雷公藤内酯醇C14位羟基结构修饰及抗肿瘤活性研究进展

雷公藤是我国资源丰富的一种传统中草药,具有抗炎、抗肿瘤、免疫抑制等多种生物活性。本文综述了近年来雷公藤内酯醇C14位羟基的结构修饰和抗肿瘤活性的研究进展。     

海洋微生物中二酮哌嗪类化合物的研究进展

二酮哌嗪类化合物的基本结构是由两个氨基酸缩合而成的环二肽, 因其骨架具有稳定的六元环结构, 且有两个氢键给体和两个氢键受体, 使得DKPs具有较强的生物活性和药理活性, 在药物化学中成为一个重要的药效团。近年来从海洋微生物中发现一系列环二肽类化合物, 研究表明其功能不局限于抗菌、细胞毒活性等方面,在群体感应调控机制中也充当着信号分子的重要角色, 已成为化学生态学的研究热点。本文综述了近年来二酮哌嗪类化合物在海洋微生物代谢产物中的研究进展, 并对其研究方向进行了讨论和展望。     

双氯雷公藤内酯四醇的分离与结构研究

从雷公藤（Ｔｒｉｐｔｅｒｙｇｉｕｍ ｗ ｉｌｆｏｒｄｉｉＨｏｏｋ．ｆ．）的叶中分离出１个新的含氯环氧二萜内酯化合物。据其理化数据和光谱分析,并结合分子图形学和分子力学计算,确定了它的化学结构,命名为双氯雷公藤内酯四醇（ｄｉｃｈｌｏｒｏｔｒｉｐｔｅｔｒａｏｌｉｄｅ）。     

大戟科Casbane烷型二萜化合物的研究进展

本文综述了目前在自然界发现的Casbane烷型二萜化合物的结构特点、生物活性、分布状况和合成研究,同时针对文献中该类成分的骨架编号顺序混乱并造成化合物命名错误问题,我们采用J Buckingham的编号方法,对所有casbane烷型二萜化合物结构进行重新编号,对部分化合物命名进行修改.     

水稻化感品种根分泌物中非酚酸类化感物质的鉴定与抑草活性

水稻化感品种能从根系分泌释放化感作用物质 ,长期以来 ,酚酸类物质被认为是水稻根分泌的主要化感物质 ,但这一结论常常被质疑。利用连续循环和直接树脂吸收两种方法采集典型的水稻化感品种 PI31 2 777幼苗的根分泌物 ,并用液相色谱 /质谱(L C/ MS)联用技术鉴定了根分泌物中的非酚酸类物质。结果显示 ,水稻 PI31 2 777幼苗根系能分泌释放 7-甲氧基羟基肟酸、羟基肟酸、3-异丙基 - 5 -乙酰氧基环己烯酮 - 1、5 ,7,4′-三羟基 - 3′,5′-二甲氧基黄酮、二萜内酯 A和二萜内酯 B6个非酚酸类化合物。经液相色谱 (HPL C)定量分析 ,这些化合物在水稻生长 1 0 d的根分泌物中的浓度为 5～ 1 9μmol/ L。进一步的生测结果显示 ,这些化合物在其释放的浓度范围能对稻田常见的稗草和异型莎草有抑制活性 ,尤其是这些化合物的等摩尔混合物的抑草活性增加 ,同时水稻根分泌物的抑草活性与土壤载体显著相关。表明羟基肟酸、环己烯酮、黄酮和二萜内酯四类非酚酸类物质是水稻的主要化感物质 ,这与近期愈来愈多的研究结果一致     

昆明山海棠茎中化合物的分离及其抗炎活性

从昆明山海棠茎的氯仿提取物中分离得到6个化合物,经鉴定为雷公藤内酯甲(Ⅰ)、昆明山海棠二萜内酯(Ⅱ)、雷公藤内酯乙(Ⅲ)、雷酚二萜酸(Ⅳ)、雷公藤碱(Ⅴ)及3-epikatonic acid(Ⅵ)。其中,化合物Ⅲ及Ⅵ为首次从该植物中分离得到,化合物Ⅴ为首次从该植物茎中分离得到。药理实验显示化合物Ⅰ和Ⅱ对大鼠足跖部角叉菜胶炎症模型具有明显的抑制作用。     

荚迷属植物化学成分及生物活性研究进展

不少荚迷属植物有悠久的药用历史,从该属植物中分离到的化学成分有二萜、三萜、环烯醚萜苷、黄酮类、木脂素及酚苷.二萜类化合物主要是vibsane型化合物,某些具有生物活性;三萜类化合物主要是齐墩果烷型和重排达玛烷型;环烯迷醚萜苷类其糖苷的连接位置主要在环烯迷醚的C11位上,C1位连有异戊烯基.生物活性研究发现一些提取物具有抗氧化作用,对A549、HT-29和PC-3和NUGC癌细胞有毒性.本文对国内外有.关荚迷属植物化学成分和生物活性的研究作一综述,为开发利用荚迷属植物资源提供科学依据.     

红根草中的新二萜——红根草酮内酯和新红根草酮

由红根草(Salvia prionitis Hance)中分得三个abietane类二萜成分:红根草酮内酯(prioketolactone,1)、新红根草酮(neoprionitone,2)和二氢异丹参酮1(dihydroisotanshinone1,3)。经波谱分析确定了它们的化学结构。其中,1,2为新化合物,1是鼠尾草植物中首次发现的具有七元环内酯结构的二萜醌类化合物,3为首次从红根草中发现。     

雷公藤组织培养物中化学成分的研究

雷公藤植物的茎,叶在含激动素0.1mg/1,2.4-D 1mg/l的6.7-v培养基上诱导出愈伤组织。在22±2℃的条件下进行扩大培养后,收集培养物进行提取、分离。从薄层层析上显示出培养物中含有雷公藤甲素、雷公藤乙素等二萜内酯化合物。柱层析分离出5个萜类化合物,根据它们的mp、TLC、IR、~1HNMR、MS等图谱资料,其中4个分别鉴定为雷公藤酮,雷公藤内酯甲、3-Epikatonic acid,齐墩果酸,另一个化合物的结构有待进一步研究。     

雷公藤茎中的二萜类成分及生物活性研究

综合运用正相硅胶柱色谱、中压液相色谱(MPLC)、羟丙基葡聚糖凝胶(Sephadex LH-20)及高效液相色谱等多种方法,从雷公藤Tripterygium wilfordii Hook.f.茎乙醇提取物的乙酸乙酯相中分离鉴定了1个新的松香烷型二萜wiltriptobenzene(1)和19个已知的二萜,包括雷藤二萜醌H(2)、triptoquinone B(3)、hinokione(4)、雷酚萜(5)、triptonediol(6)、triptobenzene A(7)、wilforol F(8)、triptobenzene B(9)、abietatrien-3β-ol(10)、triptobenzene S(11)、hypoglicin B(12)、triregelin H(13)、雷酚内酯(14)、雷酚新内酯(15)、16α-hydroxy-19,20-epoxy-19R~*-methoxy-kaurane(16)、16α-hydroxy-19,20-epoxy-20R~*-ethoxy-kaurane(17)、16α-hydroxy-19,20-epoxy-19R~*-ethoxy-kaurane(18)、fischericin D(19)和ent-pimara-8(14),15-diene-19-ol(20)。化合物的结构通过与文献对比核磁共振波谱数据确定。化合物10、19和20首次报道从雷公藤中分离得到。在脂多糖(LPS)诱导小鼠单核巨噬细胞(RAW 264.7)的模型中,评价了化合物1～20的体外抗炎活性;采用MTT法评价了化合物1～20的体外抗人体宫颈癌(Hela)细胞株活性。化合物2、3和20具有显著的抗炎活性,其半数抑制NO生成的IC_(50)值分别为2.01、1.70和1.77μmol/L。化合物11具有微弱的体外抗肿瘤活性,IC_(50)值为18.41μmol/L。     

Novel targets of pentacyclic triterpenoids in Staphylococcus aureus: A systematic review

BackgroundStaphylococcus aureus is an important pathogen both in community-acquired and healthcare-associated infections, and has successfully evolved numerous strategies for resisting the action to practically all antibiotics. Resistance to methicillin is now widely described in the community setting (CMRSA), thus the development of new drugs or alternative therapies is urgently necessary. Plants and their secondary metabolites have been a major alternative source in providing structurally diverse bioactive compounds as potential therapeutic agents for the treatment of bacterial infections. One of the classes of natural secondary metabolites from plants with the most bioactive compounds are the triterpenoids, which comprises structurally diverse organic compounds. In nature, triterpenoids are often found as tetra- or penta-cyclic structures.AimThis review highlights the anti-staphylococcal activities of pentacyclic triterpenoids, particularly α-amyrin (AM), betulinic acid (BA) and betulinaldehyde (BE). These compounds are based on a 30-carbon skeleton comprising five six-membered rings (ursanes and lanostanes) or four six-membered rings and one five-membered ring (lupanes and hopanes).MethodsElectronic databases such as ScienceDirect, PubMed and Scopus were used to search scientific contributions until March 2018, using relevant keywords. Literature focusing on the antimicrobial and antibiofilms of effects of pentacyclic triterpenoids on S. aureus were identified and summarized.ResultsPentacyclic triterpenoids can be divided into three representative classes, namely ursane, lupane and oleananes. This class of compounds have been shown to exhibit analgesic, immunomodulatory, anti-inflammatory, anticancer, antioxidant, antifungal and antibacterial activities. In studies of the antimicrobial activities and targets of AM, BA and BE in sensitive and multidrug-resistant S. aureus, these compounds acted synergistically and have different targets from the conventional antibiotics.ConclusionThe inhibitory mechanisms of S. aureus in novel targets and pathways should stimulate further researches to develop AM, BA and BE as therapeutic agents for infections caused by S. aureus. Continued efforts to identify and exploit synergistic combinations by the three compounds and peptidoglycan inhibitors, are also necessary as alternative treatment options for S. aureus infections.     

Interactions between cardiac glycosides and sodium/potassium-ATPase: three-dimensional structure-activity relationship models for ligand binding to the E2-Pi form of the enzyme versus activity inhibition

Sodium/potassium-ATPase (Na/K-ATPase) is a transmembrane enzyme that utilizes energy gained from ATP hydrolysis to transport sodium and potassium ions across cell membranes in opposite directions against their chemical and electrical gradients. Its transport activity is effectively inhibited by cardiac glycosides, which bind to the extracellular side of the enzyme and are of significant therapeutic value in the treatment of congestive heart failure. To determine the extent to which high-affinity binding of cardiac glycosides correlates with their potency in inhibiting pump activity, we determined experimentally both the binding affinities and inhibitory potencies of a series of 37 cardiac glycosides using radioligand binding and ATPase activity assays. The observed variations in key structural elements of these compounds correlating with binding and inhibition were analyzed by comparative molecular similarity index analysis (CoMSIA), which allowed a molecular level characterization and comparison of drug-Na/K-ATPase interactions that are important for ligand binding and activity inhibition. In agreement with our earlier comparative molecular field analysis studies [Farr, C. D., et al. (2002) Biochemistry 41, 1137-1148], the CoMSIA models predicted favorable inhibitor interactions primarily at the alpha-sugar and lactone ring moieties of the cardiac glycosides. Unfavorable interactions were located about the gamma-sugar group and at several positions about the steroid ring system. Whereas for most compounds a correlation between binding affinity and inhibitory potency was found, some notable exceptions were identified. Substitution of the five-membered lactone of cardenolides with the six-membered lactone of bufadienolides caused binding affinity to decline but inhibitory potency to increase. Furthermore, while the removal of ouabain's rhamnose moiety had little effect on inhibitory potency, it caused a dramatic decline in ligand binding affinity.     

Halo enol lactones: studies on the mechanism of inactivation of alpha-chymotrypsin

In a previous investigation [Daniels, S. B., Cooney, E., Sofia, M. J., Chakravarty, P. K., & Katzenellenbogen, J. A. (1983) J. Biol. Chem. 258, 15046-15053], we demonstrated that alpha-aryl-substituted five- and six-membered ring halo enol lactones were effective inhibitors of chymotrypsin, and we proposed that they reacted by an enzyme-activated mechanism: acyl transfer to the active site serine generates a halomethyl ketone that remains tethered in the catalytic site until it alkylates an accessible nucleophilic residue. In this study, we have investigated in greater detail the process of chymotrypsin inactivation by an alpha-naphthyl-substituted five- and six-membered bromo enol lactone. Inactivation by both compounds appears to be active site directed, since the time-dependent inactivation is retarded by competing substrate. The possible involvement of a paracatalytic mechanism for inactivation (generation of a free, rather than active site bound, inactivating species) was investigated by comparing the inactivation efficiencies of the lactones with that of the bromomethyl keto acid hydrolysis products. The bromomethyl ketone derived from the five-membered lactone is ineffective, whereas that derived from the six-membered lactone is highly efficient. However, the possible involvement of the free keto acid in chymotrypsin inactivation by the six-membered lactone is ruled out by experiments involving selective scavenging. The long-term inactivation of chymotrypsin requires the presence of the bromine substituent and appears to involve an alkylation rather than an acylation reaction (hydrazine resistant). Furthermore, a 1:1 lactone:enzyme stoichiometry is demonstrated with the 14C-labeled six-membered lactone. These results are consistent with the mechanism-based inactivation process previously presented.     

Biological activity assessment of the 26,23-lactones of 1,25-dihydroxyvitamin D3 and 25-hydroxyvitamin D3 and their binding properties to chick intestinal receptor and plasma vitamin D binding protein

The binding of the natural and unnatural diastereoisomers 25-hydroxyvitamin D3-26,23-lactone and 1,25 dihydroxyvitamin D3-26,23-lactone to the vitamin D-binding protein (DBP) and 1,25 dihydroxyvitamin D3 [1,25(OH)2D3] chick intestinal receptor have been investigated. Also, the biological activities, under in vivo conditions, of these compounds, in terms of intestinal calcium absorption (ICA) and bone calcium mobilization (BCM), in the chick are reported. The presence of the lactone ring in the C23-C26 position of the seco-steroid side chain increased two to three times the ability of both 25(OH)D3 and 1,25(OH)2D3 to displace 25(OH)[3H]D3 from the D-binding protein; however, the DBP could not distinguish between the various diastereoisomers. In contrast, the unnatural form (23R,25S) of the 25-hydroxy-lactone was found to be 10-fold more potent than the natural form, and the unnatural (23R,25S)1,25(OH)2D3-26,23-lactone three times more potent than the natural 1,25-dihydroxy-lactone in displacing 1,25(OH)2[3H]D3 from its intestinal receptor. While studying the biological activity of these lactone compounds, it was found that the natural form of the 25-hydroxy-lactone increased the intestinal calcium absorption 48 h after injection (16.25 nmol), while bone calcium mobilization was decreased by the same dose of the 25-hydroxy-lactone. The 1,25-dihydroxyvitamin D3-26,23-lactone in both its natural and unnatural forms was found to be active in stimulating ICA and BCM. These results suggest that the 25-hydroxy-lactone has some biological activity in the chick and that 1,25(OH)2D3-26,23-lactone can mediate ICA and BCM biological responses, probably through an interaction with 1,25-(OH)2D3 specific receptors in these target tissues.     

Inhibition of the cathepsin cysteine proteases B and K by square-planar cycloaurated gold(III) compounds and investigation of their anti-cancer activity

Gold(III) compounds have been examined for potential anti-cancer activity. It is proposed that the molecular targets of these compounds are thiol-containing biological molecules such as the cathepsin cysteine proteases. These enzymes have been implicated in many diseases including cancer. The catalytic mechanism of the cathepsin cysteine proteases is dependent upon a cysteine at the active site which is accessible to the interaction of thiophilic metals such as gold. The synthesis and biological activity of square-planar six-membered cycloaurated Au(III) compounds with a pyridinyl-phenyl linked backbone and two monodentate or one bidentate leaving group is described. Gold(III) cycloaurated compounds were able to inhibit both cathepsins B and K. Structure/activity was investigated by modifications to the pyridinyl-phenyl backbone, and leaving groups. Optimal activity was seen with substitution at the 6 position of the pyridine ring. The reversibility of inhibition was tested by reactivation in the presence of cysteine with a bidentate thiosalicylate compound being an irreversible inhibitor. Five compounds were evaluated for in vitro cytotoxicity against a panel of human tumor cell lines. The thiosalicylate compound was tested in vivo against the HT29 human colon tumor xenograft model. A modest decrease in tumor growth was observed compared with the untreated control tumor.     

Auspicious role of the steroidal heterocyclic derivatives as a platform for anti-cancer drugs

Steroids are polycyclic compounds that have a wide range of biological activities. They are bio-synthesized from cholesterol through a series of enzyme-mediated transformations, so they are highly lipophilic and readily enter most cells to interact with intracellular receptors, making them ideal vehicles for targeting a broad array of pathologies. New curative agents for cancers have been developed from several steroidal derivatives. Some biologically important properties of modified steroids are dependent on structural features of the steroid moiety and their side chains. Therefore, chemical derivatization of steroids provides a way to modify their function, and many structure–activity relationships have been confirmed by such synthetic modifications. Several studies demonstrate that steroidal heterocyclic derivatives can be effective in the prevention and treatment of many types of hormone-dependent cancers. The present review is a concise report on steroidal heterocyclic derivatives, with special emphasis on steroid heterocyclic derivatives with 5 membered rings or six-membered rings having interesting therapeutic potential as enzyme inhibitors and cytotoxic drugs to be used as candidates for anti-cancer drug development.     

Synthesis of highly substituted dibenzo[b,f]azocines and their evaluation as protein kinase inhibitors

Synthetic routes towards highly substituted eight membered ring heterocycles fused to aryl rings such as the dibenzo[b,f]azocine system are still lacking. Herein, we present a convenient convergent synthetic route towards this heterocyclic class of compounds with possible variations at positions 4, 7, and 11. One member of a library of dibenzo[b,f]azocines with different substituents at position 11 was identified to inhibit protein kinase A activity (IC(50)=122microM) but not protein kinase C.     

Enantio- and diastereoselective syntheses of cyclic Calpha-tetrasubstituted alpha-amino acids and their use to induce stable conformations in short peptides

C(alpha)-tetrasubstituted alpha-amino acids are widely used to design and prepare peptides and peptide mimics with constrained conformations. Subcategories of these compounds are cyclic C(alpha)-tetrasubstituted alpha-amino acids, in which both alpha-substituents are covalently connected. This survey presents recent advances in the synthesis and application of cyclic C(alpha)-tetrasubstituted alpha-amino acids in a systematic order beginning with cyclopropane amino acids, continuing with four, five, six membered rings, and ring structures larger than six-membered. We discuss synthetic routes to the cyclic C(alpha)-tetrasubstituted alpha-amino acids and their use as conformation determining elements in peptides.     

SAR studies of epoxycurcuphenol derivatives on leukemia CT-CD4 cells

Bioactive natural products are a potential source of new pharmaceuticals since they offer new modes of action and more specific activities. The use of derivatization also enables the optimal structure for their biological activity to be determined. In this study several epoxycurcuphenol derivatives were synthesized. The substitution pattern on the aromatic and oxirane rings was varied along with that at the benzylic position and the length of the side chain was altered. These changes were made in order to gain a deeper understanding of the structural requirements for activity. The biological activities of these compounds were evaluated on the human leukemia cell line Jurkat using an antiproliferative assay. The activity results and structural requirements are discussed.