Nine new cytotoxic monotetrahydrofuranic Annonaceous acetogenins from Annona montana

Nine monotetrahydrofuranic Annonaceous acetogenins, montalicins A-E (1-5), cis-annoreticuin (6), montalicins F (7), I (8), and J (9), along with eight known acetogenins 10-17, were isolated from the seeds of Annona montana by a high performance liquid chromatographic (HPLC) method. The structures of all new isolates were elucidated and characterized by spectroscopic and chemical methods. These monotetrahydrofuranic Annonaceous acetogenins showed selectively potent cytotoxicity against two human cancer cell lines, 1A9 and Hep G2.     

番荔素亚微乳的制备及其抗肿瘤作用研究

目的制备番荔素亚微乳,并进行体内外抗肿瘤作用研究,为番荔素的口服给药提供可行方案。方法以离心稳定常数(Ke)为指标,采用正交试验对注射用大豆油的用量、混合乳化剂总量和混合乳化剂的质量比进行考察,优化最佳处方配比。考察纳米乳匀机的运转压力和运转次数对番荔素亚微乳的粒径大小和分布的影响,优化工艺参数。透射电镜观察最佳工艺所得番荔素亚微乳,考察其在生物介质中的稳定性。采用噻唑蓝(MTT)比色法评价番荔素亚微乳对鼠乳腺癌4T1、人黑色素瘤A875细胞和人肝癌细胞Hep G2的细胞毒性。建立鼠源肝癌H22细胞实体瘤模型,小鼠ig番荔素亚微乳、番荔素油溶液,计算抑瘤率。结果番荔素亚微乳的最佳处方配比和制备工艺为:注射用大豆油用量为10%,乳化剂总量为3%,其中精制蛋黄卵磷脂与聚山梨酯80质量比为8∶2;均质压力为1 500 bar,均质次数为9次。番荔素亚微乳在人工胃肠液中稳定,呈球形,粒径较小,主要在100 nm左右。番荔素亚微乳对4T1、A875、Hep G2细胞IC50值分别为3.082、2.001、1.762μg/m L;ig给药1 mg/kg番荔素亚微乳与4 mg/kg油溶液对H22荷瘤鼠的抑瘤效果相当(65.0%vs 56.5%)。结论番荔素亚微乳可以解决番荔素难溶于水、难于给药的问题,能在不降低疗效的同时将用药剂量降低到传统油溶液的1/4,在一定程度上具有增效减毒作用。     

刺果番荔枝化学成分的研究

从番荔枝科番荔枝属植物刺果番荔枝(Annona muricata )的种子分得五种番荔素类成分,经光谱分析,鉴定其中两种为新化合物,命名为:muricatalicin(I)和muricatalin(VI),另三种为已知化合物:annonacin(I),annonacin-A(II)和annonacin-10-one(IV)。在制酸酯(mesitoate)衍生物过程中,又得到一新番荔素的酸酯Vb,与模型化合物比较,确认Vb是cis-THF-annonacin-A mesitoate。Vb的原化合物定名为annonacin-B。     

Two epimeric pairs of C-4-acetyl annonaceous acetogenins from Goniothalamus donnaiensis

Further studies on the roots of Goniothalamus donnaiensis Finet et Gagnap (Annonaceae) led to the isolation of two pairs of Annonaceous acetogenins, donnaienin C ( 1) and 34- EPI-donnaienin C ( 1'), donnaienin D ( 2) and 34- EPI-donnaienin D ( 2'), containing a rare gamma-hydroxymethyl-gamma-lactone moiety and a C-4-acetoxy group. Their structures were elucidated by spectral data and chemical derivatization. Preliminary pharmacological tests showed that the mixture of donnaienin C( 1) and 34- EPI-donnaienin C ( 1') inhibited human hepatoma (Bel) cell lines in vitro (IC (50), 7.1 microg/ml).     

Potent antitumor mimetics of annonaceous acetogenins embedded with an aromatic moiety in the left hydrocarbon chain part

Annonaceous acetogenins are a large family of naturally occurring polyketides exhibiting remarkable anticancer activities. The first generation of annonaceous acetogenin mimetic (1, AA005) exhibits comparable activity as that of natural products and presents much higher selectivity between cancer and normal cells. In this work, we report the design, synthesis, and evaluation of a new series of compound 1 analogues in which a variety of conformation-constrained fragments were embedded in the left hydrocarbon chain part. Compound 7 bearing a biphenyl moiety was identified to exhibit more potent antiproliferative activity and preferentially target cancer cells over normal cells and thus represents a new lead for further optimization.     

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.     

Acetogenins, Aporphinoids, and Azaanthraquinone from Annona cherimolia Seeds

We have isolated several known steroids, glycosides, isoquinoline, and azaanthraquinone alkaloids, and five acetogenins belonging to a new group of secondary metabolites, the bis-tetrahydrofuran gamma-lactones, from the seeds of ANNONA CHERIMOLIA. The azaanthraquinone alkaloid isolated was identified as cleistopholine. One new acetogenin is reported here: laherradurine; a second new one was isolated, but its structure has not been determined. The other three: cherimoline, dihydrocherimoline, and asimicine have already been reported.     

A new epimeric pair of mono-THF annonaceous acetogenins from Goniothalamus gardneri

From the roots of Goniothalamus gardneri Hook f. et. Thoms (Annonaceae), we have isolated a novel epimeric pair, gardnerinin ( 1) and 34- EPI-gardnerinin ( 1'), characterized by the presence of a gamma-hydroxymethyl-gamma-lactone moiety. These compounds represent an unusual type of mono-THF Annonaceous acetogenins, bearing one flanking hydroxy group on the hydrocarbon side, and another hydroxy group on the lactone side, that is only one carbon away from the THF ring.     

Coronin from roots of Annona muricata, a putative intermediate in acetogenin biosynthesis (1)

A novel acetogenin, coronin, was isolated from the roots of Annona muricata L. The structure was elucidated by a combination of chemical and spectral methods including MS and NMR measurements. Coronin is probably an intermediate in the biosynthetic pathway of bis-tetrahydrofuran acetogenins, and is proposed as a biogenetic precursor of neoannonin-B.     

Current topics of organic and biological chemistry of annonaceous acetogenins and their synthetic mimics

Annonaceous acetogenins are a large family of natural polyketides. So far, more than 430 compounds have been isolated. Biologically, they are among the most potent of the known inhibitors of complex I (NADH-ubiquinone oxidoreductase) in mitochondrial electron transfer system. Herein, we would like to conduct an overview on the progress of the total synthesis, structural revisions, structure activity relationship for the inhibition of complex I, and action mechanism.     

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.     

A new adjacent bis-tetrahydrofuran annonaceous acetogenin from the seeds of Uvaria chamae

A novel acetogenin, joolanin ( 1), along with eight known acetogenins, squamocin ( 2), desacetyluvaricin ( 3), chamuvarinin ( 4), tripoxyrollin ( 5), diepoxyrollin ( 6), dieporeticanin-1 ( 7), dieporeticanin-2 ( 8) and dieporeticenin ( 9) were isolated from the seeds of Uvaria chamae (Annonaceae). Compound 1, the first adjacent bis-tetrahydrofuranic ring acetogenin bearing a ketone group at C-5, shows significant cytotoxicity towards the KB 3 - 1 cell line (IC (50) = 0.4 nM).     

圆滑番荔枝种子化学成分研究圆滑番荔枝种子化学成分研究

目的研究圆滑番荔枝(Annona glabra)种子的抗肿瘤活性成分。方法利用色谱技术分离纯化, 根据化合物的理化性质和光谱数据鉴定结构。结果从己烷提取物鉴定18个化合物,其中14个为番荔素:glabrencin A (1), bullatencin (2), glabrencin B (3), uvariamicin-I (4), uvariamicin-II (5), uvariamicin-III (6), reticulatain-1 (7), desacetyluvaricin (8), 4-deoxyasimicin (9), asimicin (10), bullatacin (11), squamocin (12), motrilin (13), cherimolin-2 (14);豆甾醇(stigmasterol,15)及脂肪酸酰胺混合物:棕榈酸酰胺(palmitic amide,16),硬脂酸酰胺(stearic amide,17)和花生酸酰胺(arachidic amide,18)。结论glabrencin A (1),glabrencin B (3)为新番荔素;2,4～7,9,11,13,16～18是首次从该植物中分离得到。     

Folate-targeting annonaceous acetogenins nanosuspensions: significantly enhanced antitumor efficacy in HeLa tumor-bearing mice

Annonaceous acetogenins (ACGs) are one of the most active constituents isolated from Annona species with potent antitumor activity. However, the poor solubility and severe side effect greatly limit their use in clinic. In this study, folic acid (FA) modified annonaceous acetogenins nanosuspensions (FA-PEG-ACGs-NSps) had been successfully prepared using DSPE-PEG-FA and soybean lecithin (SPC) as stabilizers. The resultant FA-PEG-ACGs-NSps had a mean particle size of 119.7?nm, a zeta potential of –23.0?mV and a high drug payload of 49.68%. The obtained ACGs-NSps had a good stability in various physiological media, and showed sustained drug release. Compared to common ACGs nanoparticles (PEG-ACGs-NSps), FA-PEG-ACGs-NSps showed significantly enhanced in vitro cytotoxicity against folate receptor-positive HeLa cell lines (IC50, 0.483?μg/mL vs. 0.915?μg/mL, p?In vivo experiments demonstrated that FA-PEG-ACGs-NSps brought more drug molecules into tumors and greatly improved the antitumor efficacy (TIR, 76.45% vs. 25.29%, p?相似文献   

Antitumor activity and toxicity relationship of annonaceous acetogenins

Annonaceous acetogenins (ACGs) are one of the most interesting classes of natural products appearing in the past two decades. Here, we studied the antitumor activity and toxicity relationship of ACGs including annosquamin B (1), bullatacin (2) and annosquatin B (3) in vivo. A single intraperitoneal (i.p.) injection of 100 μg/kg of annosquamin B, bullatacin and annosquatin B did not cause side effects in normal mice. Bullatacin treatment with five doses of 25 and 50 μg/kg in H₂₂ hepatoma cells bearing mice resulted in about 61% reduction in tumor growth with hematologic parameters increased significantly in normal mice. Annosquamin B and annosquatin B treatments with 10 doses of 25, 50 and 100 μg/kg in the H₂₂ hepatoma cells transplantation tumor model mice resulted in maximum 53.7% and 58.7% reduction in tumor growth, respectively, and did not cause severe side effects in normal mice. This study provided the evidence that adjacent bis-THF ACGs showed higher antitumor activity and toxicity than mono-THF and nonadjacent bis-THF ACGs in vivo. Furthermore, it was found that bullatacin led to liver and kidney toxicity via increasing calcium concentration, ROS production, and Bax expression and Bax/Bcl-2 ratio in rats with repeated treatment with bullatacin for 3 weeks.     

牛心番荔枝种子中两种异番荔素的化学结构研究

从牛心番荔枝Annona reticulata L.种子中分得两个番荔素( Annonaceous acetogenin):Squamone(1)和Isoannonareticin(2)。经制备TLC分离,将1和2的乙酰化物1a和2a分离得到两对2-位差向异构体:2,4-cis-Squamonediacetate(1a-1),2,4-trans-Squamonediacetate(1a-2),2,4-cis-Isoannonareticin diacetate(2a-1)和2,4-trans-Isoannonareticindiacetate(2a-2)。其中2,4-顺式体的1-1和2-1是新的番荔素成分。根据光谱(¹H-¹HCOSY,NOE)数椐分析,阐明它们的结构和相对立体化学。     

HPLC法测定番荔枝科植物中番荔素含量

目的　建立番荔枝科植物中抗肿瘤活性成分番荔素的HPLC含量测定方法。方法　Squamostatin-B (1) ,squamocin (2 )和annonin-VI (3)为标准品。色谱柱:反相C₁₈柱;流动相:甲醇-水(90∶10 ) ;流速:1.0mL·min^-1 ;检测波长:220nm。结果　进样量在2.3- 13.8μg有良好的线性关系。(1) ,(2)和(3)的回收率分别为100.3% ,100.3%和100.0 %。结论　本法快速、简便、灵敏和分离度好,适用于番荔枝科植物中抗肿瘤活性成分番荔素的含量测定。     

番荔枝种子化学成分研究

目的研究药用植物番荔枝(Annona squamosa L)种子的抗肿瘤活性成分。方法利用各种色谱技术进行分离纯化, 根据化合物的理化性质和光谱数据鉴定化学结构。结果从乙醇提取物分离鉴定了11个番荔素: squamocenin (1), annotemoyin-2 (2), reticulatain-2 (3), squamocin-I (4), squamocin-B (5), squamocin (6), motrilin (7), squamostatin-D (8), squamostatin-E (9), cherimolin-1 (10)和cherimolin-2 (11)。结论Squamocenin (1)为新番荔素; annotemoyin-2 (2)和reticulatain-2 (3)是首次报道该植物含有的化合物。     

大花紫玉盘中的新抗肿瘤活性番荔枝内酯及其绝对构型研究

从番荔枝科紫玉盘属植物大花紫玉盘(Uvaria grandiflora Roxb.)根茎中分得两种新的抗肿瘤活性番荔枝内酯(1和3),用X-ray衍射分析和Mosher方法对1的绝对构型进行了研究,全部6个手性碳的构型分别是15S,17R,18R,21R,22R,36S。命名为大花紫玉盘素(uvarigrin)。用Mosher方法对3的绝对构型也进行了测定,命名为大花紫玉盘素A(uvarigrandin A)。对以前得到的大花紫玉盘脂素(uvarigranin,2)的相对构型进行了修正。     

Polyether mimics of naturally occurring cytotoxic annonaceous acetogenins

On the basis of the ionophore model, polyether analogues 4 and 6 were designed and synthesized to mimic the naturally occurring annonaceous acetogenins corossolin (2) and bullatin (5), which were discovered as members of a large family of novel polyketides with cytotoxicity, antitumoral, and other biological activities since 1982. The preliminary screening shows that they have compatible cytotoxicity with the corresponding natural annonaceous acetogenins. These results open a potential way to find more active antitumor agents with simplified structures based on natural annonaceous acetogenins.