Three new manzamine alkaloids from a common Indonesian sponge and their activity against infectious and tropical parasitic diseases

Three new manzamine-type alkaloids, 12,34-oxamanzamine E (3), 8-hydroxymanzamine J (4), and 6-hydroxymanzamine E (8), as well as 12 previously characterized manzamine alkaloids have been isolated from a common Indonesian sponge of the genus Acanthostrongylophora. The structures of the new compounds have been established on the basis of 1D and 2D NMR spectroscopic analysis and comparison of the data to literature values of related compounds. The biological activities and structure-activity relationship of the manzamines against malaria, Mycobacterium tuberculosis, Leishmania, HIV-1, and AIDS opportunistic infections are discussed. A plausible pathway for the formation of the 12,34-oxaether bridge in compound 3 is also provided.     

Manzamine B and E and ircinal A related alkaloids from an Indonesian Acanthostrongylophora sponge and their activity against infectious, tropical parasitic, and Alzheimer's diseases

Four new manzamine-type alkaloids, 12,28-oxamanzamine E (2), 12,34-oxa-6-hydroxymanzamine E (3), 8-hydroxymanzamine B (5), and 12,28-oxaircinal A (11), were isolated from three collections of an Indonesian sponge of the genus Acanthostrongylophora together with 13 known manzamine alkaloids, ircinal A, ircinol A, xestomanzamine A, manzamines A, E, F, J, and Y, manadomanzamines A and B, neo-kauluamine, 8-hydroxymanzamine A, and manzamine A N-oxide. The structures of the new compounds were elucidated by means of 1D and 2D NMR spectroscopic methods. Three of these compounds (2, 3, and 11) possess a unique manzamine-type aminal ring system generated through an ether linkage between carbons 12-28 or between carbons 12-34. In the case of manzamine B and related metabolites, carbons 11 and 12 of the typical manzamine structure have an epoxide group and add to our growing understanding of manzamine structure-activity relationships (SAR) and metabolism. The bioactivity and SAR for a number of previously reported manzamine-related metabolites against malaria, leishmania, tuberculosis, and HIV-1 are also presented. Manzamine Y (9) showed significant inhibitory activity of GSK3, an enzyme implicated in Alzheimer's disease pathology. The toxicity of manzamine A and neo-kauluamine was evaluated against both medaka fry and eggs.     

Semisynthetic studies on the manzamine alkaloids

Chemical transformation studies were conducted on (-)-8-hydroxymanzamine A ( 1), (-)-manzamine F ( 2), manzamine A ( 3), and (+)-8-hydroxymanzamine A ( 4), isolated from Indo-Pacific Acanthostrongylophora sponges. Thirteen new semisynthetic manzamine derivatives, including four Delta (34,35) manzamines ( 5, 6, 8, and 9) and the unprecedented manzamine derivative 17, are reported. The potent in vitro activities of the obtained semisynthetic manzamines against activated brain microglia and the AIDS opportunistic infection pathogen Mycobacterium tuberculosis are presented.     

Kinetic studies and bioactivity of potential manzamine prodrugs

The manzamines represent a class of marine natural products that show considerable promise in the control of malaria but generate GI distress in rodents when administered orally in high doses. In an effort to generate manzamine prodrugs with improved antimalarial activity and reduced GI toxicity, we prepared acetylated 8-hydroxymanzamine A analogues including 8-acetoxymanzamine A (3) and 8,12-diacetoxymanzamine A (4), and 8-methoxymanzamine A (5) beginning with 8-hydroxymanzamine A (2). The semisynthetic analogues were assayed for antimalarial and antimicrobial activities, cytotoxicity, and biological and chemical stability. Due to gradual hydrolysis of the ester group, application of monoacetate 3 as an antimalarial prodrug was investigated. The in vitro and in vivo bioassays show that acetylated analogues exhibit significant antimalarial activity (IC50( 3) 9.6-30 ng/mL), which are comparable to the parent molecule; however the monoaceate 3 was shown to actually produce higher toxicity at 30 mg/kg when administered orally.     

总合草苔虫的化学成分研究

对采自深圳大亚湾的总合草苔虫Bugula neritinaL.中化学成分进行研究,从石油醚层和正丁醇层分离得到7个化合物。利用波谱分析和文献对照的方法,确定它们的结构分别为胆甾醇(Ⅰ);胆甾-4-烯-3-酮(Ⅱ);胆甾醇肉豆蔻酸酯(Ⅲ);3,β5,α9α-三羟基-(22E,24R)-麦角甾-7,22-二烯-6-酮(Ⅳ);3,β5,α6β-三羟基-(22E,24R)-麦角甾-7,22-二烯(Ⅴ);尿嘧啶(Ⅵ);胸腺嘧啶(Ⅶ)。其中化合物Ⅱ-Ⅶ为首次从总合草苔虫中分离得到。     

Phelligridins C-F: cytotoxic pyrano[4,3-c][2]benzopyran-1,6-dione and furo[3,2-c]pyran-4-one derivatives from the fungus Phellinus igniarius

Three unique pyrano[4,3-c][2]benzopyran-1,6-dione derivatives and a new furo[3,2-c]pyran-4-one, named phelligridins C-F (2-5), together with hispolon (8), (E)-4-(3,4-dihydroxyphenyl)but-3-en-2-one (9), 4-hydroxybenzaldehyde, protocatechualdehyde, syringic acid, protocatechuic acid, caffeic acid, isoergosterone, and octadecyl ferulate were isolated and identified from the ethanolic extract of Phellinus igniarius. Their structures were determined by spectroscopic methods including IR, MS, and 1D and 2D NMR experiments. The structures of the new compounds were characterized as 3-(4-hydroxystyryl)-8,9-dihydroxypyrano[4,3-c]isochromene-4-one (2), 3-(3,4-hydroxystyryl)-8,9-dihydroxypyrano[4,3-c]isochromene-4-one (3), 8,9-dihydroxy-3-[5',6'-dihydroxy-5' '-methyl-3' '-oxo-spiro[fural-2' '(3' 'H),1'-indene]-2'-yl]-1H,6H-pyrano[4,3-c][2]benzopyran-1,6-dione (4), and (3Z)-3-(3,4-dihydroxybenzylidene)-6-(3,4-dihydroxystyryl)-2,3-dihydro-2-methoxy-2-(2-oxo-propyl)furo[3,2-c]pyran-4-one (5), respectively. Some compounds including 2 and 3 showed in vitro selective cytotoxicity against a human lung cancer cell line (A549) and a liver cancer cell line (Bel7402). Possible biogenetic sequences to the formation of 1-9 are postulated.     

Reinvestigation of structure of porritoxin,a phytotoxin of Alternaria porri

The structure of porritoxin, a phytotoxin of Alternaria porri, was reinvestigated by detailed 2D NMR analysis including (1)H-(13)C and (1)H-(15)N HMBC experiments. The structure of porritoxin was determined to be 2-(2'-hydroxyethyl)-4-methoxy-5-methyl-6-(3' '-methyl-2' '-butenyloxy)-2,3-dihydro-1H-isoindol-1-one (1). Thus our previous proposed structure, 8-(3',3'-dimethylallyloxy)-10-methoxy-9-methyl-1H-3,4-dihydro-2,5-benzoxazocin-6(5H)-one (2), is incorrect.     

Bioactive secondary metabolites from Boesenbergia pandurata of Myanmar and their preferential cytotoxicity against human pancreatic cancer PANC-1 cell line in nutrient-deprived medium

The chloroform extract of rhizomes of Boesenbergia pandurata demonstrated marked preferential cytotoxicity against human pancreatic PANC-1 cancer cells in nutrient-deprived medium. Bioactivity-directed investigation of this extract yielded four new secondary metabolites, geranyl-2,4-dihydroxy-6-phenethylbenzoate ( 1), 2',4'-dihydroxy-3'-(1'-geranyl)-6'-methoxychalcone ( 2), (1' R,2' S,6' R)-2-hydroxyisopanduratin A ( 3), and (2 R)-8-geranylpinostrobin ( 4), and twenty known compounds ( 5- 24). Among the known compounds, (2 S)-6-geranylpinostrobin ( 5), (+/-)-6-methoxypanduratin A ( 6), and (2 S)-7,8-dihydro-5-hydroxy-2-methyl-2-(4'-methyl-3'-pentenyl)-8-phenyl-2 H,6 H-benzo[1,2- b:5,4- b']dipyran-6-one ( 7) were isolated for the first time from a natural source. The structures of these compounds were elucidated using extensive spectroscopic techniques including CD measurements. All the isolated compounds showed varying degrees of in vitro preferential cytotoxicity against PANC-1 cells. Nicolaioidesin B ( 11) and panduratin A ( 17) were most potent, each showing a PC 100 at 2.5 microM.     

Furanosesquiterpenoids of Commiphora myrrha.

An investigation on the gum exudates of Commiphora myrrha has led to the isolation of six sesquiterpenoids. On the basis of spectroscopic data interpretation, they were determined as two new furanosesquiterpenoids, rel-1S,2S-epoxy-4R-furanogermacr-10(15)-en-6-one (1) and rel-2R-methyl-5S-acetoxy-4R-furanogermacr-1(10)Z-en-6-one (2), and four known furanosesquiterpenoids, rel-3R-methoxy-4S-furanogermacra-1E,10(15)-dien-6-one (3), rel-2R-methoxy-4R-furanogermacr-1(10)E-en-6-one (4), furanogermacra-1(10)Z,4Z-dien-6-one, and curzerenone [6,7-dihydro-5beta-isopropenyl-3,6beta-dimethyl-6-vinylbenzofuran-4(5H)-one]. This is the first report of the relative stereochemistry for the known compounds 3 and 4. Compound 1 exhibited weak cytotoxic activity against a MCF-7 breast tumor cell line in a clonogenic assay, while the other five compounds were inactive in this assay.     

Mono-, Bi-, and triphenanthrenes from the tubers of Cremastra appendiculata

Six newphenanthrene derivatives, including three monophenanthrenes (1-3), two biphenanthrenes (4 and 5), and a triphenanthrene (6), have been isolated from an ethanolic extract of the tubers of Cremastra appendiculata. Using spectroscopic methods, the structures of compounds 1-6 were determined as 1-hydroxy-4,7-dimethoxy-1-(2-oxopropyl)-1H-phenanthren-2-one (1), 1,7-dihydroxy-4-methoxy-1-(2-oxopropyl)-1H-phenanthren-2-one (2), 2-hydroxy-4,7-dimethoxyphenanthrene (3), 2,7,2'-trihydroxy-4,4',7'-trimethoxy-1,1'-biphenanthrene (4), 2,2'-dihydroxy-4,7,4',7'-tetramethoxy-1,1'-biphenanthrene (5), and 2,7,2',7',2' '-pentahydroxy-4,4',4' ',7' '-tetramethoxy-1,8,1',1' '-triphenanthrene (6), respectively. Compounds 1-6 and two known compounds, cirrhopetalanthin (7) and flavanthrinin (8), obtained previously from this plant, were evaluated against six human cancer cells and a normal cell line.     

麦冬须根高异黄酮类成分及其清除氧自由基作用

目的：研究川麦冬须根中高异黄酮类成分及其清除氧自由基作用。方法：对川麦冬须根提取物高异黄酮类成分进行分离鉴定，并采用化学发光法测定其清除超氧阴离子（O2^-）、羟自由基（·OH）、过氧化氢（H2O2）的能力。结果：分离得到10个高异黄酮类化合物，经鉴定分别为：甲基麦冬黄烷酮A（1）、甲基麦冬黄烷酮B（2）、麦冬黄烷酮A（3）、麦冬黄烷酮E（4）、5，7-dihydroxy-6，8-dimethyl-3-（4′-hydroxy-3′，5′-dimethoxybenzyl）chroman-4-one（5）、甲基麦冬黄酮A（6）、甲基麦冬黄酮B（7）、去甲基异麦冬黄酮B（8）、5，7，2′-trihydroxy-8-methyl-3-（3′，4′-methylenedioxybenzyl）chromone（9）、5，7，2′-trihydroxy-6，8-dimethyl-3-（3′，4′-methylenedioxybenzyl）chromone（10）。结论：化合物8和9首次从麦冬中分离得到，麦冬中多数高异黄酮类化合物具有不同程度的清除·OH及H2O2作用，活性与其分子结构相关。     

Dibenzyl bromophenols with diverse dimerization patterns from the brown alga Leathesia nana

Six novel dibenzyl bromophenols (1-6) with different dimerization patterns and two propyl bromophenol derivatives (7 and 8), together with 11 known bromophenol derivatives, were isolated from the ethanolic extract of the brown alga Leathesia nana. On the basis of spectroscopic methods the structures of the new compounds were determined as 5,6'-diethyloxymethyl-3,4,2'-tribromo-2,3',4'-trihydroxydiphenyl ether (1), 2-(2,3-dibromo-4,5-dihydroxybenzyl)-3,5-dihydroxy-4-methoxybenzyl alcohol (2), 6-(2,3-dibromo-4,5-dihydroxybenzyl)-2,3-dibromo-4,5-dihydroxy benzyl methyl ether (3), 9,10-dihydro-9,10-dimethoxy-3,4,7,8-tetrabromo-1,2,5,6-tetrahydroxyanthracene (4), (+)-3-(2,3-dibromo-4,5-dihydroxyphenyl)-4-bromo-5,6-dihydroxy-1,3-dihydroisobenzofuran (5), rel-(4aS,10aR)-(+/-)-6,7-dibromo-4a-hydroxy-3,8-dihydroxymethyl-10a-methoxy-1,4,4a,10a-tetrahydrodibenzo[b,e][1,4]dioxin-1-one (6), (E)-2-methyl-3-(2,3-dibromo-4,5-dihydroxyphenyl)propenal (7), and 2-methyl-3-(2,3-dibromo-4,5-dihydroxyphenyl)-1-propanol (8). Some compounds including 3 showed in vitro selective cytotoxicity against several human cancer cell lines. This is the first brown alga to be reported containing bromophenols.     

刺异叶花椒根中香豆素类成分

目的:对刺异叶花椒Zanthoxylum dimorphophyllum var. spinifolum根的化学成分进行研究.方法:采用现代色谱分离技术进行化学成分的分离,运用波谱方法确定结构.结果:从中分离得到5个化合物,分别鉴定为5-甲氧基-7-羟基-6-(3'-甲基-2',3'-二羟基丁基)-香豆素(Ⅰ),6-(3'-甲基-2',3'-二羟基丁基)-7-甲氧基-8-(3″-甲基-丁-2″-烯基)-香豆素(Ⅱ),6-(3'-甲基-2',3'-二羟基丁基)-7-羟基-8-(3″-甲基-丁-2″-烯基)-香豆素(Ⅲ),6-(3'-甲基-2',3'-环氧丁基)-7-甲氧基-8-(3″-甲基-丁-2″-烯基)-香豆素(Ⅳ),7-甲氧基-8-(3'-甲基-丁-2'-烯基)-香豆素(Ⅴ).结论:以上化合物均为首次从该植物中分得.     

Bioactive constituents from Asparagus cochinchinensis

Bioassay-directed fractionation of the dried roots of Asparagus cochinchinensis led to the isolation of a new spirostanol saponin, asparacoside (1), two new C-27 spirosteroids, asparacosins A (2) and B (3), a new acetylenic derivative, 3' '-methoxyasparenydiol (4), and a new polyphenol, 3'-hydroxy-4'-methoxy-4'-dehydroxynyasol (6), as well as five known phenolic compounds, asparenydiol (5), nyasol (7), 3' '-methoxynyasol (8), 1,3-bis-di-p-hydroxyphenyl-4-penten-1-one (9), and trans-coniferyl alcohol (10). Compounds 1, 6, and 8 demonstrated moderate cytotoxicities in a panel comprised of KB, Col-2, LNCaP, Lu-1, and HUVEC cells, with IC(50) values ranging from 4 to 12 microg/mL. The structures were determined by spectroscopic and chemical methods.     

Cytotoxic 4-phenylcoumarins from the leaves of Marila pluricostata

Bioassay-guided fractionation of the CH(2)Cl(2) extract of the leaves of Marila pluricostata led to the isolation of 17 naturally occurring 4-phenylcoumarins, three of them, 5-hydroxy-8,8-dimethyl-4-phenyl-9,10-dihydro-8H-pyrano-[2,3-f]chromen-2-one (1), 5-hydroxy-8,8-dimethyl-4-phenyl-6-propionyl-9,10-dihydro-8H-pyrano-[2,3-f]chromen-2-one (2), and 5,7-dihydroxy-8-(3-methylbut-2-enyl)-4-phenylchromen-2-one (3), are new natural compounds; the remaining (4-17) are known mammea-type coumarins. Their structures were established by spectroscopic means. All compounds were tested in cytotoxicity assays against the MCF-7, H-460, and SF-268 human cancer cell lines.     

Trypanocidal diarylheptanoids from Aframomum letestuianum

Three new diarylheptanoids, (4Z,6E)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-7-(4-hydroxyphenyl)hepta-4,6-dien-3-one, letestuianin A (1), (4Z,6E)-5-hydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-4,6-dien-3-one, letestuianin B (2), and 1,7-bis(4-hydroxyphenyl)heptan-3,5-dione, letestuianin C (3), as well as the known (4Z,6E)-5-hydroxy-1,7-bis(4-hydroxyphenyl)hepta-4,6-dien-3-one (5) were isolated from Aframomum letestuianum. The known flavonoids 3-acetoxy-5,7,4'-trihydroxyflavanone, 3-acetoxy-7-methoxy-5,4'-dihydroxyflavanone, 7-methoxy-3,5,4'-trihydroxyflavone, and 3,3',4',5,7-pentahydroxyflavan were also obtained from this plant. Their structures were determined using a combination of 1D and 2D NMR techniques. The four diarylheptanoids were tested for growth inhibitory activity in vitro versus bloodstream forms of African trypanosomes. IC(50) values in the range of 1-3 microg/mL were found for compounds 3 and 5.     

网状软柳珊瑚化学成分研究

从南海网状软柳珊瑚中分离鉴定了9个化合物:胆甾醇(1)、ergostra-7,22diene-3β,5α,6β-triol(2)、cholesta7,22diene-3β,5α,6β-triol(3)、5,8-epidioxycampesta6,22-dien3-ol(4)、鲨肝醇(5)、咖啡碱(6)、胸腺嘧啶(7)、尿嘧啶(8)、鸟嘌呤(9),所有化合物均为首次从软柳珊瑚属中分离得到。     

6-Alkyl-3,4-dihydro-2H-pyrans: chemical secretion compounds in neotropical harvestmen

The defensive secretions of five neotropical species of harvestmen (Opiliones: Gonyleptidae) from the Brazilian Atlantic Forest were analyzed and chemically characterized by GC-MS and NMR methods. Three of the species, Cobania picea, Roweria virescens, and Serracutisoma proximum, secrete a mixture of 2,3-dimethyl-1,4-benzoquinone and 2-ethyl-3-methyl-1,4-benzoquinone. The secretions produced by the other two species, Iporangaia pustulosa and Neosadocus maximus, contain 1-hepten-3-one, 5-methyl-1-hexen-3-one, and 1-(6-butyl-3,4-dihydro-2H-pyran-2-yl)pentanone (1) as major components, as well as 2,3-dimethyl-1,4-benzoquinone and 2-ethyl-3-methyl-1,4-benzoquinone as minor constituents. The dihydropyran 1-(6-butyl-3,4-dihydro-2H-pyran-2-yl)pentanone (1) is a new natural product, composed of two 1-hepten-3-one subunits formally linked in a hetero-Diels-Alder reaction. The natural product was proven to be racemic, and its biogenetic origin is discussed.     

知母须根化学成分的研究

目的研究知母Anemarrhena asphodeloides Bge.须根的化学成分。方法知母须根70%乙醇提取物采用硅胶、ODS、半制备HPLC进行分离纯化,根据理化性质及波谱数据鉴定所得化合物的结构。结果从中分离得到8个化合物,分别鉴定为7-hydroxy-3-(4-methoxybenzyl)-chroman(1)、4′-hydroxyphenyl ethyl vanillate(2)、methyl 4-hydroxybenzoate(3)、1,3,6,7-tetrahydroxy-9H-xanthen-9-one(4)、6′,7′-dihydroxy-2-methoxy-3′,4′-dihydro-2′H-spiro[cyclohexane-1,1′-naphthalene]-2,5-dien-4-one(5)、michehedyoside D(6)、demethyleugenolα-D-glucopyranoside(7)、2′,3′-dihydroxyl-osthole(8)。结论化合物3～8均为首次从该植物中分离得到。     

Mixed lignan-neolignans from Tarenna attenuata

Six new mixed lignan-neolignans and 20 known compounds were isolated from the whole plant of Tarenna attenuata. By analysis of physical and spectroscopic data, the structures of the new compounds were elucidated as (1R,5R,6R)-6-{4-O-[2-(1-(4-hydroxy-3-methoxyphenyl))glycerol]-3,5-dimethoxyphenyl}-3,7-dioxabicyclo[3.3.0]octan-2-one (1), 5' '-methoxyhedyotisol A (2), 4' '-O-(8-guaiacylglycerol)buddlenol A (3), 5' '-methoxy-4' '-O-(8-guaiacylglycerol)buddlenol A (4), 4,6-dimethoxy-5-hydroxy-3-hydroxymethyl-2-(3,4,5-trimethoxyphenyl)-2,3-dihydrobenzofuran (5), and 7-O-ethylguaiacylglycerol (6). Compounds 1, 5, 6, and 8 showed potent antioxidant activities against H2O2-induced impairment in PC12 cells, and compounds 1, 2, 5, and 7 scavenged DPPH radical strongly with IC50 values of 72, 87, 45, and 55 microM, respectively.