs) during the formation of MVs. By elaborately coupling intracellular biochemical reactions and metabolism pathways, the MCF-7 cells can be illuminated brightly by intracellular-biosynthesized fluorescent CdSe QDs. Simultaneously, intracellular-synthesized QDs can be in situ encapsulated by the secreted MVs budding from the plasma membrane of the fluorescing cells to label the MVs with an efficiency of up to 89.9%. The whole labeling process skillfully combines designer precise cell-tuned intricate synthesis of CdSe QDs with mild in-situ labeling via cell-selfimplementation just after feeding the cell with suitable chemicals, which is structure-or function-nondestructive and much more straightforward and milder than those by chemical conjugation or indirect encapsulation with conventional fluorogenic labels.

摘要：Cyclic dinucleotides(CDNs) are known to activate stimulator of interferon genes(STING) and induce type I interferon responses, therefor possess great potentials to be of immunotherapeutic value for cancers and infectious diseases. However, the existence of different single nucleotide polymorphism(SNP) of human STING(hSTING) gene poses an obstacle to achieve broad-spectrum activation by CDNs. We reported here the design and synthesis of a total of 36 CDNs, representing all structural variations, that contain four bases(A, G, C, U) and two linkage directions(2′-5′-linked and 3′-5′-linked phosphodiester).Through systematic evaluation of IFN-β induction with a dual-luciferase reporter assay, we discovered that wild type hSTING and two isoforms(HAQ and AQ) showed strong response while hSTING-R232 H and R293 Q exhibited the relatively weak response to CDNs stimulation. For the first time, we found that the c[G(2′,5′)U(2′,5′)] showed excellent activity against all five hSTING variants even equivalent to the endogenous ligand c[G(2′,5′)A(3′,5′)]. Furthermore, we have also demonstrated that 3′-3′CDNs with two 3′-5′ phosphodiesters showed higher serum and hydrolase stability than 2′-2′ CDNs with two 2′-5′ phosphodiesters and 2′-3′ CDNs with one 2′-5′ and one 3′-5′ phosphodiester. It is very interesting to note that 2′-2′ CDNs has been found for the first time to show strong activity. These findings will stimulate our exploration for the new functional role of CDNs, and provide guidelines to design CDNs based hSTING targeted drugs.

摘要：Since the PI3K signaling pathway is the most commonly activated in human cancers,inhibition of PI3K is a promising approach to cancer *** this study,a series of 2-methyl-5-nitrobenzeneacylhydrazones were designed and *** the new derivatives were tested by p110α enzymatic and Rh30 cellular *** enzyme selectivity profiling proved that 6e and 7 were potential selective PI3K inhibitors.

摘要：Strategies for CADD vary depending on the extent of structural and other information available regarding the target (enzyme/receptor) and the ligands. Computer-aided drug design (CADD) is an exciting and diverse discipline where various aspects of applied and basic research merge and stimulate each other. In the early stage of a drug discovery process, researchers may be faced with little or no structure activity relationship (SAR) information. The process by which a new drug is brought to market stage is referred to by a number of names most commonly as the development chain or “pipeline” and consists of a number of distinct stages. To design a rational drug, we must firstly find out which proteins can be the drug targets in pathogenesis. In present review we reported a brief history of CADD, DNA as target, receptor theory, structure optimization, structure-based drug design, virtual high-throughput screening (vHTS), graph machines.

摘要：Inhibition of VEGFR-2 signaling pathway is one of the most promising approaches for the treatment of cancer. In this paper, we reported the design, synthesis, and biological evaluation of a series of biphenylurea derivatives as VEGFR-2 inhibitors. Among these compounds, 39 exhibited potent inhibitory activity against VEGFR-2 both in vitro and in vivo. The antiangiogenesis activity of 39 was further confirmed by both tube formation assay and chick chorioallantoic membrane assay.

摘要：Inhibition of VEGFR-2 signaling pathway has already become one of the most promising approaches for the treatment of *** this study,we describe the design,synthesis,and biological evaluation of a series of O-linked indoles as potent inhibitors of *** these compounds,18 showed significant anti-angiogenesis activities via VEGFR-2 in enzymatic proliferation assays,with IC50 value of3.8 nmol/L Kinase selectivity profiling revealed that 18 was a multitargeted inhibitor,and it also exhibited good potency against VEGFR-1,PDCFR-α and β.