Ericifolin: an eugenol 5-O-galloylglucoside and other phenolics from Melaleuca ericifolia

Ericifolin, an eugenol 5-O-beta-(6'-O-galloylglucopyranoside) possessing the naturally unknown phenolic moiety, 5-hydroxyeugenol, together with the two new phenolics, 2-O-p-hydroxybenzoyl-6-O-galloyl-(alpha/beta)-4C1-glucopyranose and 3-methoxyellagic acid 4-O-rhamnopyranoside have been isolated from the antibacterial leaves extract of Melaleuca ericifolia. In addition, 19 known phenolics were also separated and characterized. All structures were elucidated on the basis of analysis of 1H, 13C NMR, HMQC, HMBC and FTMS spectral data.     

Oleanane-type triterpenoids from Panax stipuleanatus and their anticancer activities

One newly (1) and 10 known oleanane-type triterpenoids (2-11) were isolated from the methanol extract of Panax stipuleanatus rhizomes. Based on their spectroscopic data, these compounds were identified as spinasaponin A methyl ester (1), pesudoginsenoside RP(1) methyl ester (2), spinasaponin A 28-O-glucoside (3), pseudoginsenoside RT(1) methyl ester (4), pseudoginsenoside RT(1) (5), stipuleanoside R(2) methyl ester (6), stipuleanoside R(2) (7), araloside A methyl ester (8), 3-O-β-D-glucopyranosyl (1→3)-β-D-glucuronopyranoside-28-O-β-D-glucopyranosyl oleanolic acid methyl ester (9), 3-O-β-D-xylopyranosyl (1→2)-β-D-glucopyranosyl-28-O-β-D-glucopyranosyl oleanolic acid (10), and chikusetsusaponin IVa (11). When the cytotoxic activities of the isolated compounds were evaluated, compound 1 exhibited significant cytotoxic activity with IC(50) values of 4.44 and 0.63 μM against HL-60 (leukemia) and HCT-116 (colon cancer) cell lines, respectively. Compound 2 showed potent cytotoxicity with an IC(50) of 6.50 μM against HCT-116, whereas it was less cytotoxic against HL-60 (IC(50)=41.45 μM). After HL-60 and HCT-116 were treated with compounds 1 and 2, increased production of apoptotic bodies was observed. Furthermore, compounds 1 and 2 in HCT-116 cells activated intrinsic and extrinsic apoptosis pathways by upregulating DR-5 and Bax, downregulating Bcl-2, activating caspase-9, and cleaving poly-ADP-ribose polymerase (PARP). We also observed the activation of ERK1/2 MAPK by both compounds in the HCT-116 cells. Together, compounds 1 and 2 might induce intrinsic and extrinsic apoptosis pathways through the activation of the ERK1/2 MAPK pathway in HCT-116 colon cancer cells. Structure-activity relationship analysis indicated that a carboxyl group at position-28 is potentially responsible for the cytotoxic effects.     

Synthesis of novel ciprofloxacin analogues and evaluation of their anti-proliferative effect on human cancer cell lines

A series of twenty two novel 1-cyclopropyl-6-fluoro-4-oxo-7-(4-substituted piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid analogues have been synthesized, characterized (¹H NMR, ¹³C NMR and LCMS) and evaluated for their inhibitory activity on the proliferation of human caucasian acute lymphoblastic leukemia cells (CCRF-CEM), breast adenocarcinoma cells (MDA-MB-468) and human colon carcinoma cells (HCT-116). Among all the synthesized ciprofloxacin analogues 3t at 50 μM showed comparable potency to doxorubicin (10 μM) in all three cell lines and 3j inhibited proliferation of MDA-MB-468 up to 35% selectively over other two cell lines.     

Cytotoxic activity of proflavine diureas: synthesis, antitumor, evaluation and DNA binding properties of 1',1'-(acridin-3,6-diyl)-3',3'-dialkyldiureas

The synthesis of novel 1',1'-(acridin-3,6-diyl)-3',3'-dialkyldiureas was reported. Their biological activity to inhibit cell proliferation was assessed by a MTT assay on two cell lines, HeLa and HCT-116, at micromolar concentration. 1',1'-(Acridin-3,6-diyl)-3',3'-dihexyldiurea hydrochloride was active on a HCT-116 cell line with an IC(50) value of 3.1 microM. The interaction of these compounds with calf thymus DNA was investigated by a variety of spectroscopic techniques including UV-vis, fluorescence and CD spectroscopy. From spectrofluorimetric titrations, binding constants for the DNA-drug complexes were determined (K=0.9-4.2x10(5) M(-1)). Antiproliferative activity of synthesized derivatives might be related to their intercalation into DNA.     

Cytotoxic withanolides from Physalis angulata L

Four new withanolides, physagulins L-O (1-4), were isolated from the MeOH extract of the aerial parts of Physalis angulata L. (Solanaceae), together with seven known withanolides, compounds 5-11. Their structures were determined by spectroscopic techniques, including 1H-, 13C-NMR (DEPT), and 2D-NMR (HMBC, HMQC, 1H,1H-COSY, NOESY) experiments, as well as by HR-MS. All eleven compounds were tested for their antiproliferative activities towards human colorectal-carcinoma (HCT-116) and human non-small-cell lung-cancer (NCI-H460) cells. Compound 5 exhibited the highest anticancer activity against the HCT-116 cell line, with an IC50 value of 1.64+/-0.06 microM. Compound 9 exhibited the highest cytotoxicity towards the NCI-H460 cell line, with an IC50 value of 0.43+/-0.02 microM.     

土壤真菌Curvularia affinis HS-FG-196抗肿瘤化学成分的再研究

为对土壤真菌Curvularia affinis HS-FG-196的次级代谢产物及其体外抗肿瘤活性进行进一步研究。实验采用大孔吸附树脂HP-20树脂柱、硅胶柱、凝胶LH-20柱及半制备高效液相色谱柱从Curvularia affinis HS-FG-196的发酵培养物中分离得到六个单体化合物(1～6)。利用~1H NMR、¹³C NMR、~1H-~1H COSY、HMQC、HMBC、IR、UV和MS等波谱分析方法对其进行了结构鉴定,分别是:pyrenocine S (1)、pyrenocine B (2)、pyrenocine E (3)、pyrenocine I (4)、pyrenochaetic acid B (5)和pyrenochaetic acid C (6),其中化合物1是新化合物。对所得单体化合物进行了体外抗肿瘤活性测试,结果显示化合物1、2、3对肿瘤细胞A549、HCT-116、ACHN、K562和HepG2表现出较强的活性。     

A facile approach to anhydrogalactosucrose derivatives from chlorinated sucrose

Three new anhydrosucrose derivatives: 1,4:3,6-dianhydro-beta-D-fructofuranosyl 4-chloro-4-deoxy-alpha-D-galactopyranoside (4), 1,4:3,6-dianhydro-beta-D-fructofuranosyl 3,6-anhydro-4-chloro-4-deoxy-alpha-D-galactopyranoside (6) and 1,6-dichloro-1,6-dideoxy-beta-D-fructofuranosyl-3,6-anhydro-4-chloro-4-deoxy-alpha-D-galactopyranoside (8) were prepared from chlorinated sucrose. The structures of these anhydrides were confirmed by their (1)H and (13)C NMR spectra, ESIMS and elemental analysis. The crystal structures of 6 and the acetate of 4 (5) are presented. The relative reactivity of the chloromethyl groups towards S(N)2 reactions in 1,6-dichloro-1,6-dideoxy-beta-d-fructofuranosyl 4,6-dichloro-4,6-dideoxy-alpha-D-galactopyranoside was found to be in order 6>6'>1'.     

A precursor to the beta-pyranosides of 3-amino-3,6-dideoxy-D-mannose (mycosamine).

SN2-type reaction of 3-O-(1-imidazyl)sulfonyl-1,2:5,6-di-O-isopropylidene-alpha-D-gluco furanose with benzoate gave the 3-O-benzoyl-alpha-D-allo derivative 2, which was hydrolysed to give the 5,6-diol 3. Compound 3 was converted into the 6-deoxy-6-iodo derivative 4 which was reduced with tributylstannane, and then position 5 was protected by benzyloxymethylation, to give 3-O-benzoyl-5-O-benzyloxymethyl-6-deoxy-1,2-O-isopropylidene-alpha -D- allofuranose (6). Debenzoylation of 6 gave 7, (1-imidazyl)sulfonylation gave 8, and azide displacement gave 3-azido-5-O-benzyloxymethyl-3,6-dideoxy- 1,2-O-isopropylidene-alpha-D-glucofuranose (9, 85%). Acetolysis of 9 gave 1,2,4-tri-O-acetyl-3-azido-3,6-dideoxy-alpha,beta-D-glucopyranose (10 and 11). Selective hydrolysis of AcO-1 in the mixture of 10 and 11 with hydrazine acetate (----12), followed by conversion into the pyranosyl chloride 13, treatment with N,N-dimethylformamide dimethyl acetal in the presence of tetrabutylammonium bromide, and benzylation gave 3-azido-4-O-benzyl-3,6-dideoxy-1,2-O-(1-methoxyethylidene)-alpha-D -glucopyranose (15). Treatment of 15 with dry acetic acid gave 1,2-di-O-acetyl-3-azido-4-O-benzyl-3,6-dideoxy-beta-D-glucopyranose (16, 86% yield) that was an excellent glycosyl donor in the presence of trimethylsilyl triflate, allowing the synthesis of cyclohexyl 2-O-acetyl-3-azido-4-O-benzyl-3,6-dideoxy-beta-D-glucopyranoside (17, 90%).(ABSTRACT TRUNCATED AT 250 WORDS)     

5-alk(en)ylresorcinols as the major active components in wheat bran inhibit human colon cancer cell growth

We and others have found that wheat bran oil is the active constituent in wheat bran for colon cancer prevention. However, the active components in wheat bran oil are still unknown. Using human colon cancer cells (HCT-116 and HT-29) as the guiding assays, we further purified the active components from wheat bran using column chromatography. In this study, we identified that a fraction containing 5-n-alk(en)ylresorcinols had the strongest inhibitory effect on the proliferation of human HCT-116 and HT-29 colon cancer cells. Further purification led to the identification of 14 5-alk(en)ylresorcinols. Among them, 7, (10'Z,13'Z,16'Z)-5-(nonadeca-10',13',16'-trienyl)resorcinol, is a novel compound and 5, 6, 9, 10, and 13 were purified as individual compounds for the first time. The identification and structural elucidation of these compounds were based on 1D and 2D NMR and tandem mass spectral analyses. All these compounds (1-14) except 10 were evaluated for growth inhibition of human colon cancer cell lines (HCT-116 and HT-29). Our results indicate that increasing the length of the side chain will diminish the inhibitory activity, and the existence of a double bond and a carbonyl group will strengthen such an activity.     

Reduction of Orc6 Expression Sensitizes Human Colon Cancer Cells to 5-Fluorouracil and Cisplatin

Previous studies from our group have shown that the expression levels of Orc6 were highly elevated in colorectal cancer patient specimens and the induction of Orc6 was associated with 5-fluorouracil (5-FU) treatment. The goal of this study was to investigate the molecular and cellular impact of Orc6 in colon cancer. In this study, we use HCT116 (wt-p53) and HCT116 (null-p53) colon cancer cell lines as a model system to investigate the impact of Orc6 on cell proliferation, chemosensitivity and pathways involved with Orc6. We demonstrated that the down regulation of Orc6 sensitizes colon cancer cells to both 5-FU and cisplatin (cis-pt) treatment. Decreased Orc6 expression in HCT-116 (wt-p53) cells by RNA interference triggered cell cycle arrest at G1 phase. Prolonged inhibition of Orc6 expression resulted in multinucleated cells in HCT-116 (wt-p53) cell line. Western immunoblot analysis showed that down regulation of Orc6 induced p21 expression in HCT-116 (wt-p53) cells. The induction of p21 was mediated by increased level of phosphorylated p53 at ser-15. By contrast, there is no elevated expression of p21 in HCT-116 (null-p53) cells. Orc6 down regulation also increased the expression of DNA damaging repair protein GADD45β and reduced the expression level of JNK1. Orc6 may be a potential novel target for future anti cancer therapeutic development in colon cancer.     

Synthesis of β-D-Fructopyranosyl-(2→6)-D-glucopyranose from D-Glucose and D-Fructose by a Thermal Treatment

The synthesis is reported of β-D-fructopyranosyl-(2→6)-D-glucopyranose that had previously been isolated from a fermented plant extract as a new saccharide. A disaccharide was predominately formed from an equal amount of D-glucose and D-fructose under melting conditions at 140 °C for 60 to 90 min. This saccharide was isolated from the reaction mixture by carbon-Celite column chromatography and preparative HPLC, and was confirmed to be β-D-fructopyranosyl-(2→6)-D-glucopyranose by TOF-MS and NMR analyses.     

花叶中的新没食子酰黄酮甙和没食子丹宁

从花叶(Loropetalum chinense Oliv.)的70％Me_2CO提取物中经Toyopearl HW-40凝胶反复柱层析,得到3种没食子酰黄酮甙(LC-3,LC-13和LC-16),3种没食子丹宁(LC-20,LC-21和LC-22)和一种黄酮甙元(LC-14)。经化学和波谱分析,确定它们分别为黄芪甙-2’’-0-没食子酸酯(astragalin-2’’-0-gallate,LC-3,1)、黄芪甙-6’’-0-没食子酸酯(astragalin-6’’-0-gallate,LC-13,2)、黄芪甙-2’’,6’’-二-0-没食子酸酯(astragalin-2’’,6’’-di-0-gallate,LC-16,3)、八没食子酰葡萄糖(octagalloyl-glucose,8GG,LC-20)、六没食子酰葡萄糖(hexagalloyl-glucose,6GG,LC-21)、七没食子酰葡萄糖(heptagalloyl-glucose,7GG,LC-22)和木犀草素(luteolin,LC-14)。其中LC-16为一同时具有可水解丹宁和黄酮甙双重性质的新化合物,命名为花丁素(Loropetalin D,3)。上述成分均为首次从该植物中得到。     

Targeting Colon Cancer Cells with Pyrazino-Imidazolinone Derivatives: Synthesis,Molecular Docking,and in Vitro Evaluation of Anti-Proliferative and Pro-Apoptotic Activities

We report the synthesis, spectroscopic characterization, molecular docking and biological evaluation of nine pyrazino-imidazolinone derivatives. These derivatives were evaluated for their anticancer activity against three cancer cell lines: 518A2 melanoma, HCT-116, and HCT-116 p53 knockout mutant colon carcinoma. The MTT assay was employed to assess their effectiveness. Among the nine compounds tested, four compounds (5 a, 5 d, 5 g, and 5 h) exhibited promising antiproliferative activity specifically against HCT-116 p53-negative cells (IC₅₀ 0.23, 0.20, 2.07 and 58.75 μM, respectively). Interestingly, treatment with the 3,4-dimethoxyphenyl derivative 5a resulted in a significant increase (199 %) in caspase activity in HCT-116 p53-negative cells compared to untreated cells while the bromo-pyrazine derivative 5d demonstrated (190 %) increase. These findings suggest that compounds 5a and 5 d induce p53-independent apoptotic cell death. Additionally, in silico molecular docking studies with EGFR and tyrosinase proteins indicated that compounds 5 d and 5 e have the potential to bind to important anticancer drug targets.     

SN2 DNA-alkylating agent-induced phosphorylation of p53 and activation of p21 gene expression

p53 is an important player in the cellular response to genotoxic stress whose functions are regulated by phosphorylation of a number of serine and threonine residues. Phosphorylation of p53 influences its DNA-binding and gene regulation activities. This study examines p53 phosphorylation in HCT-116 (MMR-deficient) and HCT-116+ch3 (MMR-proficient) human colon cancer cells treated with a S(N)2 DNA-alkylating agent, methylmethane sulfonate (MMS). MMS induces phosphorylation of p53 on Ser15 and Ser392 in a dose- and time-dependent manner. MMS-induced p53 phosphorylation is independent of DNA mismatch repair (MMR) activity. Nuclear extracts from MMS-treated HCT-116 cells had higher p21WAF1/Cip1 (p21) promoter DNA-binding activity in vitro opposed to untreated cells. After MMS treatment, the activation of the cloned p21 promoter in a transient transfection assay and endogenous p21 mRNA levels in HCT-116(p53+/+) versus HCT-116(p53-/-) cells increased, which correlates with an increased levels of phospho-p53(Ser15) and phospho-p53(Ser392). These results suggest that SN2 DNA-alkylating agent-induced phosphorylation of p53 on Ser15 and Ser392 increases its DNA-binding properties to cause an increased expression of p21 that may play a role in cell cycle arrest and/or apoptosis of HCT-116 cells.     

Antitumor dinuclear platinum(II) complexes derived from a novel chiral ligand

A new chiral ligand, 2-(((1R,2R)-2-aminocyclohexyl)amino)acetic acid (HL), was designed and synthesized to prepare a series of novel dinuclear platinum(II) complexes with dicarboxylates or sulfate as bridges. The evaluation of these metal complexes in vitro cytotoxicity against human HCT-116, MCF-7 and HepG-2 cell lines were made. All compounds showed antitumor activity to HCT-116 and MCF-7. Particularly, compounds M3 and M5 not only exhibited better activity than carboplatin against MCF-7 and HepG-2, but also showed very close activity to oxaliplatin against HCT-116.     

GHRH antagonist when combined with cytotoxic agents induces S-phase arrest and additive growth inhibition of human colon cancer

Treatment of colon cancer with an antagonist of growth hormone-releasing hormone (GHRH), JMR-132, results in a cell cycle arrest in S-phase of the tumor cells. Thus, we investigated the effect of JMR-132 in combination with S-phase-specific cytotoxic agents, 5-FU, irinotecan and cisplatin on the in vitro and in vivo growth of HT-29, HCT-116 and HCT-15 human colon cancer cell lines. In vitro, every compound inhibited proliferation of HCT-116 cells in a dose-dependent manner. Treatment with JMR-132 (5 μM) combined with 5-FU (1.25 μM), irinotecan (1.25 μM) or cisplatin (1.25 μM) resulted in an additive growth inhibition of HCT-116 cells in vitro as shown by MTS assay. Cell cycle analyses revealed that treatment of HCT-116 cells with JMR-132 was accompanied by a cell cycle arrest in S-phase. Combination treatment using JMR-132 plus a cytotoxic drug led to a significant increase of the sub-G₁ fraction, suggesting apoptosis. In vivo, daily treatment with GHRH antagonist JMR-132 decreased the tumor volume by 40–55% (p < 0.001) of HT-29, HCT-116 and HCT-15 tumors xenografted into athymic nude mice. Combined treatment with JMR-132 plus chemotherapeutic agents 5-FU, irinotecan or cisplatin resulted in an additive tumor growth suppression of HT-29, HCT-116 and HCT-15 xenografts to 56–85%. Our observations indicate that JMR-132 enhances the antiproliferative effect of S-phase-specific cytotoxic drugs by causing accumulation of tumor cells in S-phase.     

Isoprenylated xanthones and flavonoids from Cudrania tricuspidata

Further phytochemical investigation on the roots of Cudrania tricuspidata afforded a new isoprenylated xanthone, cudratricusxanthone I (1), two new isoprenylated flavanones, cudraflavanones C and D (2 and 3, resp.), and seven known compounds, 1,7-dihydroxy-3,6-dimethoxyxanthone (4), macluraxanthone C (5), cudraxanthones E, K, and L (6, 7, and 8, resp.), cudraflavanone A (9), and cudraflavone C (10). Their structures were identified by spectroscopic methods. Cudratricusxanthone H (12), macluraxanthone B (13), two xanthones previously isolated from this plant, and 5, showed significant inhibitory effects on four kinds of human digestive apparatus tumor cell lines (HCT-116, SMMC-7721, SGC-7901, and BGC-823) with IC50 values of 2.70-12.66 microM.     

Porpoisamides A and B, two novel epimeric cyclic depsipeptides from a Florida Keys collection of Lyngbya sp

NMR-guided fractionation of a non-polar extract of a Florida Keys collection of Lyngbya sp. resulted in the isolation of two novel epimeric cyclic depsipeptides, porpoisamides A (1) and B (2). The planar structures of these compounds were determined using NMR spectroscopic techniques. The absolute configurations of amino and hydroxy acid subunits were assigned by enantioselective HPLC analysis. These compounds showed weak cytotoxicity towards HCT-116 colorectal carcinoma and U2OS osteosarcoma cells. The porpoisamides are a unique pair of cyclic depsipeptides that are epimeric at C-2 of the β-amino acid, 3-amino-2-methyloctanoic acid.     

Daturametelins H, I, and J: three new withanolide glycosides from Datura metel L

Three new withanolide glycosides named daturametelins H-J (1-3), together with two known ones, daturataturin A (4) and 7,27-dihydroxy-1-oxowitha-2,5,24-trienolide (5), were isolated from the MeOH extract of the aerial parts of Datura metel L. (Solanaceae). Their structures were determined mainly by spectroscopic techniques including 2D-NMR (HMBC, HMQC, (1)H,(1)H-COSY, NOESY) and MS experiments. Compounds 1-5 were tested for their antiproliferative activity towards the human colorectal carcinoma (HCT-116) cell line. The nonglycosidic compound 5 exhibited the highest activity of the tested withanolides, with an IC(50) value of 3.2+/-0.2 microM (Table 3).