HMG-CoA还原酶抑制剂的合成(上)

本文综述了近年来上市的全合成HMG-CoA还原酶抑制剂药物的合成方法,主要叙述了含醛基、炔基、磺酰基、膦酸酯基或氨基官能团的侧链的制备以及这些侧链通过Wittig-Homor或Julia-Kocienski Olefination等反应与芳杂环的缩合.     

头孢氨苄酶法缩合工艺的研究进展

综述了青霉素乙酰化固定化酶和头孢氨苄酶法缩合工艺的研究进展;探讨了头孢氨苄酶法缩合工艺中酶催化缩合反应的影响因素、产品的分离与纯化以及过量原料的回收和酶反应器的选择等问题.结果认为头孢氨苄酶缩合反应的适宜条件为侧链与7-氨基脱乙酰氧基头孢烷酸(7-ADCA)的投料比率为11～21,反应底物的浓度为300～600mmol·L-,反应温度在5～35℃之间,7-ADCA的转化率可以达到93%以上.     

西多福韦的合成

目的:合成西多福韦。方法:以(R)-缩水甘油为原料,经保护羟基、与碱基缩合,保护氨基,与侧链缩合和脱保护等反应合成西多福韦。结果:目标化合物经核磁共振氢谱、红外、熔点等确证其化学结构,总收率达22%。结论:该路线反应条件温和,步骤较短,适合工业化生产。     

巴多昔芬的合成工艺及其晶型A的制备研究

目的改进巴多昔芬的合成工艺并制备晶型A。方法以对苄氧基溴代苯丙酮为起始原料,经Bischler吲哚成环制得母核;以对羟基苯甲醇为起始原料,经缩合、氯代两步反应制得侧链;母核与侧链经缩合、氢解、成盐、转晶得到晶型A。结果与结论目标化合物的结构经1H-NMR、MS、IR谱等确证,晶型经X-RD衍射确证。新合成路线操作简便,反应条件温和,适合工业化生产,总收率为38.7%。HPLC法检测纯度达99.88%,单个杂质含量小于千分之一,符合中国药典标准。     

不对称氨羟化反应合成抗癌药物紫杉醇

目的通过半合成法高收率制得紫杉醇。方法在可回收手性配体的催化作用下,通过不对称氨羟化反应一步合成紫杉醇C13侧链,对侧链的羟基和氨基进行保护后生成(4S,5R)-N-苯甲酰基-2-(4′-甲氧基)苯基-4-苯基-1,3-氧氮杂戊环-5-甲酸,进而和7-三乙基硅烷巴卡亭-Ⅲ缩合、去保护得到紫杉醇。结果获得了高光学纯度的紫杉醇C13侧链(化学收率41%,光学纯度99%)和紫杉醇(化学收率39%,光学纯度99%)。结论此方法反应步骤少、操作简单,为紫杉醇的半合成开辟了一条新路线。     

抗癌药物Combretastatin A-4及其水溶性衍生物的合成

目的:合成抗癌药物Combretastatin A-4及其水溶性衍生物.方法:以三甲氧基苯乙酸与异香兰素为原料,经缩合或进一步连接侧链、脱羧等反应合成Combretastatin A-4及其水溶性衍生物.结果:目标化合物经核磁共振氢谱、碳谱、质谱、熔点等确证其化学结构,总收率均达到40%左右.结论:该路线反应条件简便,步骤较短,对顺式产物选择性高,适合工业化生产.     

泰利霉素侧链的合成

3-溴乙酰基吡啶经氨解、甲酰化、环合反应制得4-(3-吡啶基)-1H-咪唑,进而与N-(4-溴丁基)邻苯二甲酰亚胺缩合后肼解,制得泰利霉素侧链化合物4-[4-(3-吡啶基)-1H-咪唑-1-基]-1-丁胺,总收率为33%.     

厄洛替尼合成工艺改进

目的改进和优化厄洛替尼的合成工艺,以便于工业化生产。方法以3,4-二羟基苯甲醛为原料,依次通过醛基还原缩合、侧链烷氧基化、硝化、硝基还原和关环等反应步骤合成目标化合物。结果与结论目标产物总收率约为48.5%,其结构经核磁共振氢谱、质谱、元素分析确证。该路线操作简便,条件温和,有利于工业化生产。     

维生素K_1缩合反应进展

维生素K_1(VK_1)已工业化生产多年,但由于缩合反应中极易产生2-位取代、环合及侧链的脱氢等副产物,以致产品中带有深褐色的杂质,经水解及氧化成醌。由于其物理性质及分子量与VK_1极其相近,所以分离困难。质差的“成品”含量低至80％,色呈橙红。(USPXXI版规定高压液相测定含量应为     

γ-丁内酯类衍生物的合成及其脂肪酸合成酶抑制活性的研究

目的 以C75为先导化合物,设计、合成γ-丁内酯类衍生物,并研究其脂肪酸合成酶（fatty acid synthase, FAS）的抑制活性,以期发现新颖的FAS抑制剂。方法 以衣康酸酐为起始原料,经酯化、烃代、缩合/环合、水解4步反应合成目标化合物,采用体外方法初步筛选其FAS的抑制作用。结果与结论 合成了11个目标化合物,其结构经核磁和质谱确证;初步活性评价结果显示,含饱和烷烃侧链的化合物具有较好的FAS抑制活性,随侧链烷基的延长,其抑酶活性有增强的趋势。     

N-ACYLSUCCINIMIDES AS ACYLATING AGENTS FOR PROTEINS: THE SELECTIVE ACYLATION OF LYSINE RESIDUES

The suitability of N-acylsuccinimides as reagents for the selective acylation of reactive side chains in proteins has been examined. A detailed study of the reaction of N-acetylsuccinimide with ribonuclease and bovine serum albumin showed that acetylation occurred in the pH range 3 to 8. Lysine side chains were acetylated selectively, with little or no modification of tyrosine side chains. There was no evidence for acetylation of serine, threonine or histidine side chains. The analogous N-propionyl, N-n-butyryl, N-i-butyryl and N-n-valerylsuccinimides also selectively acylate lysine side chains in proteins. This series of reagents, capable of changing the charge of lysine side chains and adding acyl groups of increasing hydrocarbon chain length, should prove a useful tool in studies of protein structure.     

Heparan sulfate chains potentiate cadmium cytotoxicity in cultured vascular endothelial cells

The monolayer of vascular endothelial cells, which is rich in heparan sulfate chains, is an important target of cadmium cytotoxicity. To investigate the effects of heparan sulfate chains on cadmium cytotoxicity, bovine aortic endothelial cells were cultured in the presence of cadmium, with or without exogenous heparan sulfate. The following results were obtained: (1) Heparan sulfate chains potentiated cadmium cytotoxicity. (2) Such a potentiation did not occur in bovine aortic smooth muscle cells. (3) Heparin chains as well as heparan sulfate chains potentiated cadmium cytotoxicity, while other glycosaminoglycan chains failed to exhibit such an activity. (4) The disaccharide units of heparan sulfate chains did not potentiate cadmium cytotoxicity in the endothelial cells. (5) Heparan sulfate chains did not potentiate mercury and arsenite cytotoxicity. (6) Fibroblast growth factor-2 (FGF-2) also potentiated cadmium cytotoxicity in the endothelial cells. (7) Heparan sulfate chains significantly increased intracellular cadmium accumulation by inducing the expression of metallothionein. Taken together, these results suggest that heparan sulfate chains activate FGF-2, which in turn elevates the expression and/or activity of metal transporter(s) that facilitate cadmium influx from the extracellular space into the cytoplasm.     

Free immunoglobulin light chains as target in the treatment of chronic inflammatory diseases

Immunoglobulin free light chains were long considered irrelevant bystander products of immunoglobulin synthesis by B lymphocytes. To date, different studies suggest that free light chains may have important functional activities. For instance, it has been shown that immunoglobulin free light chains can elicit mast cell-driven hypersensitivity responses leading to asthma and contact sensitivity. Free light chains also show other biologic actions such as anti-angiogenic and proteolytic activities or can be used as specific targeting vehicles. Levels of free light chain levels in body fluids increase markedly in diseases such as multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. In this review, we will focus on the unexpected biological activities of immunoglobulin free light chains with special attention to its possible role in the induction of chronic inflammatory diseases.     

Interaction of double-chained cationic surfactants,dimethyldialkylammoniums, with erythrocyte membranes: stabilization of the cationic vesicles by phosphatidylcholines with unsaturated fatty acyl chains

We studied the interaction of double-chained cationic surfactants, dimethyldialkylammoniums, (CH3)2N+(CnH2n+1)2, with the lipid bilayer of guinea-pig erythrocytes by observing the haemolysis, aggregation and shape change in the erythrocytes. In the presence of sonicated dispersions of the five dimethyldialkylammoniums tested (n = 10, 12, 14, 16 and 18), haemolysis was induced dose dependently, and at 0.1 mM or higher concentrations, haemolysis was induced more rapidly by dimethyldialkylammoniums with shorter alkyl chains. The cationic surfactants with longer alkyl chains, such as dimethyldipalmitylammonium, induced aggregation of the erythrocytes before haemolysis fully progressed. The vesicles of these long-chain dimethyldialkylammoniums in the presence of phosphatidylcholines with unsaturated fatty acyl chains markedly reduced the haemolysis rates. Furthermore, in the presence of phosphatidylcholines with unsaturated acyl chains the formation of tightly aggregated structures of several erythrocytes was observed. These findings, and analysis by spin label 5-doxylstearic acid, indicate that phosphatidylcholines enriched with unsaturated acyl chains stabilize the cationic vesicles of long-chain dimethyldialkylammoniums and the interaction with the lipid bilayer of erythrocyte membranes as cationic vesicles became prominent.     

Effect of 8-substituted cyclic AMP derivatives on soluble guanylate cyclase activity from human platelets

Inhibitory effect of 8-alkyl cyclic AMP derivatives on the soluble guanylate cyclase activity from human platelets was investigated. Cyclic AMP derivatives with alkyl chains of 6 or less carbons at 8-position of the purine base were not inhibitory, but the derivatives with alkyl chains of 7 or more carbons produced significant inhibition of the soluble guanylate cyclase activity. The extent of inhibitory effect increased when a longer alkyl chain was introduced at the 8-position of cyclic AMP. In contrast, 8-alkyl adenosine derivatives did not inhibit the cyclase activity. These results suggest that the platelet guanylate cyclase has an affinity for cyclic AMP derivatives with hydrophobic property as well as for several guanine nucleotides such as GTP or cyclic GMP.     

Conformationally constrained analogues of diacylglycerol (DAG). 17. Contrast between sn-1 and sn-2 DAG lactones in binding to protein kinase C

In previous work, we have obtained potent protein kinase C (PK-C) ligands with low-namomolar binding affinities by constructing diacylglycerol (DAG) mimetics in which the sn-2 carbonyl of DAG was constrained into a lactone ring. An additional structural element that helped achieve high binding affinity was the presence of branched acyl or alpha-alkylidene chains. In the present study, the effects of similarly branched chains on a different lactone system, where the lactone carbonyl is now equivalent to the sn-1 carbonyl of DAG, are investigated. In this new lactone template, the two chiral centers must have the S-configuration for enzyme recognition. As with the sn-2 DAG lactones, the branched chains were designed to optimize van der Waals contacts with a group of conserved hydrophobic amino acids located on the rim of the C1 domain of PK-C. The acyl and alpha-alkylidene chains were also designed to be lipophilically equivalent (8 carbons each). Eight new compounds (7-14) representing all possible combinations of linear and branched acyl and alpha-alkylidene were synthesized and evaluated. The sn-1 DAG lactones were less effective as PK-C ligands than the sn-2 DAG lactones despite having a similar array of linear or branched acyl and alpha-alkylidene chains     

Expression and role of sugar chains on airway mucus in induction and exacerbation of airway inflammation

Human bronchial mucins, such as MUC5AC, have traditionally been defined as a family of high-molecular weight glycoproteins. Changes in the contents of sugar chains on MUC5AC are among the fundamental features in inflammatory respiratory disease. The changes have been shown to lead to unfavorable alterations in the viscosity of mucus, resulting in impairment of mucociliary transport, vulnerability to viral/bacterial infection as sugar chains play an important role in adhesion of some viruses and bacteria to the epithelium, and finally inflammatory cell infiltration in the airway. Recently, we found that expression of some glycosyltransferases associated with the contents and structure of sugar chains is regulated by phosphatidylinositol-phospholipase (PI-PL) C signaling in cells. L-Carbocisteine, a mucoregulatory drug, normalized or balanced fucosylated and sialylated sugar chains, such as sialyl Lewis x through inhibition of PI-PL C signaling. We prepared MUC5AC fusion protein with tandem repeats associated with MUC5AC, and confirmed that L-carbocisteine inhibited the increases in viscosity associated with sialyl Lewis x expression levels. In addition, the clinical study (2008) noted that L-carbocisteine reduced the frequency of common colds and exacerbation of symptoms in patients with COPD. These favorable effects in patients may be due to normalization of sugar chain contents on mucins. We suggest that the inhibitory effect on infection of airway epithelial cells by rhinoviruses, respiratory syncytial virus, and influenza viruses by treatment with L-carbocisteine may also be based on the regulation of sugar chain contents or structures on mucins.     

Enhanced adhesion of oxidized mouse polymorphonuclear leukocytes to macrophages by a cell-surface sugar-dependent mechanism

Mouse thioglycollate-induced peritoneal macrophages effectively, in the absence of serum, recognized mouse polymorphonuclear leukocytes (PMNs) mildly oxidized with diamide, superoxide (hypoxanthine/xanthine oxidase) or t-butyhydroperoxide, or modified with N-ethylmaleimide (NEM). The recognition reached a maximum when PMNs were treated wtih each of the reagents at relatively low concentrations, and the recognition was decreased on treatment with reagents at higher concentrations. Glutathione depletion in the diamide-oxidized PMNs may cause enhanced adhesion to macrophages. Sialylated sugar chains attached to a peptide chain in glycophorin A and sialylated poly-N-acetyllactosaminyl sugar chains in lactoferrin and band 3 glycoprotein effectively inhibited the increased adhesion of the diamide-oxidized PMNs. Enzymatic removal of sialyl residues and the degradation of poly-N-acetyllactosaminyl sugar chains by pretreatment of PMNs with neuraminidase or endo-beta-galactosidase, respectively, lost their increasing ability for macrophage adhesion after oxidation with diamide, superoxide or t-butylhydroperoxide. Clustered sialylated poly-N-acetyllactosaminyl sugar chains on the cell surface may be involved in the increased adhesion of the oxidized PMNs to macrophages.     

The use of anti-ricin antibodies to protect mice intoxicated with ricin

Antibodies raised in rabbits to ricin or its constituent polypeptide chains are effective at rescuing mice from ricin intoxication if given soon enough after administration of the toxin. The maximum safe period for intravenous injection of 100 micrograms antibody is 40 min after intravenous injection of 1 microgram ricin, increasing to 640 min in the case of subcutaneously injected ricin. The antibodies raised against the isolated A and B chains are as effective as those against whole ricin. The antibody is as effective when administered intracerebrally as by the intravenous route; this result, combined with the very high toxicity for ricin administered intracerebrally suggests a neurotoxic role for the lectin.     

Regulation of neuronal cell function by glyco-signals

Gangliosides and proteoglycans with various sugar chains exist abundantly in the brain. They participate in intercellular recognition by revealing the sugar chains on the cell surface, and some of them show neurite-extension activity. Several recognition features that are mediated by the sugar chains are known such as saccharide-saccharide interaction and cell-surface sugar-chain receptor-mediated recognition. Experiments on animals lacking the sugar-chain synthetic system with the technique of gene targeting suggest that phylogenetically "old" sugar chains such as chondroitin sulfate appear necessary for early development of the organism while relatively "new" sugar chains such as gangliosides, which appear with further development of the brain, are necessary for differentiation maturity processes. On the other hand, research using primary cultured neurons showed similar effects of the gangliosides and chondroitin sulfate on cell differentiation. It is possible that these sugar chains share the glyco-receptor-mediated signal transduction system.