| Dihydropyrrole and its derivatives are important pentatomic heterocyclic compounds. They are widely applied in medicine, pesticides, food, house hold chemicals and so on. Because of the application of pyrrole and its derivatives in sensitive material and polymer materials, people pay more attention to the synthesis of pyrrole derivatives.Many natural products and synthetic compounds with clinical value contain the basical structure of dihydropyrrolidone. Nitrogen heterocycles have been the subject of intense research due to their outstanding biological properties and wide range of applications to pharmaceutical compounds, agrochemicals and synthetic inter-mediates. For example, dihydropyrrol-2-ones have been used as the inhibitors of cardiac cyclic AMP phosphodiesterase, HIV (human immunodeficiency virus) integrase, and vascular endothelial growth factor receptors as well as useful intermediates. Therefore, a diversity of methodologies has been developed for the synthesis of protein kinase C (PKC) inhibitor, the serotonin receptor (5-HT2C) inhibitor, as well as glycogen synthase kinase (GSK-3β) inhibitor. They are also useful intermediates in the synthesis of natural products. So modification on such compound has good prospects. In recent years, people pay more enthusiasm to the synthesis of pyrroles, not only to improve and extend the scope of application of some classical synthesis pyrrole derivatives, and even put forward a novel type of reaction. The methods for the synthesis of pyrroles via alkynyl compounds and multi-component are more attractive. Synthesis and characterization of polysubstituted pyrroles is a novel and efficient method for construction of polysubstituted pyrroles, which included an intermolecular amination and intramolecular hydroamidation.Recently, multi-component reactions (MCRs), which response to the simple procedure, efficiency and superior atom economy, have gradually become one of the development trends of synthetic organic chemistry. In2009, multisubstituted pyrrolidone and pyrimidine derivatives had been synthesized in our laboratory via multicomponent reation methed, with the advantages of simple operation, mild reaction conditions, short reaction time, and the catalyst is cheap and easy.We reported the novel efficient four-component reactions (4CRs) of but-2-ynedioates, same/different primary amines and aldehydes for the synthesis of tetra-and pentasubstituted polyfunctional dihydropyrroles. If using aromatic and aliphatic amines as reagents, four different series of products should be obtained via the permutation and combination of aromatic and aliphatic primary amines. However, only three/two rather four different series of tetra/pentasubstisuted dihydropyrroles could be prepared via the proton/heat-promoted4CRs. Herein, Cu(OAc)2·H2O, a Lewis acid being stable in air and water, was found to be an efficient catalyst for the4CRs synthesis of all the four different series of tetra-/pentasubstisuted dihydropyrroles. The copper-catalyzed4CRs could produce target products at room temperature in good to excellent yields. Interestingly, benzaldehyde, besides being used as a useful reactant for the synthesis of pentasubstituted dihydropyrroles, was found to be an excellent additive for preventing the oxidation of aromatic amines with copper(II) and ensuring the sooth conduct of the4CRs for the synthesis of tetrasubstituted dihydropyrroles with aryl R3. In addition, salicylic acid was found to be needed to increase the activities and yields of the copper-catalyzed4CRs for the synthesis of petasubstituted diyhydropyrroles. Basing on experimental results, the enamination/amidation/inter-molecular cyclization mechanism was proposed and amidation is expected to be the rate-limited step in the copper-catalyzed4CRs.Apoptosis is an autonomous genetically-controlled cell death process with great biological significance, which organisms use to maintain its stability and normal physiological functions. It plays an important role in development and treatment of tumor, because of a large number of chemotherapeutics exert their anticancer effect through inducing tumor cell apoptosis. Excessive apoptosis associated with many diseases, such as immunodeficiency disease, Alzheimer’s, Parkinson, ischemia, traumatic brain injury, stroke, cardiac obstruction, amyotrophic lateral sclerosis. Therefore, the effective method of inhibiting cell apoptosis can be the treatment of these diseases.Apoptosis is a process which is strictly controled by multiple genes. These genes are well conserved between species, such as Bcl-2family, Caspase family, cancer genes such as C-myc, tumor suppressor gene P53. Caspase is a family of cysteine proteases, plays a key role in the process of apoptosis. Apoptosis is a protease cascade reaction process of a complex. Although apoptosis induced by the different cells or different signal transductional pathway, the Caspase-3is the only way which must be passed to apoptotic protease cascade. Caspase-3is the key enzyme and the executor and apoptosis. Gene knockout experiments and animal model is demostrate that cell apoptosis in vitro and in vivo is deleted out due to knockout caspase. Therefore, Caspase-3is expected to a new target for treatment of neurodegenerative diseases, abnormal apoptosis caused by cardiovascular, cerebrovascular disease, as well as rheumatoid arthritis. Therefore, it is urgent to synthesis effective inhibitors of Caspase-3for treating diseases mentioned above.The design of Caspase inhibitors include3strategies:Firstly, base on cysteine residues and Caspase activity center with cysteine protease inhibition; Secondly, base on specific Caspase substrate cleavage sites and the development of specific inhibitors; Thirdly, focus on the indole, isoindole basical nucleus of small molecular compounds, as well as the novel active small molecules in recent years, such as two hydrogen pyrrolidone, aspartic acid vinyl sulfones. There exist catalytic region of Caspases by the nucleophilic cysteine residues and histidine imidazoles, all in the aspartic acid residue peptide substrates each fracture. Based on the specificity of the amino acid sequence of Caspase-3restriction enzyme recognize to-(P4)DXXD(P1), especially-DEVD-, Caspase-3inhibitor Ac-DEVD-fmk, Ac-DEVD-CHO were designed. But these inhibitors are as same as the polypeptide, could easily enzymatic hydrolysis in the vivo, and their pharmacokinetic property is poor, need multiple dosing. Therefore, the synthesis of high selectivity, good activity, pharmacokinetic properties and stable Caspase-3inhibitor has become urgent demand.Dennis Lee had found isatin compounds selectively inhibit Caspase-3,-7, Caspase-3inhibitory activity of IC50=0.25μmol/L via high throughputs creening.30compounds had been synthesized as non-isatin lead compound, also showed good selectivity and permeability of cell. There are lots of reports of Isatin and aniline quinazoline inhibitors based on Caspase-3as the lead compound, even the new small molecule inhibitors appear in recent years caused great concern, such as dihydrogen pyrrolidone, aspartic acid vinyl sulfones.A series of terra-and pentasubstituted polyfunctional dihydropyrroles5and6had been synthesized via practical multicomponent reactions (MCRs) for research on their structure activity relationship as Caspase-3inhibitors in our laborary in2012. Among39compounds evaluated,14of them exhibited inhibition against Caspase-3with IC50ranging from5to20μM. The inhibitory activities of5and6depend on the nature of substituents on different positions.5and6possess a different scaffold from those previously reported and were the first Caspase-3inhibitors prepared via MCRs. The most active compounds5k (IC50=5.27μM) could therefore be used as a lead for the development of highly potent Caspase-3inhibitors as drug candidates for therapeutic agents by taking advantage of MCRs.In this paper, three series of dihydrogen pyrrolidine derivatives had been done flow cell experiments, via cell model of leukemia lymphoid T cell (Jurkat T). Jurkat T apoptosis induced by Cam-ptothecin (Cam) and as the positive control. Among38compounds evaluated, six compounds had been found with anti-apoptotic activity. Western blot assay experiment show that5rr{1,13,4,1} can inhibit apoptosis of leukemic lymphoid T cells (Jurkat T) induced by camptothecin and lower the expression of activated Caspase-3,witch is related to Caspase-3inhibition.PC-12cells are the rat adrenal medullary pheochromocytoma clonal cell lines and are basic biological characteristics of neuron cell. The cell membrane contain NMD A receptor, cholinergic M, N receptor, has been widely used to nerve cell functional experiment. The brain is very sensitive as extremely prone to cause the damage of nerve cells when encounter with ischemia and hypoxia. PC-12is commonly cell used in study of cerebral ischemia injury. Methods commonly used cell hypoxia model including physical method and chemical hypoxia. Chemical hypoxia method refers to the method of cellular hypoxia by chemical reagent. Cobalt chloride is a chemical reagent induced cell injury in vitro, can simulate neurons injury. In this paper, the PC-12neural cell hypoxia model is induced by cobalt chloride. Experimental results show that5rr{1,13,4,1} has protective effect in inhibiting PC-12apoptosis, witch possible related to lower the expression of Caspase-3zymogen.The structures of all products were cllaractetized by1H NMR spectroscopy,13C NMR spectra and MS analysis. The absolute structures of one compound were confirmed by single crystal X-ray diffraction analysis, and a reasonable reaction mechanism was suggested. At the same time, some novel synthetic methods of some heterocyclic compounds containing-nitrogen were provided in this paper. |
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