Identification of novel saponins from edible seeds of Japanese horse chestnut (Aesculus turbinata Blume) after treatment with wooden ashes and their nutraceutical activity

Natural seeds of Japanese horse chestnut (Aesculus turbinata Blume) contain large amounts of mixed triterpenoidal saponins called escins. Recent studies have shown that escins have several biological activities including anti-inflammatory action and inhibitory effects on the absorption of ethanol and glucose. For the edible utilization of the seeds, natural seeds are usually treated with wooden ashes to remove harshness. Here, we found the novel compounds derived from escins in the edible seeds after the food processing with wooden ashes. The instrumental analyses revealed the chemical structures of escins and the derivatives. These compounds are identified as four types of deacetylescins Ia, IIa, Ib, and IIb as well as two types of desacylescins I and II. To determine their biological activity, the purified compounds were tested for their potential nutraceutical activity. The oral glucose tolerance test in mice revealed that a single oral administration of the isolated components of deacetylescins at a dose of 100 mg/kg was clearly effective in attenuating the elevation of blood glucose levels. The inhibitory effects of escins and their derivatives were in the order of escins > deacetylescins > desacylescins. Moreover, we found the inhibitory activity of those compounds on pancreatic lipase. Escins were the most potent in inhibiting the enzyme activity, and followed by desacylescins and then deacetylescins. Taken together, our results suggest the potential usefulness of novel saponins including deacetylescins and desacylescins from edible seeds as novel sources for nutraceutical foods with anti-obese effects.     

Gastroprotections of escins Ia, Ib, IIa, and IIb on ethanol-induced gastric mucosal lesions in rats.

Effects of escins Ia, Ib, IIa, and IIb isolated from horse chestnuts on ethanol-induced gastric mucosal lesions and the roles of capsaicin-sensitive afferent neurons, endogenous nitric oxide (NO), sulfhydryls, prostaglandins, as well as gastric secretion and the sympathetic nervous system, were investigated in rats. Test samples were given orally to fasted rats 1 h before ethanol (1.5 ml/rat, p.o.) treatment or ligation of the pylorus. Escins Ia-IIb (10-50 mg/kg) potently inhibited ethanol-induced gastric mucosal lesions, whereas desacylescins I and II (50 mg/kg) showed no such effect. These active saponins (10 and 20 mg/kg) did not decrease the gastric secretion. The gastroprotections of escins Ia-IIb were attenuated by the pretreatment with capsaicin, N(G)-nitro-L-arginine methyl ester, and indomethacin, but not by N-ethylmaleimide. The effects of escins Ia-IIb were also attenuated in streptozotocin-induced diabetic rats, in which the activity of the sympathetic nervous system was abnormal. These results suggest that the gastroprotections of escins Ia-IIb on ethanol-induced gastric mucosal lesions are acid-independent, whereas endogenous prostaglandins, NO, capsaicin-sensitive afferent neurons, and the sympathetic nervous system participate.     

Evaluation of Perylenediimide Derivatives for Potential Therapeutic Benefits on Cancer Chemotherapy

Perylene derivatives, known to have potential therapeutic benefits on particular cancer types as photosensitizers, may also function as small‐molecule inhibitors with promising therapeutic value for diverse diseases. This recently recognized biological activity was attributed to their capacity to modulate the function of various enzymes as biological targets in vitro. Although the inhibitory activity on glutathione transferase and Src tyrosine kinase is important in determining the anticancer potential of compounds for target‐specific drug design and development, to date, there are no successful inhibitors of this kind. Moreover, there are only a few studies about the effects of perylene derivatives on glutathione transferase and various kinases. In this study, four novel perylene compounds, N,N′‐disubstituted perylenediimides and their 1,7‐dibromo derivatives, were synthesized and evaluated for their biological activities. Here, among the compounds analyzed, one of them was identified with strong glutathione transferase inhibition and two with dual activity for both glutathione transferase and c‐src inhibition. These results revealed that perylene derivatives may be employed as potential chemosensitizers to prevent chemotherapy‐dependent drug resistance and identified as prospective anticancer agents with dual activity on both glutathione transferase and c‐src enzymes.     

Inhibitory effects of some traditional medicines on proliferation of HIV-1 and its protease

In attempts to discover anti-HIV agents from natural sources, various traditional medicine extracts were tested for their inhibitory effects on HIV-1 proliferation and its protease. An extract of the seeds of Croton tiglium showed potent inhibitory effects on the proliferation of HIV-1. The active principle was determined to be phorbol esters. Several derivatives of phorbol ester were evaluated for inhibition of proliferation as well as activation of protein kinase C (PKC). Of these compounds, 12-O-acetylphorbol 13-decanoate (6) showed the most potent inhibition of proliferation without activating PKC. Some triterpenes from the stems of Cynomorium songaricum and the woody part of Xanthoceras sorbifolia showed inhibitory activity against HIV-1 protease. Various derivatives of oleanolic acid were synthesized and evaluated for their inhibitory activity against HIV-1 protease. Their inhibitory mechanism was also investigated.     

Long hydrocarbon chain diols and diacids with central ether or ketone moieties that favorably alter lipid disorders

Long hydrocarbon chain derivatives with bis-terminal hydroxyl or carboxyl groups and various central moieties (ketone, ether, ester, amide, carbamate, etc.) have been synthesized and evaluated for their effects on the de novo incorporation of radiolabeled acetate into lipids in primary cultures of rat hepatocytes as well as for their effects on lipid, glycemic and body weight variables in female obese Zucker fatty rats following one and two weeks of oral administration. The most active compounds were found to be symmetrical with four to five methylene groups separating the ether or ketone central functionality from the gem dimethyl, cycloalkyl or methyl/aryl substituents. Cycloalkyl substitution alpha to the carboxyl group in keto-acids lowered the in vitro activity to micromolar values. Furthermore, in vivo biological activity was found to be greatest for cyclopropyl-substituted ketone derivatives, particularly the ketodiacid with five methylene groups on each side of the central ketone functionality, which was identified as an HDL elevator and was also found to reduce insulin and glucose.     

Chemistry and biological activity of natural and synthetic prenyloxycoumarins

Prenyloxycoumarins and prenyloxyfuranocoumarins (isopentenyloxy-, geranyloxy-, linear and cyclic sesquiterpenyloxy compounds and their biosynthetic derivatives) represent a family of secondary metabolites that have been considered for years just as intermediates of other coumarin-based compounds. Only in the last two decades these secondary metabolites have been recognized as interesting and valuable biologically active natural products. Up to now more than 160 compounds have been isolated from plants mainly belonging to the families of Rutaceae and Umbelliferae, comprising common edible vegetables and fruits like lemons, oranges and grapefruits. In view of the biological activity of some natural prenyloxycoumarins, very recently syntheses of structurally related analogs aimed to establish detailed structure-activity relationships have also been carried out. Many of the isolated prenyloxy- and prenyloxy-furanocoumarins and their semisynthetic derivatives were shown to exert in vitro and in vivo remarkable anti-tumoral, anti-inflammatory and anti-viral effects. The object of this review is to examine in detail the different types of prenyloxycoumarins and prenyloxyfuranocoumarins from the chemical, phytochemical and biological point of view.     

中华七叶树种子化学成分及生物活性研究进展

目的对中华七叶树种子的化学成分及生物活性研究进展进行综述。方法结合数据库检索及文献查阅,对其化学成分及生物活性进行系统分析和归纳总结。结果中华七叶树种子主要含有五环三萜皂苷类化合物26个、黄酮苷类化合物10个,具有抗炎消渗、抗肿瘤、抗病毒、抗血管生成和减肥等方面的生物活性。结论七叶皂苷Ⅰa和七叶皂苷Ⅰb,异七叶皂苷Ⅰa和异七叶皂苷Ⅰb是中华七叶树种子中含量最高的4种功效成分,其药理作用显著,临床应用前景广阔。     

Synthesis and antiinflammatory evaluation of 9-anilinoacridine and 9-phenoxyacridine derivatives

Mast cells, neutrophils, and macrophages are important inflammatory cells that have been implicated in the pathogenesis of acute and chronic inflammatory diseases. To explore a novel antiinflammatory agent, we have synthesized two types of acridines, 9-anilinoacridine and 9-phenoxyacridine derivatives, for evaluation on the grounds that acridine is a versatile heterocycle possessing a wide variety of biological properties. The title compounds were synthesized by reaction of 9-chloroacridine with appropriate Ar-NH(2) and Ar-OH, and their antiinflammatory activities on inhibitory effects on the activation of mast cells, neutrophils, and macrophages were studied. Three acridine derivatives 4, 10, and 11 were proved to be more potent than the reference inhibitor mepacrine for the inhibition of rat peritoneal mast cell degranulation with similar IC(50) values (16-21 microM). Compound 3 also showed potent inhibitory activity (IC(50) = 8.2 and 4.4 microM, respectively) for the secretion of lysosomal enzyme and beta-glucuronidase from neutrophils. Moreover, compounds 5 and 9 were shown to be efficacious inhibitors of TNF-alpha production in macrophage-like cell lines RAW 264.7. Compounds 2 and 12 were the potent inhibitors of TNF-alpha production in murine microglial cell lines N9. To further explore the cytotoxic properties of these acridine derivatives, (E)-12 was selected for NCI's in vitro disease-oriented tumor cells screen. The results indicated that this compound had no significant cytotoxicity with a mean GI(50) of 58.0 microM. These results indicated that the antiinflammatory effects of acridine derivatives were mediated, at least in part, through the suppression of chemical mediators released from mast cells, neutrophils, and macrophages and that these compounds have the potential to be novel antiinflammatory agents with no significant cytotoxicity.     

1,5-二取代吡唑-3-甲酰胺类新化合物的合成及其生物活性

目的 设计合成新型1,5-二取代吡唑-3-甲酰胺类化合物,并对其抗ALK5活性进行初步评价.方法 以取代的苯乙酮及草酸二甲酯为原料,经多步反应合成目标化合物,用化学发光法检测报告基因表达产物萤火虫萤光素酶活性,计算化合物对ALK5的抑制率.结果与结论 共合成15个未见文献报道的新化合物,其结构经IR、1H-NMR和MS确证.初步生物活性评价结果显示化合物4g具有一定的抗ALK5活性.     

Synthesis of β‐amino acid derivatives and their inhibitory profiles against some metabolic enzymes

Sulfamate and its derivatives have a range of biological activities. One‐pot cyclocondensation of alkenes ( 1a–i ) with chlorosulfonyl isocyanate generates β‐lactams. β‐Amino acid derivatives ( 2a–i ) from β‐lactams were synthesized. Then, these highly reactive compounds were opened with MeOH to produce the corresponding sulfamate derivatives in good yields. The inhibitory effects of the novel sulfamate derivatives were tested on human carbonic anhydrase I and II isoenzymes (hCA I and hCA II), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and α‐glycosidase (α‐Gly). Novel sulfamate derivatives showed K_i values in the range of 23.81–42.97 nM against hCA I, 8.95–52.23 nM against hCA II, 8.10–45.51 nM against AChE, 23.16–81.84 nM against BChE, and 14.02–48.68 nM against α‐Gly. As a result, the novel sulfamate derivatives had potent inhibitory effects against both isoenzymes. Overall, due to the inhibitory effects of the novel sulfamate derivatives on the tested metabolic enzymes, they are promising drug candidates for the treatment of diseases like glaucoma, epilepsy, leukemia, Alzheimer's disease, and type 2 diabetes mellitus, which are associated with high enzymatic activity of the indicated metabolic enzymes.     

Effects of escins Ia, Ib, IIa, and IIb from horse chestnuts on gastric emptying in mice

Inhibitory effects of the saponin fraction and its principal constituents, escins Ia, Ib, IIa, and IIb, from horse chestnuts on gastric emptying were investigated in mice loaded with a non-nutrient or nutrient meal. The saponin fraction and escins Ia-IIb inhibited gastric emptying of a 1.5% carboxymethyl cellulose sodium salt (CMC-Na) meal by 11.1-54.2% (12.5-200 mg/kg). Escins Ia-IIb (50 mg/kg) also inhibited gastric emptying of a 40% glucose meal by 21.1-23.5% except for escin Ia, a milk meal by 18.4-33.1%, and a 30% ethanol meal by 13.5-15.9%. The effects of escins Ia-IIb on gastric emptying of the CMC-Na meal were attenuated by pretreatment with streptozotocin (100 mg/kg, i.v.), capsaicin (75 mg/kg in total, s.c.), or insulin (1 U/kg, s.c.). The effect of insulin was reduced by glucose (2 g/kg, i.v.) which can directly nourish the brain, but not by fructose (2 g/kg, i.v.) which cannot be utilized by the brain. The effects of escins Ia-IIb (50 mg/kg) were overridden in 60% ethanol-loaded mice, in which the central nervous system was suppressed by ethanol. These results suggest that capsaicin-sensitive sensory nerves and central nervous system partly participate in the effects of escins Ia-IIb.     

毛冬青中有效成分的分离及其对两种主要口腔致病菌的抑制作用

目的 观察、追踪毛冬青抑制口腔常见致龋菌（变形链球菌和具核梭杆菌）的有效部位和成分。方法 通过系统溶剂萃取、大孔树脂及硅胶柱色谱分离等方法以及质谱和核磁共振等鉴定技术,结合液体二倍稀释法,研究毛冬青不同部位及单体对变形链球菌和具核梭杆菌的最低抑菌浓度（MIC）,1%玉洁纯作为阳性对照药。结果 毛冬青三萜总皂苷和冬青素对两种主要口腔致病菌均具有一定的抑制作用,特别对变形链球菌具有显著地抑制效果。结论 毛冬青三萜总皂苷和冬青素对变形链球菌具有很强的抑制作用,具有开发成为抗龋齿的保健牙膏或药品的潜力。     

化学合成具有抗肿瘤活性甾体皂苷的研究进展

甾体皂苷是天然产物中～类重要的生物活性物质，人们已经发现了许多具有抗肿瘤活性的甾体皂苷化合物，对该类化合物的合成、结构改造及药理活性的研究也取得了一些进展，并初步总结出一些构效关系的规律。对进一步开发抗癌新药具有指导作用。该文对近10年来，化学合成的具有抗肿瘤活性的甾体皂苷的研究情况进行综述。     

Design,synthesis and evaluations of spiro‐fused benzoxaborin derivatives as novel boron‐containing compounds

Drug design using boron‐containing heterocycles has attracted a great deal of attention because these compounds are believed to possess high biological activity. However, information on the synthetic methodology and pharmacokinetic profiling of boron‐containing compounds is limited. In this study, we provide a new synthetic route for preparation of spiro‐fused benzoxaborin derivatives and investigate their in vitro pharmacokinetic properties. Our efforts led to the successful construction of a chemical library of spiro‐fused benzoxaborin derivatives with appropriate physicochemical and in vitro pharmacokinetic properties for oral drugs. These results indicate that the synthesized boron‐containing compounds are therefore eligible for classification in a novel chemical library.     

New 2H-tetrahydro-1, 3, 5-thiadiazine-2-thiones incorporating glycine and glycinamide as potential antifungal agents

The new title derivatives (4b-h and 5a-i) were synthesized by reaction of the appropriate primary amine, carbon disulphide, and formaldehyde. These derivatives were prepared in order to study the effects of introducing polar groups at N3 or N5 or at both positions on the biological activity. The compounds were tested for their antifungal activity in vitro against pathogenic (Trichophyton rubrum and Candida albicans), phytopathogenic (Penicillum expansum, Trichoderma hazianum, and Fasarium oxysporum), and aflatoxin-producing (Aspergillus flavus) fungi. These compounds exhibited varied inhibitory effects on growth or sporulation of some tested fungal species.     

Generation of novel epothilone analogs with cytotoxic activity by biotransformation

The epothilones represent a new class of bacterial natural products with broad spectrum of antiproliferative activity against various types of human tumors and tumor cell lines. The attractive preclinical profile of epothilones has made them promising lead compounds for novel anticancer agents and has spurred a strong interest in obtaining different derivatives to fully evaluate their therapeutic potentials. We have generated a number of novel epothilone D and 10,11-dehydroepothilone D (Epo490) analogs via biotransformation using Amycolata autotrophica to alter the oxidation state of the parental compounds. The bioconverted compounds displayed different degrees of potency in cytotoxicity assays against a panel of human tumor cell lines, with 11-hydroxyepothilone D, 14-hydroxyepothilone D, and 21-hydroxyepothilone D showing comparable activity to that of epothilone D, and 21-hydroxy Epo490 being comparable to Epo490. The addition of hydroxyl group(s) seems to cause a decrease in cytotoxic activity against multiple drug resistant cell lines (with overexpressed P-glycoprotein). The compounds generated by biotransformation exert differential effects on tubulin polymerization, which correlate with their biological activities.     

浙江七叶树种子中三萜皂苷成分的分离和鉴定*

目的:研究浙江七叶树Aesculus chinensis Bunge var.chekiangensis(Huet Fang)Fang种子中的化学成分。方法:采用大孔吸附树脂柱色谱、高效液相色谱等方法进行分离和纯化,根据化合物的谱学数据鉴定其结构。结果:从浙江七叶树种子的70%乙醇提取物中分离得到3个三萜皂苷类化合物,分别鉴定为七叶树皂苷(escins)IVe和IVh及七叶树皂苷(aesculuside)A。结论:这3个化合物皆为首次从浙江七叶树种子中分离得到。     

Inhibition of proliferation by agricultural plant extracts in seven human adult T-cell leukaemia (ATL)-related cell lines

Adult T-cell leukaemia (ATL) is caused by human T-cell leukaemia virus type I (HTLV-I) infection and is resistant to conventional chemotherapy. We evaluated the inhibitory effects of agricultural plants on the proliferation of seven ATL-related human leukaemia cells, using three ATL cell lines (ED, Su9T01 and S1T), two human T-cell lines transformed by HTLV-I infection (HUT-102 and MT-2) and two HTLV-I-negative human T-cell acute lymphoblastic leukaemia cell lines (Jurkat and MOLT-4). A total of 52 samples of 80% ethanol extracts obtained from 30 types of agricultural plants were examined. On the basis of IC(50) values, we selected samples with greater activity than genistein, which was used as a positive control. The highest inhibitory effect was observed with extracts from leaves of Vaccinium virgatum Aiton (blueberry) on four cell lines (ED, Su9T01, HUT-102 and Jurkat); seeds of Momordica charantia L. (bitter gourd) exhibited the second highest activity. The bitter gourd seeds suppressed the proliferation of three cell lines (Su9T01, HUT-102 and Jurkat). The extracts from edible parts of Ipomea batatas LAM. (sweet potato), edible parts of Colocasia esculenta (L.) Schott (taro), skin of taro and seeds of Prunus mume Sieb. et Zucc. (mume) showed markedly greater inhibitory effects on Su9T01 than genistein. These findings suggest that ATL-preventative bioactive compounds may exist in these agricultural plants, which are considered to be functional foods.     

虎杖苷及其衍生物抑制SGLT2降血糖活性研究

目的 揭示虎杖苷及其衍生物抑制钠-葡萄糖协同转运体2（sodium-glucose cotransporter 2,SGLT2）活性的构效关系。方法 以虎杖苷为起始物,经S_N2取代反应、催化氢化获得5个衍生物,以¹H-NMR和HR-ESI-MS进行结构表征。采用荧光标记的1-脱氧葡萄糖{1-[N-（7-nitrobenz-2-oxa-1,3-diazol-4-yl）amino]-1-deoxy-D-glucose,1-NBDG}作为底物对虎杖苷及其衍生物进行体外抑制SGLT2活性测试,对衍生物1b进行体内活性测试,大鼠口服糖耐量实验及促尿糖实验。结果 获得5个虎杖苷衍生物,¹H-NMR和HR-ESI-MS表征结构正确,体外实验显示虎杖苷及其衍生物能较好地抑制SGLT2活性,且化合物1b在10^-5 mol·L^-1时对SGLT2的抑制率达98.6%,但是大鼠体内实验显示1b在120 mg·kg^-1时抑糖率只有11%,尿糖量只有122 mg每200 g,其活性远远低于阳性对照药达格列净。结论 虎杖苷及其衍生物作为O-芳基糖苷化合物具有较弱的抑制SGLT2降血糖活性,其分子结构对后续设计新的C-芳基糖苷SGLT2抑制剂具有一定的指导意义。