抗癌有效成分番荔枝内酯化合物末端内酯环和四氢呋喃环的化学分类及NMR鉴别特征

抗癌有效成分番荔枝内酯化合物末端内酯环和四氢呋喃环的化学分类及ＮＭＲ鉴别特征陈瑛于德泉（中国医学科学院、中国协和医科大学药物研究所，北京１０００５０）１９８２年Ｊｏｌａｄ等［１］从番荔枝科紫玉盘属植物Ｕｖａｒｉａａｃｕｍｉｎａｔａ根中分离得到第１个...     

新型降血脂药——氟伐他汀

氟伐他汀为通用名称,英文名称Ｌｅｓｃｏｌ。１药理作用氟伐他汀系人工合成催化酶羟甲戊二酰辅酶Ａ（ＨＭＧＣｏＡ）还原酶抑制剂,具有一个氟苯吲哚环的甲羟戊酸内酯衍生物,它的吲哚环模拟ＨＭＧＣｏＡ的底物,甲羟戊酸内酯链模拟产物（甲羟戊酸）。所以氟伐他汀能...     

银杏叶的药理作用及其机制的研究进展

银杏为银杏科植物 (ＧｉｎｋｏｇｏｂｉｌｏｂａＬ .) ,6 0年代以来国内外学者对银杏的化学成分、药理作用进行了广泛的研究 ,证实它们对心脑血管及多种疾病有确切的治疗作用。其中尤以银杏叶的研究最为大量。银杏叶成分复杂 ,主要为黄酮类、萜类内酯化合物、多糖类等。银杏叶提取物 (ＥＧｂ及银杏叶标准提取物ＥＧｂ 76 1)中萜类内酯化合物 (银杏内酯ｇｉｎｋｇｏｌｉｄｅｓ ,白果内酯ｂｉｌｏｂａｌｉｄｅ ,以下分别简称内酯及ＢＢ)因为是血小板激活因子 (ｐｌａｔｅｌｅｔａｃｔｉｖｉｎｇｆａｃｔｏｒ,ＰＡＦ)的特异性受体拮抗剂 ,一直…     

刺果番荔枝叶中两个新单四氢呋喃环乙酰精宁

番荔枝乙酰精宁(annonaceousacetogenins)是仅存于番荔枝科的一类新的天然产物,其中大部分具有很强的生物活性,如抗肿瘤、细胞毒、杀灭昆虫、抗菌、抗寄生虫和免疫抑制作用。迄今为止已分得250多个此类化合物。作者从该科植物刺果番荔枝Annona muricata L.叶中发现了17个具细     

天然去甲二萜生物碱的研究进展

二萜生物碱是一类结构复杂的天然产物 ,主要存在于毛莨科 (Ｒａｎｕｎｃｕｌａｃｅａｅ)乌头属 (Ａｃｏｎｉｔｕｍ )、翠雀属 (Ｄｅｌｐｈｉｎｉｕｍ )和飞燕草属 (Ｃｏｎｓｏｌｉｄａ)植物中。该类化合物有广泛的生理活性 ,尤其在抗炎、镇痛等方面作用显著。目前 ,已有 3种化合物高乌甲素 (ｌａｐｐａｃｏｎｉｔｉｎｅ)、草乌甲素 (ｃｒａｓｓｉｃａｕｌｉｎｅＡ)和 3 乙酰乌头碱 (3 Ｏ ａｃｅｔｙｌａｃｏｎｉｔｉｎｅ)作为镇痛药物应用于临床。此外 ,高乌甲素在国外临床上己用于抗心律不齐。而国内关附甲素 (ｇｕｆｕｂａｓｅＡ)作为抗心…     

番荔枝科植物Uvaria hamiltonii茎叶中具有分裂DNA束活性的新化合物

在寻找对癌症有治疗作用的天然产物的过程中,作者从番荔枝科紫玉盘属植物 U.hamiltonii Hook.f et th.茎和叶中分离得到4个具有生物活性的黄酮类化合物。另外还得到一个△~5-四氢呫吨的高度取代的同系物。这些化合物分别鉴定为:hamiltone A(6-羟基-5,7,4′-三甲氧基黄酮)(1);hamiltoneB(3′,4′-二羟基-5,6,7-三甲氧基黄酮)(2);     

2000年美国上市的新药和生物制品

20 0 0年在美国上市的新药 2 7个 ,新的生物制品6个 ,详细见附表。附表　 2 0 0 0年美国上市的新药和生物制品　　　药　品　　创制公司　　　适应证二十二烷醇 (ｄｏｃｏｓａｎｏｌ,Ａｂｒｅｖａ)Ａｖａｎｉｒ/ＧＳＫ唇疱疹比伐卢定 (ｂｉｖａｌｉｒｕｄｉｎ ,Ａｎｇｉｏｍａｘ)ＴｈｅＭｅｄｉｃｉｎｅｓＣｏ抗凝血药阿加曲班 (ａｒｇａｔｒｏｂａｎ ,Ａｃｏｖａ)针剂ＧＳＫ/ＴｅｘａｓＢｉｏｔｅｃｈ肝素诱发的血小板减少西曲瑞克 (ｃｅｔｒｏｒｅｌｉｘ ,Ｃｅｔｒｏｔｉｄｅ)Ａｓｔａ/Ｓｅｒｏｎｏ促黄体激素过早升高巴柳氮 (ｂａｌｓａ…     

A Novel Angular Furanocoumarin Isolated from Cnidium monnieri Fruit

从辽宁新民产蛇床Ｃｎｉｄｉｕｍｍｏｎｎｉｅｒｉ果实中分离鉴定出８个化合物，分别为２′乙酰白芷素（２′ａｃｅｔｙｌａｎｇｅｌｉｃｉｎ，８）、欧山芹素（ｏｒｏｓｅｌｏｎｅ，１）、β谷甾醇（βｓｉｔｏｓｔｅｒｏｌ，２）、哥伦比亚内酯（ｃｏｌｕｍｂｉａｎａｄｉｎ，３）、佛手柑内酯（ｂｅｒｇａｐｔｅｎ，４）、Ｏ乙酰基哥伦比亚甙元（Ｏａｃｅｔｙｌｃｏｌｕｍｂｉａｎｅｔｉｎ，５）、Ｏ乙酰异蛇床素（ｃｎｉｆｏｒｉｎＡ，６）和爱得尔庭（ｅｄｕｌｔｉｎ，７）。其中化合物８为一新化合物，化合物１系首次从该植物中分得。     

光叶紫玉盘中的新番荔枝内酯类成分

从番荔枝科紫玉盘属植物光叶紫玉盘(Uvaria boniana Finet.)的地上茎分离出4种单THF环型番荔枝内酯类成分,经光谱分析,鉴定其中3种为新化合物,分别命名为uvaribonone(I),uvaribonin(II)和uvaribonianin(II),另一种为已知化合物solamin(IV)。     

热休克蛋白90抑制剂Geldanamycin的抗肿瘤作用研究进展

Ｇｅｌｄａｎａｍｙｃｉｎ(ＧＤＭ )属于苯醌安莎霉素类抗生素 ,其衍生物 17 烯丙胺 17 脱甲氧格尔德霉素 (17 ａｌｌｙｌａｍｉｎｏ 17 ｄｅｓｍｅｔｈｏｘｙｇｅｌｄａｎａｍｙｃｉｎ ,17 ＡＡＧ ) ,目前正进行治疗肿瘤的Ｉ期临床试验 ,这类抗生素还包括ｈｅｒｂｉｍｙｃｉｎＡ和ｍａｃｂｅｃｉｎ。它们的结构特征是一个苯醌部分与一个平面性大环安莎桥相连 (图 1)。现发现苯醌安莎霉素类抗生素的生物活性与分子伴侣 (ｍｏｌｅｃｕｌａｒｃｈａｐｅｒｏｎｅ)热休克蛋白 90 (ｈｅａｔｓｈｏｃｋｐｒｏｔｅｉｎ 90 ,Ｈｓｐ90 )有关。Ｈｓｐ…     

Inhibitory activities of three annonaceous acetogenins on NADH oxidase of chicken liver mitochondria

Annonaceous acetogenins (ACG) are natural products found in the plant family Annonaceae and which strongly inhibited mitochondrial complex I. The inhibition of NADH oxidase of chicken liver mitochondria by three different structural ACG was studied here, and ACG was shown to have potent inhibitory activities similar to rotenone for NADH oxidase. The IC(50) values indicated that bis-adjacent tetrahydrofuran (THF) type squamocin C was more potent than non-adjacent bis-THF type squamostatin B, and the latter was more potent than non-THF type compound 1 in the assay. The roles of structural factors of ACG such as the terminal gamma-lactone, the features of other ring moieties and hydroxyl groups, as well as the alkyl chain were simply discussed in this study.     

Interaction of cyanide and nitric oxide with cytochrome c oxidase: implications for acute cyanide toxicity.

Acute cyanide toxicity is attributed to inhibition of cytochrome c oxidase (CcOX), the oxygen-reducing component of mitochondrial electron transport; however, the mitochondrial action of cyanide is complex and not completely understood. State-3 oxygen consumption and CcOX activity were studied in rat N27 mesencephalic cells to examine the functional interaction of cyanide and nitric oxide (NO). KCN produced a concentration-dependent inhibition of cellular respiration. Cyanide's median inhibitory concentration (IC50) of oxygen consumption (13.2 +/- 1.8microM) was higher than the CcOX IC50 (7.2 +/- 0.1microM). Based on respiratory threshold analysis, 60% inhibition of CcOX was necessary before oxygen consumption was decreased. Addition of high levels of exogenous NO (100microM S-nitroso-N-acetyl-DL-penicillamine) attenuated cyanide inhibition of both respiration and CcOX. On the other hand, when endogenous NO generation was blocked by an NOS inhibitor (N(omega)-monomethyl-L-arginine ester), the cyanide IC50 for both respiration and CcOX increased to 59.6 +/- 0.9microM and 102 +/- 10microM, respectively, thus showing constitutive, low-level NO production enhanced cyanide inhibition. Laser scanning cytometry showed that cyanide elevated mitochondrial NO, which then was available to interact with CcOX to enhance the inhibition. It is concluded that the rapid, potent action of cyanide is due in part to mitochondrial generation of NO, which enhances inhibition of CcOX. At low mitochondrial oxygen tensions, the cyanide-NO interaction would be increased. Also, the antidotal action of sodium nitrite is partly explained by generation of high mitochondrial levels of NO, which antagonizes the CcOX inhibition.     

Defining the mechanism of action and enzymatic selectivity of psammaplin A against its epigenetic targets

Psammaplin A (11c) is a marine metabolite previously reported to be a potent inhibitor of two classes of epigenetic enzymes: histone deacetylases and DNA methyltransferases. The design and synthesis of a focused library based on the psammaplin A core has been carried out to probe the molecular features of this molecule responsible for its activity. By direct in vitro assay of the free thiol generated upon reduction of the dimeric psammaplin scaffold, we have unambiguously demonstrated that 11c functions as a natural prodrug, with the reduced form being highly potent against HDAC1 in vitro (IC(50) 0.9 nM). Furthermore, we have shown it to have high isoform selectivity, being 360-fold selective for HDAC1 over HDAC6 and more than 1000-fold less potent against HDAC7 and HDAC8. SAR around our focused library revealed a number of features, most notably the oxime functionality to be important to this selectivity. Many of the compounds show significant cytotoxicity in A549, MCF7, and W138 cells, with the SAR of cytotoxicity correlating to HDAC inhibition. Furthermore, compound treatment causes upregulation of histone acetylation but little effect on tubulin acetylation. Finally, we have found no evidence for 11c functioning as a DNMT inhibitor.     

Inhibition of xanthine oxidase by 4-hydroxy-6-mercaptopyrazolo[3,4-d]pyrimidine

Compound B103U, 4-hydroxy-6-mercaptopyrazolo[3,4-d]pyrimidine, was investigated as an inhibitor of human xanthine oxidase. Studies in vitro demonstrated that it was significantly more potent than oxypurinol, 4,6-dihydroxypyrazolo[3,4-d]pyrimidine. It formed an initial complex with electron-rich (reduced) human xanthine oxidase that was tighter than the corresponding complex formed by oxypurinol. The initial complexes with each inhibitor and reduced enzyme were internally rearranged into more stable complexes with first-order rate constants of 2.5 to 3 per min. However, the half-life of the isomerized (stable) complex with B103U was three to four times longer than the half-life of the analogous complex with oxypurinol. This stability was previously noted by Massey et al. (J. Biol Chem 254: 2837-2844, 1970) with B103U and bovine xanthine oxidase. The overall Ki values accounting for the initial and isomerized complexes were 5 nM for B103U and 100 nM for oxypurinol. B103U was also more potent as an inhibitor of bovine xanthine oxidase-catalyzed generation of superoxide radicals. Studies in mice revealed that the relative in vitro potency of B103U was not sustained in vivo. Compared to the inhibition of xanthine oxidase by oxypurinol, inhibition by B103U was neither more potent nor longer lasting. This shortcoming was not caused by weaker inhibition of mouse xanthine oxidase. Instead, it was the result of poor bioavailability. Plasma levels of available B103U rapidly decreased from samples of mouse and human blood because of reversible binding to serum proteins. B103U was also susceptible to oxidation. Two equivalents of H2O2 stoichiometrically oxidized the 6-thiol substituent to a sulfinic acid. This oxidized product was three orders of magnitude weaker as an inhibitor of xanthine oxidase than was B103U.     

Epoxy-acetogenins and other polyketide epoxy derivatives as inhibitors of the mitochondrial respiratory chain complex I

Annonaceous acetogenins (ACG), an extensive group of cytotoxic natural products, are antitumor agents whose main mode of action is inhibition of the mammalian mitochondrial complex I. Herein we describe the importance of the different chemical groups along the alkyl chain for optimal inhibitory potency, discussing the structurally relevant factors present in these compounds. For this purpose, a series of epoxide derivatives from alpha-linolenic acid were prepared and their activity compared with that of epoxy-acetogenins and tetrahydrofuranic (THF) acetogenins isolated from Rollinia membranacea.     

Inhibition of 1-deoxy-D-xylulose-5-phosphate reductoisomerase by lipophilic phosphonates: SAR, QSAR, and crystallographic studies

1-Deoxy-D-xylulose-5-phosphate reductoisomerase (DXR) is a novel target for developing new antibacterial (including antituberculosis) and antimalaria drugs. Forty-one lipophilic phosphonates, representing a new class of DXR inhibitors, were synthesized, among which 5-phenylpyridin-2-ylmethylphosphonic acid possesses the most activity against E. coli DXR (EcDXR) with a K(i) of 420 nM. Structure-activity relationships (SAR) are discussed, which can be rationalized using our EcDXR:inhibitor structures, and a predictive quantitative SAR (QSAR) model is also developed. Since inhibition studies of DXR from Mycobacterium tuberculosis (MtDXR) have not been performed well, 48 EcDXR inhibitors with a broad chemical diversity were found, however, to generally exhibit considerably reduced activity against MtDXR. The crystal structure of a MtDXR:inhibitor complex reveals the flexible loop containing the residues 198-208 has no strong interactions with the 3,4-dichlorophenyl group of the inhibitor, representing a structural basis for the reduced activity. Overall, these results provide implications in the future design and development of potent DXR inhibitors.     

REV 2871 (CHBZ): a potent antiallergic agent with a novel mechanism of action. I. Activity profile as an inhibitor of mediator release

REV 2871 (CHBZ) and its putative metabolite REV 3579-Z (also designated in the literature as RHC 3579-Z) were shown to be potent and orally effective inhibitors of passive cutaneous anaphylaxis (PCA) in the rat (ED50 = 12 mg/kg). The activity profiles of CHBZ, REV 3579-Z and disodium cromoglycate (DSCG) were compared as inhibitors of histamine release (HR) in vitro from rat mast cells, human basophils, and guinea pig lung slices. CHBZ was a potent inhibitor of both immunologic and non-immunologic HR (I50 2-20 microM from rat mast cells). The activity profile of CHBZ as an inhibitor of HR from rat mast cells differed from that of DSCG and REV 3579-Z in the following respects: increasing inhibition of HR with increasing preincubation time; irreversibility of the inhibition; lack of tachyphylaxis and cross-tachyphylaxis to DSCG; potentiation of the inhibition of antigen-induced release of histamine (AIR) by DSCG; and inhibition of HR induced by dextran + phosphatidyl serine, compound 48/80, ionophore A23187 and platelet activating factor (PAF). In the human basophil model, CHBZ was: a potent inhibitor (I50 = 25 microM) of anti-IgE-induced release (AbIR), whereas DSCG and REV 3579-Z had no effect on AbIR; more potent as an inhibitor of AbIR than ionophore-induced release, whereas the reverse was true for proxicromil; an inhibitor of PAF-induced release, whereas proximcromil stimulated it; and potentiative with proxicromil for inhibition of AbIR. In the guinea pig lung slice model, CHBZ inhibited AIR (I50 = 800 microM) whereas DSCG and REV 3579-Z did not (I50 greater than 300 microM). We conclude that CHBZ is an orally effective antiallergic agent whose mechanism of action as an inhibitor of mediator release is different from DSCG and proxicromil.     

3-(3,4-Dihydroisoquinolin-2(1H)-ylsulfonyl)benzoic Acids: Highly Potent and Selective Inhibitors of the Type 5 17-β-Hydroxysteroid Dehydrogenase AKR1C3

A high-throughput screen identified 3-(3,4-dihydroisoquinolin-2(1H)-ylsulfonyl)benzoic acid as a novel, highly potent (low nM), and isoform-selective (1500-fold) inhibitor of aldo-keto reductase AKR1C3: a target of interest in both breast and prostate cancer. Crystal structure studies showed that the carboxylate group occupies the oxyanion hole in the enzyme, while the sulfonamide provides the correct twist to allow the dihydroisoquinoline to bind in an adjacent hydrophobic pocket. SAR studies around this lead showed that the positioning of the carboxylate was critical, although it could be substituted by acid isosteres and amides. Small substituents on the dihydroisoquinoline gave improvements in potency. A set of "reverse sulfonamides" showed a 12-fold preference for the R stereoisomer. The compounds showed good cellular potency, as measured by inhibition of AKR1C3 metabolism of a known dinitrobenzamide substrate, with a broad rank order between enzymic and cellular activity, but amide analogues were more effective than predicted by the cellular assay.     

Effect of cyclooxygenase inhibitors and protease inhibitors on phorbol-induced stimulation of oxygen consumption and superoxide production by rat pulmonary macrophages

Oxygen consumption and superoxide anion production by pulmonary macrophages are both increased by phorbol myristate acetate (PMA) but the two processes have been separated using protease inhibitors and cyclooxygenase inhibitors. Pretreatment with the protease inhibitors (L-1-tosylamido-2-phenylethylchloromethyl ketone (TPCK) and N-alpha-p-tosyl-L-lysine chloromethyl ketone (TLCK), as well as with the cyclooxygenase inhibitors acetylsalicylic acid (ASA) and ibuprofen (IBU), inhibited the stimulation of superoxide production and oxygen consumption by phorbol myristate acetate. However, whereas the order of potency for inhibition of stimulation of superoxide production was TPCK greater than TLCK greater than IBU greater than ASA, the order of potency for inhibition of stimulation of oxygen consumption was ASA greater than IBU greater than TPCK = TLCK. Although all four agents were effective inhibitors of PMA-stimulated superoxide production and oxygen consumption when added before PMA, in contrast to the cyclooxygenase inhibitors. TPCK was unable to inhibit oxygen consumption by more than 70-80% regardless of the concentration used, although superoxide generation could be inhibited completely. When added after PMA, ASA did not suppress either oxygen consumption or superoxide production and ibuprofen was only one-half as effective as an inhibitor. TPCK and TLCK, when added after PMA, accelerated the return to basal rates of both oxygen consumption and superoxide production. None of the four agents had any effect on basal superoxide production or oxygen consumption at the concentrations used. The data support the interpretation that both prostaglandin biosynthesis and protease activity may be associated with the activation of the superoxide-generating system of pulmonary macrophages. The consumption of molecular oxygen following stimulation of the cells with phorbol myristate acetate is not due solely to the generation of superoxide, however, since each process is inhibited with different potency by the same group of inhibitors. There appears to be a component of oxygen consumption which results from the activation of cyclooxygenase and, unlike superoxide production, cannot be completely inhibited by treatment with protease inhibitors.     

Pyrido[2,3-d]pyrimidin-7-one inhibitors of cyclin-dependent kinases

The identification of 8-ethyl-2-phenylamino-8H-pyrido[2, 3-d]pyrimidin-7-one (1) as an inhibitor of Cdk4 led to the initiation of a program to evaluate related pyrido[2, 3-d]pyrimidin-7-ones for inhibition of cyclin-dependent kinases (Cdks). Analysis of more than 60 analogues has identified some clear SAR trends that may be exploited in the design of more potent Cdk inhibitors. The most potent Cdk4 inhibitors reported in this study inhibit Cdk4 with IC(50) = 0.004 microM ([ATP] = 25 microM). X-ray crystallographic analysis of representative compounds bound to the related kinase, Cdk2, reveals that they occupy the ATP binding site. Modest selectivity between Cdks is exhibited by some compounds, and Cdk4-selective inhibitors block pRb(+) cells in the G(1)-phase of the cell division cycle.