Triterpenoids from the floral spikes of Betula platyphylla var. japonica and their reversing activity against multidrug-resistant cancer cells

Four new triterpenes, together with 16 known triterpenes, were isolated from the floral spikes of Betula platyphylla var. japonica in a search for compounds capable of reversing multidrug resistance in cancer cells. The structures of the new triterpenes were elucidated as 3,4-seco-olean-4(23),13(18)-dien-3-oic acid (1), 3,4-seco-urs-4(23),20(30)-dien-3-oic acid (2), 3-O-methylmalonylepiocotillol II (6), and 3-O-methylmalonylcabraleahydroxylactone (16) by spectroscopic examination. The cytotoxicity of the isolated triterpenes against human cancer cell lines as well as multidrug-resistant cancer cell lines was evaluated. Most of the isolated triterpenes showed very weak cellular toxicities. Although no discernible differences were found in the cytotoxicities for the tested compounds against sensitive and resistant cell lines, the cytotoxicities for several triterpenes against multidrug-resistant cancer cell lines (KB-C2 or K562/Adr) were enhanced in the presence of nontoxic concentrations of colchicine or doxorubicin. Compound 10 reversed the cytotoxicity of colchicine against KB-C2 cells at 8.1 microM and showed comparable potency to 5 microM verapamil.     

Bioactive cardenolides from the stems and twigs of Nerium oleander

Four new cardenolide monoglycosides, cardenolides N-1 (1), N-2 (2), N-3 (3), and N-4 (4), were isolated from Nerium oleander, together with two known cardenolides, 5 and 12, and seven cardenolide monoglycosides, 6-11 and 13. The structures of compounds 1-4 were established on the basis of their spectroscopic data. The in vitro anti-inflammatory activity of compounds 1-13 was examined on the basis of inhibitory activity against the induction of the intercellular adhesion molecule-1 (ICAM-1). Compounds 1, 5, 6, and 11-13 were active at an IC50 value of less than 1 microM. The cytotoxicity of compounds 1-13 was evaluated against three human cell lines, normal human fibroblast cells (WI-38), malignant tumor cells induced from WI-38 (VA-13), and human liver tumor cells (HepG2). Compounds 1, 4, 6, and 11-13 were active toward V-13 cells, and compounds 1, 11, and 12 were active toward HepG2 cells at IC50 values of less than 1 microM. Compounds 4, 5, 10, and 12 showed selective cell growth inhibitory activity toward V-13 tumor cells compared with that of parental normal WI-38 cells. The MDR-reversal activity of compounds 1-13 was evaluated on the basis of the amount of calcein accumulated in MDR human ovarian cancer 2780AD cells in the presence of each compound. Compounds 4, 9, and 10 showed significant effects on calcein accumulation, compound 4 showing stronger activity than that of verapamil.     

Bioactive benzophenones from Garcinia xanthochymus fruits

A MeOH extract of Garcinia xanthochymus fruits was subjected to activity-guided fractionation, yielding two new benzophenones, guttiferone H (1) and gambogenone (2). Compound 1 contains a seven-membered ring attached to the bicyclo[3.3.1]nonane system at positions 7 and 8 and displayed cytotoxicity in the SW-480 colon cancer cell line (IC(50) = 12 microM). Compound 2 has a novel benzophenone bicyclo[3.3.2]decane system and displayed cytotoxicity in the SW-480 colon cancer cell line (IC(50) = 188 microM). Both 1 and 2 induced apoptosis in SW-480 colon cancer cells and displayed antioxidant activity in the 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay (IC(50) = 64 and 38.7 microM, respectively). The structures of 1 and 2 were established by 1D and 2D NMR data analysis. Eleven known compounds, aristophenone A, alloathyriol, amentoflavone, 3,8' '-biapigenin, cycloxanthochymol, (+/-)-fukugetin, (+/-)-fukugiside, guttiferone E, isoxanthochymol, (+/-)-volkensiflavone, and xanthochymol, were also obtained. The 11 known compounds were also tested against SW-480 colon cancer cells and in the DPPH assay.     

Sesquiterpenoids and artificial 19-oxygenated steroids from the formosan soft coral Nephthea erecta

Chemical investigations on the acetone and MeOH solubles of the soft coral Nephthea erecta have afforded five new sesquiterpenoids (1-5), one known sesquiterpene, kelsoene (6), and two known 19-oxygenated steroids (10 and 11). In addition, three unexpected artificial 19-oxygenated steroids (7-9) were obtained by letting 10 and 11 stand in CDCl(3) for prolonged periods of time. The structures of 1-9 were elucidated by extensive spectroscopic analyses, and their cytotoxicity against selected cancer cells was measured in vitro.     

Cytotoxic lignans from the stem bark of Magnolia officinalis

Three new lignans, 4'-methoxymagndialdehyde ( 1), 4'-methoxymagnaldehyde B ( 2), and 4'-methoxymagnaldehyde E ( 3), were isolated from hexane- and EtOAc-soluble fractions of the stem bark of Magnolia officinalis, together with eight known compounds ( 4- 11). The structures of compounds 1- 3 were determined on the basis of spectroscopic and physicochemical data analysis. Compounds 1- 11 were tested in vitro for their cytotoxic activity against the K562, HeLa, and A549 cancer cell lines. Among the compounds tested, compound 1 showed the most potent cytotoxic activity against these cancer cell lines, with IC50 values of 3.9, 1.5, and 3.7 microg/mL, respectively.     

Triterpenoids and steroids from the fruits of Melia toosendan and their cytotoxic effects on two human cancer cell lines

Ten new triterpenoids, named meliasenins I-R (1-10), one new steroid (11), and 11 related known compounds (12-22) were isolated from fruits of Melia toosendan. The structures of the new compounds were established on the basis of spectroscopic methods, including 2D NMR techniques and mass spectrometry. The relative configuration of 1, (20R*,23E)-25-hydroperoxyeupha-7,23-diene-3β,16β-diol (meliasenin I), was confirmed by single-crystal X-ray diffraction analysis. All isolated triterpenoids (1-10, 12-15) and two steroids (11, 20) were tested for their cytotoxicity against U20S human osteosarcoma and MCF-7 human breast cancer cells using the MTT assay, and some of them were significantly cytotoxic (IC(50) <10 μg/mL). The insecticidal properties of compounds 1-15 and 20 were also briefly evaluated.     

Anti-inflammatory, anti-tumor-promoting, and cytotoxic activities of constituents of marigold (Calendula officinalis) flowers

Ten oleanane-type triterpene glycosides, 1-10, including four new compounds, calendulaglycoside A 6'-O-methyl ester (2), calendulaglycoside A 6'-O-n-butyl ester (3), calendulaglycoside B 6'-O-n-butyl ester (5), and calendulaglycoside C 6'-O-n-butyl ester (8), along with five known flavonol glycosides, 11-15, were isolated from the flowers of marigold (Calendula officinalis). Upon evaluation of compounds 1-9 for inhibitory activity against 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation (1 microg/ear) in mice, all of the compounds, except for 1, exhibited marked anti-inflammatory activity, with ID50 values of 0.05-0.20 mg per ear. In addition, when 1-15 were evaluated against the Epstein-Barr virus early antigen (EBV-EA) activation induced by TPA, compounds 1-10 exhibited moderate inhibitory effects (IC50 values of 471-487 mol ratio/32 pmol TPA). Furthermore, upon evaluation of the cytotoxic activity against human cancer cell lines in vitro in the NCI Developmental Therapeutics Program, two triterpene glycosides, 9 and 10, exhibited their most potent cytotoxic effects against colon cancer, leukemia, and melanoma cells.     

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.     

艾里莫芬烷倍半萜抗白血病构效关系研究

目的 研究艾里莫芬烷倍半萜抗白血病作用构效关系,为该类倍半萜结构修饰和开发利用提供参考依据.方法 对呋喃艾里莫芬烷倍半萜-橐吾酮(ligularone,9)进行结构修饰,采用MTT法对从橐吾属植物中分离得到的艾里莫芬烷倍半萜以及橐吾酮结构修饰物进行体外抑制人早幼粒白血病细胞(HL-60)生长活性评价.结果 以橐吾酮为原料通过光敏氧化得内酯倍半萜(10),鉴定为6-oxo-8β-methoxyeremophilenolide,通过还原和乙酰化反应获得了2个呋喃倍半萜修饰产物,分别为epiligularol(11),epiligularolacetate(12).活性评价实验结果 表明所有内酯艾里莫芬烷倍半萜对HL-60细胞生长有明显的抑制作用,化合物1～6的IC50＜10μg/ml,化合物7,8,10的IC50在10～20μg/ml之间,具有C9和C10位不饱和结构的内酯倍半萜(1～6)活性较强;所有呋喃艾里莫芬烷倍半萜没有抑制活性,而橐吾酮通过光敏氧化转化为内酯倍半萜后有抑制活性.结论 首次研究了橐吾酮的光敏氧化反应,橐吾酮的呋喃环光敏氧化后可转化为内酯环;首次探讨了艾里莫芬烷倍半萜抗白血病作用构效关系.该类倍半萜的12(8)内酯环可能是抗白血病(HL-60)的关键活性基团,具有C9和C10位不饱和结构的内酯倍半萜活性较强.     

Bioassay-Guided Isolation of Prenylated Xanthones and Polycyclic Acylphloroglucinols from the Leaves of Garcinia nujiangensis

Bioassay-guided fractionation of the acetone extract of the leaves of Garcinia nujiangensis resulted in the isolation of two new prenylated xanthones, nujiangexanthones A (1) and B (2), three new polycyclic polyprenylated acylphloroglucinols, nujiangefolins A-C (3-5), and 10 known related analogues. The structures of compounds 1-5 were elucidated by interpretation of their spectroscopic data. Compounds 3 and 4 are unusual polycyclic polyprenylated acylphloroglucinols in which the enol hydroxy group forms a six-membered ring with a benzene ring carbon. The compounds isolated were evaluated for their cytotoxic effects against 11 cancer cell lines and immortalized MIHA normal liver cells, and the test substances demonstrated selectivity toward the cancer cells. Isojacareubin (6) was found to be the most potent cytotoxic compound of those tested.     

Sesquiterpenes from the red alga Laurencia tristicha

Seven new sesquiterpenes (1-7), together with seven known sesquiterpenes, aplysin (8), aplysinol (9), gossonorol (10), 7,10-epoxy-ar-bisabol-11-ol (11), 10-epi-7,10-epoxy-ar-bisabol-11-ol (12), johnstonol (13), and laurebiphenyl (14), have been isolated from the red alga Laurencia tristicha. The structures of new compounds were established as laur-11-en-2,10-diol (1), laur-11-en-10-ol (2), laur-11-en-1,10-diol (3), 4-bromo-1,10-epoxylaur-11-ene (4), cyclolauren-2-ol (5), laurentristich-4-ol (6), and ar-bisabol-9-en-7,11-diol (7) by means of spectroscopic methods including IR, HRMS, and 1D and 2D NMR techniques. Compound 6 possessed a novel rearranged skeleton. All compounds were tested against several human cancer cell lines including lung adenocarcinoma (A549), stomach cancer (BGC-823), hepatoma (Bel 7402), colon cancer (HCT-8), and HELA cell lines. Laurebiphenyl (14) showed moderate cytotoxicity against all tested cell lines, with IC(50) values of 1.68, 1.22, 1.91, 1.77, and 1.61 microg/mL, respectively. Other compounds were inactive (IC(50) > 10 microg/mL).     

Cytotoxic and other metabolites of Aspergillus inhabiting the rhizosphere of Sonoran desert plants

In a study to discover potential anticancer agents from rhizosphere fungi of Sonoran desert plants cytotoxic EtOAc extracts of four Aspergillus strains have been investigated. Two new metabolites, terrequinone A (1) and terrefuranone (2), along with Na-acetyl aszonalemin (LL-S490beta) (3) were isolated from As. terreus occurring in the rhizosphere of Ambrosia ambrosoides, whereas As. terreus inhabiting the rhizosphere of an unidentified Brickellia sp. afforded dehydrocurvularin (4), 11-methoxycurvularin (5), and 11-hydroxycurvularin (6). As. cervinus isolated from the rhizosphere of Anicasanthus thurberi contained two new compounds, 4R*,5S*-dihydroxy-3-methoxy-5-methylcyclohex-2-enone (7) and 6-methoxy-5(6)-dihydropenicillic acid (8), in addition to penicillic acid (9). Penicillic acid was also isolated from As. wentii occurring in the rhizosphere of Larrea tridentata. The structures of 1-9 were elucidated by spectroscopic methods and chemical derivatizations. Acetylation of 2 afforded 14-acetylterrefuranone (13) and 14-deoxy-13(14)-dehydroterrefuranone (14). Metabolites 1-9, the dienone 14, and 5(6)-dihydropenicillic acid (16) were evaluated for cytotoxicity in a panel of four human cancer cell lines and in normal human primary fibroblast cells. Compounds 4 and 5 displayed considerable cytotoxicity, whereas 1, 6, 9, and 14 were found to be moderately active, with 6 and 9 exhibiting selective cytotoxicity against cancer cell lines compared with the normal fibroblast cells.     

Potent cytotoxic lignans from Justicia procumbens and their effects on nitric oxide and tumor necrosis factor-alpha production in mouse macrophages

A new lignan glycoside, 4-O-alpha-L-arabinopyranosyl-(1' "-->2' ')-beta-D-apiofuranosyldiphyllin (2), named procumbenoside A, and 11 known compounds were isolated from the whole plant of Justicia procumbens. The structure of 2 was established by spectral analysis and chemical methods. The known compounds justicidin A (1), diphyllin (3), and tuberculatin (4) showed potent cytotoxic effects against a number of cancer cells in vitro. Compounds 1 and 4 also strongly enhanced tumor-necrosis factor-alpha (TNF-alpha) generation from mouse macrophage-like RAW 264.7 cells stimulated with lipopolysaccharide (LPS).     

Reversal of P-glycoprotein-mediated multidrug resistance by sipholane triterpenoids

Nineteen triterpenoids, possessing four different skeletons, have been reported so far from the Red Sea sponge Siphonochalina siphonella. However, no biological activity of these compounds was ever reported. This study describes the isolation of two new triterpenoids, siphonellinol C (3) and sipholenol I (4), along with several known sipholane triterpenoids from the Red Sea sponge Callyspongia (=Siphonochalina) siphonella. Allylic oxidation of the major sipholane triterpenoids, sipholenol A (1) and sipholenone A (2), by selenium dioxide afforded four C-28-oxidized derivatives. Sipholane triterpenoids along with their semisynthetic derivatives were evaluated for their cytotoxicity and effect on reversing P-glycoprotein-mediated MDR to colchicine. Sipholenol A was found to be the most potent, and it increased the sensitivity of resistant KB-C2 cells by 16 times toward colchicine. This is the first report related to reversal of cancer chemotherapy resistance using these triterpenoids.     

Malyngamide 3 and cocosamides A and B from the marine cyanobacterium Lyngbya majuscula from Cocos Lagoon, Guam

Malyngamide 3 (1) and cocosamides A (2) and B (3) were isolated from the lipophilic extract of a collection of Lyngbya majuscula from Cocos Lagoon, Guam. The planar structures of compounds 1-3 were determined by spectroscopic methods. The absolute configuration of 1 was determined by modified Mosher's method, NOESY data, and comparison with lyngbic acid (4). The absolute configurations of 2 and 3 were assigned by enantioselective HPLC analysis and comparison with the closely related compound pitipeptolide A (5). Compounds 1-3 showed weak cytotoxicity against MCF7 breast cancer and HT-29 colon cancer cells.     

安息香化学成分及其体外抗肿瘤活性

目的:对安息香化学成分进行体外抗肿瘤细胞的药效筛选,以明确安息香抗肿瘤的物质基础。方法:运用硅胶柱色谱、中压液相制备色谱、制备液相色谱等技术对安息香的95%乙醇提取物进行了系统的分离,根据理化性质和波谱数据鉴定化合物的结构;通过体外人肝癌细胞(Hep G2),人肺癌细胞(A549),人宫颈癌细胞(He La),人乳腺癌细胞(MCF-7),人前列腺癌细胞(PC-3)筛选化合物抗肿瘤活性。结果:从安息香醇提取物中分离得到15个化合物,分别鉴定为myricadiol(1),3-keto-oleanonic acid(2),(4E)-1,5-bis (4-hydroxyphenyl)-1-methoxy-2-(methoxy-methyl)-4-pentene (3a和3b),(E)-p-coumaryl alcoholγ-Ο-methyl ether(4),芝麻素(5),5-(3″-benzoyloxypropyl)-7-methoxy-2-(3’,4’-methylenedioxy phenyl)-benzofuran(6),邻苯二甲酸二丁酯(7),香草酸甲酯(8),对羟基苯甲醛(9),对羟基苯乙酮(10),香草乙酮(11),3-oxo-olean-11,13(18)-dien-28,19β-olide(12),香草醛(13),苯甲酸(14),逞罗树脂酸(15)。其中,化合物1~11为首次从安息香中分离得到。部分化合物有一定的抗肿瘤活性,其中化合物2和12抗肿瘤活性最为显著,对5种肿瘤细胞都有显著的抑制作用,显著优于阳性药顺铂。结论:安息香中萜类化合物在抗肿瘤药物的开发、应用上具有良好发展前景。     

New nitrogenous eudesmane-type compounds isolated from the Caribbean sponge Axinyssa ambrosia

Fractionation of an acetone-methanol (1:1) extract of the Caribbean marine sponge Axinyssa ambrosia yielded three new sesquiterpenes whose structures were established by spectroscopic methods as (4R*,5R*,7S*,10R*)-eudesm-11-en-4-ylamine hydrochloride (1), axinyssamine hydrochloride, (4R*,5R*,7S*,10R*)-4-isocyanatoeudesm-11-ene (3), and (4R*,5R*,7S*,10R*)-formamidoeudesm-11-ene (4). Compound 1 exhibited significant cytotoxic activity against cancer cells and was also active in a lethality test using polyps of the scleractinian coral Madracis mirabilis.     

Isolation and identification of cytotoxic compounds from the wood of Pinus resinosa

Methanol extracts of wood from Pinus resinosa were found to be selectively cytotoxic against human lung carcinoma cells, A549 (IC50 41 +/- 6 microg/mL), human colorectal adenocarcinoma cells, DLD-1 (IC50 47 +/- 4 microg/mL) in comparison with healthy cells, WS1 (IC50 130 +/- 11 microg/mL). Five known compounds were isolated and identified by 1H, 13C NMRspectroscopy and HR-ESI-MS mass spectrometry as, pinosylvin monomethyl ether (1), pinosylvin (2), pinosylvin dimethyl ether (3), pinobanksin (4) and (-)-norachelogenin (5). Compound 4 was isolated for the first time in P. resinosa. The cytotoxicity of compounds 1-5 was evaluated against A549, DLD-1 and WS1. Compound 1 exhibited the strongest cytotoxicity against both tumor cell lines and the healthy cell line with an IC50 of 25 +/- 4 microm for A549, 20 +/- 1 microm for DLD-1 and 34 +/- 3 microm for WS1.     

番荔枝皮化学成分及其抗肿瘤活性的研究

目的:研究番荔枝Annona squamosa的化学成分,并对分离化合物进行活性筛选.方法:综合运用各种色谱方法分离纯化番荔枝中的化学成分;采用NMR等波谱方法鉴定其结构;运用SRB法测定化合物对肿瘤细胞体外增殖能力的抑制作用.结果:从番荔枝皮乙醇提取物中分离得到11个化合物,分别是annosquamosin C(1),15,16-epoxy-17-hydroxy-ent-kau-ran-19-oic acid(2),16,17-dihydroxy-ent-kauran-19-oic acid(3),annosquamosin A(4),ent-kaur-16-en-19-oic acid (5),19-nor-ent-kauran-4-ol-17-oic acid(6),16-hydroxy-ent-kau-ran-19-oic acid(7),ent-15β-hydroxy-kaur-16-en-19-oic acid (8),annosquamosin B (9),ent-16β,17-dihydroxykauran-19-al(10),16,17-dihydroxy-ent-kauran-19-oic acid methyl ester(11).抗肿瘤活性实验表明,化合物1,2,3,5,9对人肺癌95-D细胞的体外增殖能力均具有不同程度的抑制作用,化合物5的活性最强,IC50为7.78 μmol·L-1;化合物2,5,9对人卵巢癌A2780细胞有抑制作用,其中化合物2和9的抑制作用较强,IC50分别为0.89,3.10 μmol·L-1.结论:化合物2,8,11分别为首次从该科、该属和该种植物分离得到;化合物5对人肺癌95-D细胞的抑制作用较强;化合物2和9对人卵巢癌细胞A2780的抑制作用较强.     

小黄皮茎的化学成分及生物活性研究

目的研究小黄皮Clausenaemarginata茎的化学成分及其保肝活性。方法采用硅藻土、硅胶等多种柱色谱、中压制备液相色谱(MPLC)及制备型HPLC等方法对小黄皮茎的化学成分进行分离纯化,根据化合物理化性质结合现代波谱学方法鉴定化合物结构;并测试其对DL-半乳糖胺诱导肝细胞损伤的保护活性及其对脂多糖(LPS)诱导小鼠小胶质BV2细胞产生一氧化氮(NO)的抑制活性。结果从小黄皮茎的95%乙醇提取物的氯仿部位分离得到11个化合物,分别鉴定为nordentatin(1)、oxanordentatin(2)、5′-羟基葡萄内酯(3)、7-[(E)-7′-羟基-3′,7′-二甲基-2′,5′-二烯]-香豆素(4)、7-羟基香豆素(5)、claulamine A(6)、γ-崖椒碱(7)、开环异落叶松脂素(8)、2-{4-[(1E)-3-hydroxyprop-1-en-1-yl]-2,6-dimethoxyphenoxy}propane-1,3-diol(9)、2-[4-(3-hydroxy-1-propenyl)-2-methoxyphenoxy]-1,3-propanediol(10)、甲基-2-O-β-D-吡喃葡萄糖基苯甲酸(11)。其中,化合物1~5为香豆素类化合物,6为咔唑生物碱,7为呋喃喹啉类生物碱,8为木脂素类化合物,9、10为苯丙素类化合物,11为酚酸类化合物。结论化合物2~4、7~11为首次从该植物中分离得到,化合物5和7对DL-半乳糖胺诱导的肝细胞损伤具有一定的保护活性,化合物11对LPS诱导BV2细胞产生NO具有一定的抑制作用。