手性吡咯烷α-碳负离子合成子的形成和反应性研究

取代的α-羟烷-β-羟基-吡咯烷和哌啶是许多具有重要生理活性化合物,特别是氮杂糖的结构单元.例如,(-)-swainsonine 2是一种具有多种生物活性的生物碱:是溶酶体的α-甘露糖酶及甘露糖酶Ⅱ的有效抑制剂,具有抑制癌细胞转移和扩散,以及抗癌的活性.它是第一个应用于临床抗癌药物测试的糖蛋白抑制剂.澳洲栗精胺3是葡萄糖苷酶的强力抑制剂,能抑制病毒复制,具有显著的抗癌、抗病毒和抗菌活性.     

4-羟基-2-吡啶酮类天然生物碱的研究进展

4-羟基-2-吡啶酮类生物碱是从植物和昆虫等内生真菌发酵液中提取分离得到的一类新型天然生物碱, 具有抗真菌、抗菌和抗肿瘤等多种生物活性. 对近年来4-羟基-2-吡啶酮类天然生物碱的分离、结构确证和全合成等进行了总结和概述, 重点介绍了Ilicilolin H, Tenellin和Sambutaxin等的全合成.     

抗肿瘤Lamellarin类生物碱的合成研究新进展

Lamellarin类化合物是从海洋软体动物中分离得到的一类生物碱. Lamellarin类生物碱及其类似物具有良好的抑制肿瘤细胞增殖、逆转p-糖蛋白介导的多药耐药等活性, 显示出成为抗肿瘤候选药物的潜力. 近年来, 对Lamellarin类生物碱结构改造和新型杂合体及类似物的研究, 已成为新型抗肿瘤候选药物研究的热点之一. 综述了Lamellarin类生物碱的全合成策略与技术等方面的研究新进展.     

抗癌天然产物苦马豆素的合成研究进展

在过去十多年中, 多羟基吲哚兹定生物碱因其结构和多样性的生物活性(抗病毒、抗肿瘤、免疫调节活性)而引起了极大的关注. 其中最著名的成员是苦马豆素, 一种从灰苦马豆等植物中提取出来的化合物, 被证明具有治疗恶性肿瘤的作用并因此进行了大量合成研究. 到目前为止文献报道的合成方法都是基于碳水化合物原料或非碳水化合物底物和不对称反应. 尽管有些合成路线有效并且有实用价值, 但进一步开发制备天然或非天然吲哚兹定生物碱的通用和实用方法仍然非常重要. 总结了苦马毒素的合成研究进展, 以便为它的规模化生产提供思路和方法.     

苯并咪唑并氮杂糖的设计、合成及其糖苷酶抑制活性

鉴于前期研究发现的源于D-核糖的苯并咪唑并氮杂糖1和2具有良好的β-葡萄糖糖苷酶抑制活性,通过关键的Mitsunobu反应,设计合成了系列新型L-核糖源和2-脱氧-D-核糖源的苯并咪唑并氮杂糖衍生物6a～6c和7a～7c;并依据电子等排的药物设计方法,设计了系列新的糖环上2位氨基取代的稠合三环氮杂糖13a、13b和17a～17e;以及4位烷氧基取代的氮杂糖28a和28b.化合物13a和13b通过苄胺对甲磺酰化的羟基(OMs)取代合成,化合物17a～17e通过氨基对三元环氧中间体15的开环制备,化合物28a和28b通过4-羟基对卤代烃的亲核取代合成.测试了化合物6a～6c、7a～7c、13a、13b、15、17a～17e、19、28a和28b对α-葡萄糖糖苷酶(黑曲霉)、β-葡萄糖糖苷酶(杏仁)和α-半乳糖糖苷酶(咖啡豆)的抑制活性,结果显示所测化合物在10μmol/L时对α-葡萄糖糖苷酶和α-半乳糖糖苷酶没有或微弱的抑制活性,部分化合物表现出较好的β-葡萄糖糖苷酶抑制活性,其中环氧中间体15和2-氨基化合物17a活性最好,IC50值分别为10.5和11.7μmol/L,但均低于阳性对照品1的活性.结果表明该类稠合三环氮杂糖是一类良好的选择性β-葡萄糖苷酶抑制剂.     

由羰基糖合成氮杂糖

在甲醇中,二羰基糖和胺形成烯胺,通过氰化硼氢化钠双还原,以较高的收率合成了具有糖苷酶抑制活性的多羟基哌啶.通过加氢钯碳还原脱烷得到了氮杂吡喃型糖苷酶抑制剂1-脱氧野尻毒素(DNJ),其立体结构通过X-单晶衍射得以确定.采用涂钼热解石墨管,硝酸锂为基体改进剂,由石墨炉原子吸收法测定了在所合成的1-脱氧野尻毒素中的钯催化剂残留量.     

脱氧野尻霉素类两亲化合物的合成及其超分子糖苷酶抑制活性研究

以葡萄糖为原料经多步反应合成了脱氧野尻霉素类两亲化合物FA-DNJ-C6,通过表面张力实验、动态光散射实验(DLS)和透射电镜(TEM)等研究了FA-DNJ-C6的自组装行为,FA-DNJ-C6在水溶液中形成稳定的超分子自组装体.经酶抑制实验研究了FA-DNJ-C6自组装体的糖苷酶抑制活性,进而发现FA-DNJ-C6自组装体对α-糖苷酶具有好的选择性,尤其是对α-甘露糖苷酶,其抑制活性的Ki值为(0.107±0.021)μmol/L,与阳性对照(米格列醇)相比,活性提高了339倍,这主要是由于α-甘露糖苷酶具有多个识别位点的空腔,可发挥多效价协同增强的键合作用,提高糖苷酶抑制活性.     

双奎宁基间苯二甲酸酯的合成及其催化烯烃不对称双羟基化反应的初步研究

1988年,Sharpless等^[1]发现金鸡纳生物碱(Cinchonaalkaloid)的衍生物对烯烃的不对称双羟基化反应(AD)具有很高的不对称诱导活性.     

Renieramycin类生物碱的合成研究进展

具有显著抗癌、抗菌等活性的海洋四氢异喹啉生物碱引起多个领域的广泛关注,renieramycin型生物碱目前是其中成员数目最多的一类.不少此类生物碱及衍生物显示纳摩尔级的抗癌活性,加上有趣的分子结构,使其成为有机合成研究的一个热点.按合成策略分类,概述了renieramycin型生物碱的全合成研究进展.     

糖苷水解酶在糖苷合成中的应用概况

糖苷是一类附加值很高的生理活性化合物; 应用糖苷水解酶催化合成这类化合物具有很好的应用前景. 综述了糖苷水解酶在催化寡糖、脂肪醇或芳香醇、多肽、萜类、酚类、生物碱以及抗生素等底物糖基化中的研究进展, 着重说明了糖苷水解酶应用于合成反应的两种反应模式, 即逆水解反应和转糖苷反应. 另外还介绍了用于糖苷酶催化生产糖苷化合物的几类生物反应器.     

Sugar-mimic glycosidase inhibitors: natural occurrence,biological activity and prospects for therapeutic application

Alkaloids mimicking the structures of monosaccharides are now believed to be widespread in plants and microorganisms, and these sugar mimics inhibit glycosidases because of a structural resemblance to the sugar moiety of the natural substrate. Naturally occurring sugar mimics with a nitrogen in the ring are classified into five structural classes: polyhydroxylated piperidines, pyrrolidines, indolizidines, pyrrolizidines and nortropanes. Glycosidases are involved in a wide range of important biological processes, such as intestinal digestion, post-translational processing of glycoproteins and the lysosomal catabolism of glycoconjugates. The realization that alkaloidal sugar mimics might have enormous therapeutic potential in many diseases such as viral infection, cancer and diabetes has led to increasing interest and demand for these compounds. Most of these effects can be shown to result from the direct or indirect inhibition of glycosidases. The glycosphingolipid (GSL) storage diseases are relatively rare hereditary disorders that are severe in nature and frequently fatal. Possible strategies for the treatment of these lysosomal storage diseases include enzyme replacement therapy, gene therapy and substrate deprivation. Recently, quite a new therapy for lysosomal storage diseases has been reported, namely a ‘chemical chaperone therapy’ for Fabry disease. In this report, the structural basis for the specificity of inhibition of alkaloidal sugar mimics and their current and potential application to biomedical problems will be reviewed.     

Studies on Syntheses and Biological Activities of Novel Triazole Compounds Containing Phosphorodithioate Groups

Sixteen new triazole organic phosphorus compounds were synthesized. Their structures were confirmed with IR, IH NMR, elemental analysis and MS. The primary biological tests show that the titled compounds have the fungicidal activities, which are influenced by R groups and the substituents attached to the P atom.     

α- and β-Glucosidase inhibitors: chemical structure and biological activity

Glycoside trimming enzymes are crucially important in a broad range of metabolic pathways, including glycoprotein and glycolipid processing and carbohydrate digestion in the intestinal tract. Amongst the large array of enzymes, glucosidases are postulated to be a powerful therapeutic target since they catalyze the cleavage of glycosidic bonds releasing glucose from the non-reducing end of an oligo- or polysaccharide chain involved in glycoprotein biosynthesis. Glucosidase inhibitors are currently of interest owing to their promising therapeutic potential in the treatment of disorders such as diabetes, human immunodeficiency virus (HIV) infection, metastatic cancer, and lysosomal storage diseases. Glucosidase inhibitors have also been useful in probing biochemical pathways and understanding structure-activity relationship patterns required for mimicking the enzyme transition state. Amongst the various types of glucosidase inhibitors, disaccharides, iminosugars, carbasugars, thiosugars, and non-sugar derivatives have received great attention. This review is aimed at highlighting the main chemical classes of glucosidase inhibitors, as well as their biological activities toward α- and β-glucosidases, but it is not intended to be an exhaustive review on the subject. Inhibition data on the compounds covered in this review are included in a tabular form as an Appendix, where the type of each glucosidase associated with a specific inhibitor is also given.     

Synthetic Strategies for Fused Benzothiazoles: Past,Present, and Future

Benzothiazole is used as a building block in organic synthesis, which serves as a key template for the development of various therapeutic agents and shows a wide spectrum of activities. The attractive application of benzothiazole in organic synthesis is undoubtedly due to the highly reactive C-2 amino group, which is responsible for the change in its bioactivity. The construction of a poly-heterocyclic compound with the fused hetero-systems has attracted increasing attention because of the diverse range of potential therapeutic activities. Significant efforts have been undertaken to exploit different synthetic routes to these compounds. This article gives a comprehensive account of the synthetic utility of benzothiazole employed in the design and synthesis of different types of compounds containing fused heterocyclic rings with greater emphasis on recent literature.     

Pentacyclic Triterpenoids with Nitrogen-Containing Heterocyclic Moiety,Privileged Hybrids in Anticancer Drug Discovery

Pentacyclic triterpenoids are well-known phytochemicals with various biological activities commonly found in plants as secondary metabolites. The wide range of biological activities exhibited by triterpenoids has made them the most valuable sources of pharmacological agents. A number of novel triterpenoid derivatives with many skeletal modifications have been developed. The most important modifications are the formation of analogues or derivatives with nitrogen-containing heterocyclic scaffolds. The derivatives with nitrogen-containing heterocyclic compounds are among the most promising candidate for the development of novel therapeutic drugs. About 75% of FDA-approved drugs are nitrogen-containing heterocyclic moieties. The unique properties of heterocyclic compounds have encouraged many researchers to develop new triterpenoid analogous with pharmacological activities. In this review, we discuss recent advances of nitrogen-containing heterocyclic triterpenoids as potential therapeutic agents. This comprehensive review will assist medicinal chemists to understand new strategies that can result in the development of compounds with potential therapeutic efficacy.     

Iminosugars: from botanical curiosities to licensed drugs

George Fleet was a pioneer in establishing the structures of naturally occurring iminosugars and in developing novel methods for the chemical synthesis of iminosugars and related compounds. Iminosugars can inhibit or moderate the activity of a wide range of enzymes that act on carbohydrates and can probably affect the function of other carbohydrate-recognising proteins. These effects can be exploited for therapeutic purposes by using iminosugars to modify the glycosylation of eukaryotic cells, the metabolism of carbohydrates and glycoconjugates, the carbohydrate-dependent properties of glycoproteins such as folding and transport and the carbohydrate-mediated interaction of host cells with infective agents. The synthetic derivative of DNJ, N-hydroxyethyl DNJ, which inhibits intestinal disaccharidases and delays postprandial hyperglycemia, was approved for use in type 2 diabetes in 1996. Initially iminosugars were found to disrupt the lysosomal catabolism of glycoconjugates by inhibition of lysosomal glycosidases thereby causing chemically induced phenocopies of genetic lysosomal storage diseases. Paradoxically iminosugars are now being tested as potential therapeutic agents for human lysosomal storage diseases by exploiting some of their other properties. N-Butyl-DNJ, which inhibits the first step in the biosynthesis of many glycosphingolipids, is licensed for substrate reduction therapy for non-neuronopathic Gaucher’s and Niemann-Pick C diseases. 1-Deoxygalactonojirimycin can act as a molecular chaperone for mutant alpha-galactosidases in patients with Fabry disease. Several other compounds are being evaluated in pre-clinical studies or early clinical trials for lysosomal storage and other diseases.     

Synthesis and Fungicidal Activities of Pyrimethanil Heterocyclic Acid Salt

Seven pyrimethanil salts were synthesized by organic base containing nitrogen atom reacting with substituted pyridine acids. They are reported for the first time. Their structures have been confirmed by IR, ^1H NMR and elemental analysis. The preliminary toxicity tests indicated that most of them exhibited excellent fungicidal activities. The relationship between the structures and the fungicidal activities of the compounds was discussed.     

Organocatalytic Asymmetric Cascade Reactions Based on Gamma‐Nitro Carbonyl Compound

The significant advancements in asymmetric organocascade reactions have been accomplished during the past decades, paving the way to the efficient and stereoselective construction of structurally complex scaffolds from simple and readily available starting materials. Nitro‐containing cyclic compounds have become a privileged molecular library given their broad and promising activities in various therapeutic areas. In various approaches to build these valuable scaffolds, the utility of γ‐nitrocarbonyl intermediates is one of the most efficient approaches due to its high efficiency, reliability and versatility. The strategies and catalyst systems described here highlight recent advances in the enantioselective synthesis of nitro‐containing cyclic molecules via organocascade strategies based on γ‐nitrocarbonyl intermediates. Various organocatalysts with distinct activation modes have found application in providing these sophisticated compounds. This review is organized according to the types of organocatalyst. These methods are of importance for the construction of complex chiral cyclic frameworks and the design of new pharmaceutical compounds. We believe that compounds based on nitro‐containing cyclic skeletons have the potential to provide novel therapeutic agents and useful biological tools.     

钒-药物分子配合物生物活性研究进展

无机钒化合物具有降血糖、抗癌、抗炎和抗菌等作用,但生物利用度低,且有一定的毒性,影响了其在药物领域的应用。选择药物分子作为钒的配体,不仅可提高钒化合物的生物利用度,而且可增强或改进药物分子的活性,同时可能降低钒的毒性,从而成为近年来钒化学领域一个新的研究方向。本文主要介绍钒与不同类型药物分子形成配合物的生物活性及相关工作。     

2-氰基-3-甲硫基-3-苄氨基丙烯酸取代苯氧乙酯的合成及其除草活性

基于D1蛋白结构模型,设计并合成了一系列2-氰基-3-甲硫基-3-苄氨基丙烯酸取代苯氧乙酯,结构经¹HNMR、元素分析和IR确证.生物活性结果表明,化合物显示出较好的Hill反应抑制活性;而酯基部分的乙氧乙氧基被苯氧乙氧基取代后,活性有所下降,其原因可能是苯环分散了β-氧原子上的电荷密度,使之与Ser268的结合力降低,这进一步证实了Ser268位点的重要性.同时实验结果证明,苯环上的取代基对化合物活性有一定影响.