Search

Supplementary Materials from Induction of Retinoid X Receptor Activity and Consequent Upregulation of p21WAF1/CIP1 by Indenoisoquinolines in MCF7 Cells

Datura innoxia Mill., Solanaceae, an underexplored ethnomedicinal plant, has been empirically evaluated in the current study for the isolation of bioactive agents. A crude extract of D. innoxia leaves was subjected to normal-phase medium pressure and vacuum liquid chromatography which led to the purification of a withanolide, isowithametelin. The chemical structure was established based on single-crystal X-ray diffraction. Isowithametelin exhibited substantial cytotoxicity against tested human cancer cell lines (breast cancer MCF-7 (ATCC® HTB-22), lung carcinoma LU-1 (human lung carcinoma established in the Department of Surgical Oncology, University of Illinois at Chicago), and prostate adenocarcinoma PC-3 (ATCC® CRL-1435)) with IC50 values of 4.3 ± 0.93, 6.9 ± 1.3, and 0.01 ± 0.001 μg/ml, respectively. It also inhibited nitric oxide production in lipopolysaccharide-activated murine macrophage RAW 264.7 cells (IC50 value of 18.5 ± 1.8 μg/ml) and demonstrated moderate protein kinase inhibition. This work suggests a possible anticancer role of isowithametelin; in vivo studies remain necessary to corroborate in vitro efficacy.

Two new helvolic acid analogues (1 and 2) and one new fumagillin derivative containing an octahydroisobenzofuran moiety (3), together with four known compounds (4-7), were isolated from an Aspergillus terreus, isolated from soil collected from Mauna Kea, the highest mountain in Hawaii. Compound 4 was recorded in SciFinder with a CAS Registry Number of 1379525-35-5, but it was not documented in the cited reference (ACS Chem. Biol. 2012, 7, 137). The structures of compounds 1-4 were elucidated by NMR spectroscopy and HRMS and ECD analysis. Compounds 5 and 6 showed significant inhibitory activity against NF-κB with IC50 values of 2.7 ± 2.6 and 6.5 ± 0.8 μM, respectively. Compounds 1 and 2 were active against S. aureus with MICs of 6.25 and 6.25 μg/mL, respectively, while compound 5 inhibited E. coli with an MIC of 3.12 μg/mL.

Solvent fractions from leaf and bark extracts of Vaccinium leschenaultii were screened for their antioxidant, cell viability, and nitric oxide (NO) inhibitory potential. Antioxidant activit...

Two new ternary platinum(II) complexes of general formula [Pt(DTC)LCl], where DTC = 4-(2-pyridyl)piperazine-1-carbodithioate (1 and 2) and L = tri(p-tolyl)phosphine (1) and tri(o-tolyl)phosphine (2), have been synthesized and characterized. Both complexes have shown phenanthriplatin and picoplatin type axial protection, albeit from both sides, offered by C H moiety of the organophosphine (X-ray single crystal and DFT analysis). Furthermore, 2 has shown greater degree of axial shielding of platinum center than 1. In vitro anticancer activity against three cancer cell lines has revealed greater anticancer potency of 2 than 1. The activity against NF-κB (a cancer promoting protein) signified that death of the cancer cells may be due to hindering the activity of NF-κB and subsequent initiation of the apoptosis. High activity of 2 than 1 can be attributed to its greater lipophilicity and stronger axial protection (C H⋯Pt = 2.752 A, H C⋯Pt 3.496 A, ∠H⋯Pt-P = 78.37° and ∠ C⋯Pt-P = 64.19°), from both sides of the axial plane, that may hinder the diversion to off target biomolecules and thus may enhance cellular uptake. Based upon DNA binding and DNA denaturing studies with CT-DNA, a cooperative binding and non-intercalative (electrostatic/covalent) mode of interaction have been suggested.

Two new helvolic acid analogues (

Background/aim There is an unmet clinical need to develop new anticancer and chemopreventive agents. The aim of the present study was to identify β-carboline derivatives with cancer chemopreventive and therapeutic potential. Materials and methods Forty-eight tetrahydro-β-carboline derivatives were synthesized and evaluated for their anticancer and chemopreventive activities, through induction of quinone reductase 1 (QR1), aromatase inhibition, as well as inhibition of nitric oxide (NO) production. Results 2-((1-Bromonaphthalen-2-yl)methyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole demonstrated the most potent activity in the QR1 induction assay with an induction ratio value of 3.2 (CD=1.3 μM). The R-isomer of the amide derivative (2-((1-bromonaphthalen-2-yl)methyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-3-yl)(4-methylpiperazin-1-yl)methanone was the most potent inhibitor of NO production with a 50% inhibitory concentration, IC50=6.54 μM and had a low cytotoxic effect (IC50=17.98 μM) on RAW 264.7 cells. Subsequent computational docking study revealed that this compound binds to the active site of inducible nitric oxide synthase with favorable interactions. Conclusion our results provided promising β-carboline leads for further optimization and development with therapeutic potential as new chemopreventive and chemotherapy agents.

Toranja 'Burarama', Citrus maxima (Burm.) Merr. (Citrus grandis), is a new citrus discovered in the State of Espirito Santo, Brazil. As several varieties of citrus are known to possess antioxidant and cancer chemopreventive properties, the aim of the study was to evaluate in vitro if this Toranja possess these properties. The antioxidant activity, the potential to induce quinone reductase 1, and the influence on cell viability were measured. ESI(-)FT-ICR MS analysis was also performed and identified flavonoids, coumarins, and fatty acids in the extract. The ethyl acetate and methanolic extracts of the peels presented the highest antioxidant activity in vitro by DPPH (IC50 = 298.3 ± 2.6 μg/ml and 303.8 ± 0.4 μg/ml), ABTS assay (IC50 = 298.2 ± 6.4 μg/ml and 296.4 ± 2.5 μg/ml), and FRAP (IC50 = 234.6 ± 1.8 μg/ml and 398.1 ± 3.8 μg/ml). The ethyl acetate extract of the peel induced quinone reductase 1 activity in Hepa1c1c7 cells, indicating that C. maxima exhibited cancer chemopreventive properties.

Terpenes are considered the main components of essential oils and an important source for the identification of novel lead molecules. This study aimed to investigate the in vitro anti-inflammatory activity of l-carveol, l-carvone, and m-cimene (monoterpenes) and of valencene and guaiene (sesquiterpenes). The influence on intracellular nitric oxide (NO) and pro- and anti-inflammatory cytokine (TNF-α, IL-1α and IL-10) production and on nuclear factor kappa B (NF-κB) activity was determined using Griess reagent, immunoenzymatic assay kits (ELISA) and chemiluminescence measurements in cell-based assays, respectively. Antioxidant activity was assayed through the protective effect against cellular oxidative damage produced by superoxide anion production (O 2 ·− ) and hydrogen peroxide on macrophages and by the quenching activity of the NO radical. Terpenes reduced the pro-inflammatory cytokines TNF-α and IL-1α and increased the production of IL-10. In addition, the terpenes, especially guaiene (53.3 ± 2.4%) and m-cymene (38.1 ± 0.6%), significantly inhibited NO production in a macrophage cell culture-based assay, whereas no effect was observed in the scavenging activity of this radical. l-carveol and m-cymene significantly inhibited O 2 ·− production with reductions of approximately 68.6 ± 2.2% and 48.2 ± 4.2%, respectively, at a concentration of 10 μM. Moreover, these terpenes were verified to suppress NF-κB activity. The results indicate that these terpenes have therapeutic potential and may be used to suppress inflammatory diseases or as a leading compounds.

In our ongoing effort of discovering anticancer and chemopreventive agents, a series of 2-arylindole derivatives were synthesized and evaluated toward aromatase and quinone reductase 1 (QR1). Biological evaluation revealed that several compounds (e.g., 2d, IC50 = 1.61 μM; 21, IC50 = 3.05 μM; and 27, IC50 = 3.34 μM) showed aromatase inhibitory activity with half maximal inhibitory concentration (IC50) values in the low micromolar concentrations. With regard to the QR1 induction activity, 11 exhibited the highest QR1 induction ratio (IR) with a low concentration to double activity (CD) value (IR = 8.34, CD = 2.75 μM), while 7 showed the most potent CD value of 1.12 μM. A dual acting compound 24 showed aromatase inhibition (IC50 = 9.00 μM) as well as QR1 induction (CD = 5.76 μM) activities. Computational docking studies using CDOCKER (Discovery Studio 3.5) provided insight in regard to the potential binding modes of 2-arylindoles within the aromatase active site. Predominantly, the 2-arylindoles preferred binding with the 2-aryl group toward a small hydrophobic pocket within the active site. The C-5 electron withdrawing group on indole was predicted to have an important role and formed a hydrogen bond with Ser478 (OH). Alternatively, meta-pyridyl analogs may orient with the pyridyl 3′-nitrogen coordinating with the heme group.

Context: Sambucus australis Cham. & Schltdl. (Adoxaceae) is used in Brazilian folk medicine to treat inflammatory disorders. Objective: To evaluate the in vitro anti-inflammatory, antioxidant and antimicrobial properties of S. australis. Materials and methods: The anti-inflammatory activity of ethanol extracts of the leaf and bark of S. australis (1–100 μg/mL) were studied in lipopolysaccharide/interferon γ stimulated murine macrophages RAW 264.7 cells (24 h incubation) by investigating the release of nitric oxide (NO) and tumour necrosis factor-alpha (TNF-α) and in the TNF-α-induced nuclear factor kappa (NF-κB) assay. Minimum inhibitory concentration (MIC) was determined by the microdilution test (24 h incubation). Antioxidant activity was determined by 2,2-diphenyl-1-picrylhydrazyl (DPPH), ferric reducing antioxidant power (FRAP) and the NO scavenging assays. Chemical composition was assessed by LC-MS/MS. Results: Antioxidant activities in the DPPH (IC50 43.5 and 66.2 μg/mL), FRAP (IC50 312.6 and 568.3 μg/mL) and NO radical scavenging assays (IC50 285.0 and 972.6 μg/mL) were observed in the leaf and bark ethanol extracts, respectively. Solely the leaf extract showed significant inhibition of NO and TNF-α production in RAW264.7 cells at concentrations of 2 and 100 μg/mL, respectively, and suppression of TNF-α inhibition of NF-κB by 12.8 and 20.4% at concentrations of 50 and 100 μg/mL, respectively. The extract also exhibited antibacterial activity against Salmonella typhimurium (MIC 250 μg/mL) and Klebsiella pneumoniae (MIC 250 μg/mL). LC-MS/MS revealed the presence of chlorogenic acid and rutin as major compounds. Discussion and conclusion: The results indicate that the ethanol leaf extract of S. australis exhibit prominent anti-inflammatory effects.

Seaweeds are related to anti-inflammatory, anti-bacterial and anti-noceptive effects. This work aimed to verify the potential of seaweed Padina gymnospora (Kützing) Sonder 1871 to improve wound healing in vitro. P. gymnospora was collected at a bethonic area in Espirito Santo. Methanolic extract of P. gymnospora was obtained by percolation. To determine cytotoxicity, colorimetric MTT tests were performed against normal fibroblasts (L929), macrophages (RAW 264.7) and human ovarian carcinoma (OVCAR-3) cell lines using concentration range of 12–110 μg ml−1. To evaluate in vitro wound healing, monolayer of fibroblasts L929 was seeded and artificial wounded. Cell proliferation was blocked by 5 μg ml−1 Mytomycin C. Nitric oxide inhibition was quantified with Raw 264.7 by Griess reaction. Minimal inhibitory concentration (MIC) against Staphylococcus aureus was determined. Eletrospray ionization with Fourier transform ion cyclotron resonance mass spectrometry (ESI-FT-ICR MS) was applied to detail composition of P. gymnospora methanolic extract. No cytotoxic effect in all cell lines was detected until the maximum concentration of 110 μg ml−1. P. gymnospora promoted significantly migration at the concentration of 25 μg ml−1 (p

Bioassay-guided fractionation of the dichloromethane extract from the apical bud of Gardenia sootepenesis Hutch. (Rubiaceae) led to the isolation of four new cycloartane triterpenes, sootepins F-I (1-4), along with four known derivatives (5-8). The structures of the new compounds were determined by 1D and 2D NMR experiments and by comparison of the physicochemical data with published values. The isolates were evaluated for cancer chemopreventive potential based on their ability to inhibit nitric oxide (NO) production and tumor necrosis factor-alpha (TNF-α)-induced nuclear factor kappa (NF-κB) activity. Compounds 6-8 inhibited TNF-α-induced NF-κB activity with half maximal inhibitory concentration (IC50) values of 8.3, 5.6, and 6.0μM, respectively; compounds 7 and 8 showed significant NO-inhibitory activity with IC50 values of 3.2 and 2.0μM, respectively.

Mangifera indica L., mango fruit, is consumed as a dietary supplement with purported health benefits; it is widely used in the food industry. Herein, the chemical profile of the Ubá mango at four distinct maturation stages was evaluated during the process of growth and maturity using negative-ion mode electrospray ionisation Fourier transform ion cyclotron resonance mass spectrometry (ESI(-)FT-ICR MS) and physicochemical characterisation analysis (total titratable acidity (TA), total soluble solids (TSS), TSS/TA ratio, and total polyphenolic content). Primary (organic acids and sugars) and secondary metabolites (polyphenolic compounds) were mostly identified in the third maturation stage, thus indicating the best stage for harvesting and consuming the fruit. In addition, the potential cancer chemoprevention of the secondary metabolites (phenolic extracts obtained from mango samples) was evaluated using the induction of quinone reductase activity, concluding that fruit polyphenols have the potential for cancer chemoprevention.

Two new heteroleptic palladium(II) complexes have been synthesized by reacting equimolar quantities of palladium(II) chloride, sodium 4-(2-methoxyphenyl)piperazine-1-carbodithioate and diphenyl-p-tolylphosphine (1) or tri-p-tolylphosphine (2). Complexes 1 and 2 have been characterized using elemental analysis, Fourier transform infrared spectroscopy, multinuclear NMR (1H, 13C and 31P) spectroscopy and single-crystal X-ray analysis. The latter technique confirms a pseudo square-planar geometry in which two adjacent positions are occupied by bidentate dithiocarbamate while chloro and substituted triphenylphosphine are present at the remaining two positions. The anticancer activity of both complexes against five different cancer cell lines (LU – human lung carcinoma, established at UIC, Department of Surgical Oncology; MCF7 – human breast adenocarcinoma, ATCC number HTB-22™; MDA-MB-231 – human breast adenocarcinoma, ATCC number HTB-26™; Hepa-1c1c7 – mouse liver hepatoma, ATCC number CRL-2026™; PC-3 – human prostate adenocarcinoma, ATCC number CRL-1435™) was determined by MTT assay, revealing 2 has higher activity than 1. A drug–calf thymus DNA binding study with UV–visible spectroscopy reveals a higher DNA binding affinity of 2 (3.511 × 104 M−1) than 1 (4.213 × 103 M−1). Density functional theory studies confirm the relatively more stable nature of 2 than 1. Copyright © 2016 John Wiley & Sons, Ltd.

Heteroleptic platinum(II) dithiocarbamates, of general formula [Pt(DTC)LCl], where DTC = 4-(4-methoxyphenyl)piperazine-1-carbodithioate (1 and 2) and 4-(furan-2-carbonyl)piperazine-1-carbodithioate (3) and L = tri(4-flourophenylphosphine) (1 and 3) and tri(4-chlorophenylphosphine) (2) have been synthesized and characterized by different analytical techniques. These complexes are square planar with picoplatin or phenanthriplatin type steric hindrance from aromatic C–H groups of the phosphine ligand as shown by single-crystal analysis. In 1, the Pt square plane is hindered by two axially oriented hydrogens, whereas by only one in 2 and 3. DNA-binding studies by UV/visible spectroscopy revealed a stronger electrostatic interaction of 1 compared to 2 and 3, and the results are further supported by viscometry and cyclic voltammetric measurements. Their in vitro anticancer activity against five different cancer cell lines using a MTT assay revealed high potency of the complexes. The higher activity of 1 than both 2 and 3 is consistent with DNA binding strength and we speculate that it may be due to the relatively inert nature of platinum towards off-target biomolecules ensured by the hindrance caused by the two axially oriented hydrogens.

This study was undertaken to investigate the in vitro wound healing effects and the anti-inflammatory and antioxidant activities of terpinolene and α-phellandrene. The in vitro stimulatory effects on the proliferation and migration of fibroblasts were assessed using the scratch assay. The anti-inflammatory activity was evaluated using cell-based assays by investigating their influence on nitric oxide (NO), superoxide anion (O2•-), tumour necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6) production and using the TNF-α-induced nuclear factor kappa (NF-κB) assay. Antioxidant activity was determined by the ABTS cation radical scavenging capacity, ferric reducing/antioxidant potential (FRAP), and NO free radical scavenging assays. Terpinolene and α-phellandrene significantly increased the migration and proliferation of fibroblasts and suppressed the pro-inflammatory cytokines IL-6 and TNF-α in a dose-dependent manner. Terpinolene and α-phellandrene at a concentration of 100 μM significantly inhibited NO production (41.3 and 63.8%, respectively) in a macrophage cell-culture-based assay, and resulted in reductions in O2•- production of 82.1 ± 3.5% and 70.6 ± 4.3%, respectively. Moreover, these monoterpenes were verified to suppress NF-κB activity. In summary, terpinolene and α-phellandrene may contribute to broadening clinical options in the treatment of wounds by attenuating inflammation and oxidative stress in vitro.

Jucara fruit (Euterpe edulis) has received attention due to its similarities to Euterpe oleracea (Acai). The aim of this study was to evaluate the cytotoxicity, bioactive compounds, antioxidant capacities and chemopreventive activities of the fruit pulps of six populations of E. edulis (J1-J6) and one population of E. espiritosantense from different ecological regions. ESI(-)-FT-ICR-MS was used to evaluate the pulp composition. The varieties J1 and J4 presented higher polyphenol contents, while J2 and J5 showed higher anthocyanin contents. ESI-FT-ICR MS identified cyanidin-3-rutinoside (J1, J2, J3, J4, J5, J7), protocatechuic acid, methylhydroxybenzoate hexoside and rutin (J1 to J7) and malvidin-glicoside (J2 to J5). The J2, J3, J4, J5 and J6 samples inhibited inducible nitric oxide synthase (iNOS). The chemoprevention biomarker quinone reductase was significantly induced by J6. Pulp from plants J3, J4, J6 and J7 significantly reduced the inflammatory cytokine TNF-α, and J6 was selected as having the most potential for cultivation and consumption.

Toranja 'Burarama', Citrus maxima (Burm.) Merr. (Citrus grandis), is a new citrus discovered in the State of Espírito Santo, Brazil. As several varieties of citrus are known to possess antioxidant and cancer chemopreventive properties, the aim of the study was to evaluate in vitro if this Toranja possess these properties. The antioxidant activity, the potential to induce quinone reductase 1, and the influence on cell viability were measured. ESI(-)FT-ICR MS analysis was also performed and identified flavonoids, coumarins, and fatty acids in the extract. The ethyl acetate and methanolic extracts of the peels presented the highest antioxidant activity in vitro by DPPH (IC

Chiral peptides and iso-peptides were synthesized in excellent yield by using benzotriazole mediated solution phase synthesis. Benzotriazole acted both as activating and leaving group, eliminating frequent use of protection and subsequent deprotection. The procedure was based on the hypothesis that epimerization should be suppressed in solution due to a faster coupling rate than SPPS. All the synthesized peptides complied with Lipinski's Ro5 except for the rotatable bonds. Inhibition of cell proliferation of cancer cell lines is one of the most commonly used methods to study the effectiveness of any anticancer agents. Synthesized peptides and iso-peptides were tested against three cancer cell lines (MCF-7, MDA-MB 231) to determine their anti-proliferative potential. NFkB was also determined. Molecular docking studies were also carried out to complement the experimental results.

(E)-4-(3,5-dimethoxystyryl)phenyl acetate (Cmpd1) is a resveratrol analog that preferentially inhibits glioma, breast, and pancreatic cancer cell growth, with IC50 values of 6-19 μM. Notably, the human U251MG glioblastoma tumor line is the most sensitive, with an IC50 of 6.7 μM, compared with normal fibroblasts, which have an IC5020 μM. Treatment of U251MG cells that harbor aberrantly active signal transducer and activator of transcription (Stat) 3 with Cmpd1 suppresses Stat3 tyrosine705 phosphorylation in a dose-dependent manner in parallel with the induction of pserine727 Stat3 and extracellular signal-regulated kinase/mitogen-activated protein kinase 1/2 (pErk1/2(MAPK)). Inhibition of pErk1/2(MAPK) induction by the mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor PD98059 [2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one] blocked both the pserine727 Stat3 induction and ptyrosine705 Stat3 suppression by Cmpd1, indicating dependency on the mitogen-activated protein/extracellular signal-regulated kinase kinase-Erk1/2(MAPK) pathway for Cmpd1-induced modulation of Stat3 signaling. Cmpd1 also blocked epidermal growth factor-stimulated pStat1 induction, whereas upregulating pSrc, pAkt, p-p38, pHeat shock protein 27, and pmammalian target of rapamycin levels. However, pJanus kinase 2 and pEpidermal growth factor receptor levels were not significantly altered. Treatment of U251MG cells with Cmpd1 reduced in vitro colony formation, induced cell cycle arrest in the G2/M phase and cleavage of caspases 3, 8, and 9 and poly(ADP ribose) polymerase, and suppressed survivin, myeloid cell leukemia 1, Bcl-xL, cyclin D1, and cyclin B1 expression. Taken together, these data identify a novel mechanism for the inhibition of Stat3 signaling by a resveratrol analog and suggest that the preferential growth inhibitory effects of Cmp1 occur in part by Erk1/2(MAPK)-dependent modulation of constitutively active Stat3.

LC-UV/MS-based metabolomic analysis of the Hawaiian endophytic fungus Paraphaeosphaeria neglecta FT462 led to the identification of four unique mercaptolactated γ-pyranol-γ-lactams, paraphaeosphaerides E-H (1-4) together with one γ-lactone (5) and the methyl ester of compound 2 (11). The structures of the new compounds (1-5 and 11) were elucidated through the analysis of HRMS and NMR spectroscopic data. The absolute configuration was determined by chemical reactions with sodium borohydride, hydrogen peroxide, α-methoxy-α-(trifluoromethyl)phenylacetyl chlorides (Mosher reagents), and DP4 + NMR calculations. All the compounds were tested against STAT3, A2780 and A2780cisR cancer cell lines, E. coli JW2496, and NF-κB. Compounds 1 and 3 strongly inhibited NF-κB with IC50 values of 7.1 and 1.5 μM, respectively. Fil: Li, Chun Shun. University of Hawai'i at Hilo; Estados Unidos Fil: Sarotti, Ariel Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentina Fil: Huang, Peng. University of Hawai'i at Hilo; Estados Unidos. Anhui University of Chinese Medicine; China Fil: Dang, Uyen T.. Texas A&M University; Estados Unidos Fil: Hurdle, Julian G.. Texas A&M University; Estados Unidos Fil: Kondratyuk, Tamara P.. University of Hawai'i at Hilo; Estados Unidos Fil: Pezzuto, J. M.. University of Hawai'i at Hilo; Estados Unidos. Arnold & Marie Schwartz College of Pharmacy and Health Sciences; Estados Unidos Fil: Turkson, James Turkson. University of Hawai'i; Estados Unidos Fil: Cao, Shugeng. University of Hawai'i at Hilo; Estados Unidos

Two new compounds heliotropiumides A (1) and B (2), phenolamides each with an uncommon carbamoyl putrescine moiety, were isolated from the seeds of a naturalized Hawaiian higher plant, Heliotropium foertherianum Diane & Hilger in the borage family, which is widely used for the treatment of ciguatera fish poisoning. The structures of compounds 1 and 2 were characterized based on MS spectroscopic and NMR analysis, and DP4+ calculations. The absolute configuration (AC) of compound 1 was determined by comparison of its optical rotation with those reported in literature. Compound 2 showed inhibition against NF-κB with an IC50 value of 36 μM. Fil: Cai, You-Sheng. University of Hawaii at Hilo; Estados Unidos. Wuhan University; China Fil: Sarotti, Ariel Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentina Fil: Gündisch, Daniela. University of Hawaii at Hilo; Estados Unidos Fil: Kondratyuk, Tamara P.. University of Hawaii at Hilo; Estados Unidos Fil: Pezzuto, John. Long Island University; Estados Unidos. University of Hawaii Cancer Center; Estados Unidos Fil: Turkson, James. University of Hawaii Cancer Center; Estados Unidos Fil: Cao, Shugeng. University of Hawaii at Hilo; Estados Unidos

New compounds 18-nor-3,17-dihydroxyspongia-3,13(16),14-trien-2-one (1), 18-nor-3,5,17-trihydroxyspongia-3,13(16),14-trien-2-one (2), and spongiapyridine (3) and the known compound 17-hydroxy-4-epi-spongialactone A (4) were isolated from an Indonesian sponge of the genus Spongia. The structures of 1-3 were deduced by analyses of physical and spectroscopic data. Diterpene 3 is unusual, as the D-ring is a pyridyl ring system rather than the standard δ-lactone. The structure elucidation of this compound was complicated by facile exchange of the axial proton at the C-11 methylene with deuterium from methanol-d4. The isolated compounds were tested for biological activity in a battery of in vitro assays (TNF-α-induced NFκB, LPS-induced iNOS, RXR stimulation, quinone reductase 1 induction, aromatase inhibition, TRPM7 ion channels, and aspartic protease BACE1 inhibition). Norditerpene 2 modestly inhibited aromatase with an IC50 of 34 μM and induced quinone reductase 1 activity with a CD (the concentration needed to double the enzymatic response) of 11.2 μM. The remaining isolates were inactive.

Hedychium coronarium J. Koenig, Zingiberaceae, is a medicinal plant popularly used to treat inflammatory conditions in different countries. Three labdane diterpenes [isocoronarin D (1), methoxycoronarin D (2), ethoxycoronarin D (3)] and benzoyl eugenol (4) were isolated from rhizomes and their chemopreventive potential was evaluated using in vitro assays, namely the inhibition of NF-κB, COX-1 and -2, the induction of antioxidant response element (ARE), and the inhibition of cell proliferation. Diterpene 1 activated ARE (EC50 57.6 ± 2.4 μM), while 2, 3 and 4 significantly inhibited NF-κB (IC50 of 7.3 ± 0.3, 3.2 ± 0.3 and 32.5 ± 4.9 μM, respectively). In addition, 2 and 3 selectively inhibited COX-1 (IC50 values of 0.9 ± 0.0 and 3.8 ± 0.0 μM, respectively). These data support the potential chemopreventive activity of constituents from H. coronarium rhizomes. Keywords: Hedychium coronarium, Zingiberaceae, COX-1 and -2, NF-κB, Labdane diterpenes

Although resveratrol can modulate multiple stages of carcinogenesis, by most common standards it is not a good drug candidate. Resveratrol lacks potency, high efficacy, and target specificity; it is rapidly metabolized and serum concentrations are low. Using resveratrol as a scaffold, we produced over 100 derivatives, some of which have target specificity in the nanomolar range. Aromatase inhibition was enhanced over 6000-fold by using 1,3-thiazole as the central ring of resveratrol. Optimizing the substitution pattern of the two phenyl rings and the central heterocyclic linker led to selective QR1 induction with a CD value of 87 nM. Several derivatives have been selected for evaluation of synergistic effects. Preliminary results with pairs of compounds are promising and further experiments, in a constant multidrug manner, will allow us to create polygonograms for larger combinations of derivatives. The objective is to develop a highly efficacious cocktail of derivatives based on the structure of resveratrol.

As with human beings, dogs suffer from the consequences of cancer. We investigated the potential of a formulation comprised of resveratrol, ellagic acid, genistein, curcumin and quercetin to modulate biomarkers indicative of disease prevention. Dog biscuits were evaluated for palatability and ability to deliver the chemopreventive agents. The extent of endogenous DNA damage in peripheral blood lymphocytes from dogs given the dietary supplement or placebo showed no change. However, H2O2-inducible DNA damage was significantly decreased after consumption of the supplement. The expression of 11 of 84 genes related to oxidative stress was altered. Hematological parameters remained in the reference range. The concept of chemoprevention for the explicit benefit of the canine is compelling since dogs are an important part of our culture. Our results establish a proof-of-principle and provide a framework for improving the health and well-being of “man’s best friend”.

A new fatty acid ester disaccharide, 2-O-(β-d-glucopyranosyl)-1-O-(2E,4Z,7Z)-deca-2,4,7-trienoyl-β-d-glucopyranose (1), a new ascorbic acid derivative, 2-caffeoyl-3-ketohexulofuranosonic acid γ-lactone (2), and a new iridoid glycoside, 10-dimethoxyfermiloside (3), were isolated along with 13 known compounds (4–16) from fermented noni fruit juice (Morinda citrifolia). The structures of the new compounds, together with 4 and 5, were determined by 1D and 2D NMR experiments, as well as comparison with published values. Compounds 2 and 7 showed moderate inhibitory activities in a TNF-α-induced NF-κB assay, and compounds 4 and 6 exhibited considerable quinone reductase-1 (QR1) inducing effects.

Endophytic fungi, being a prolific source of bioactive secondary metabolites, are of great interest for natural product discovery.Isolation and partial characterization of endophytic fungi inhabiting the leaves and woody parts of Taxus fuana Nan LiR.R. Mill. (Taxaceae) and evaluation of biological activity.Endophytic fungal isolates were identified by molecular analysis of internal transcribed spacer (ITS) regions of 18S rDNA. Extracts of the endophytic fungi cultured on potato dextrose agar and modified medium were evaluated using cancer chemoprevention bioassays [inhibition of TNF-α-induced NFκB, aromatase and inducible nitric oxide synthase (iNOS); induction of quinone reductase 1 (QR1)] and growth inhibition with MCF-7 cells.Nine of 15 fungal isolates were identified as belonging to Epicoccum, Mucor, Penicillium, Chaetomium, Paraconiothriym, Plectania or Trichoderma. Five of the 15 extracts inhibited NFκB activity (ICThe endophytic fungi studied are capable of producing pharmacologically active natural compounds. In particular, isolates derived from the wood of Taxus fuana should be prioritized for the isolation and characterization of bioactive constituents.

Three new withanolides, physaperuvin G (1), with physaperuvins I (2), and J (3), along with seven known derivatives (4-10), were isolated from the aerial parts of Physalis peruviana. The structures of 1-3 were determined by NMR, X-ray diffraction, and mass spectrometry. Compounds 1-10 were evaluated in lipopolysaccharide (LPS)-activated murine macrophage RAW 264.7 cells. Compounds 4, 5, and 10 with potent nitric oxide inhibitory activity in LPS-activated RAW 264.7 cells, with IC50 values in the range of 0.32-7.8μM. In addition, all compounds were evaluated for potential to inhibit tumor necrosis factor-alpha (TNF-α)-activated nuclear factor-kappa B (NF-κB) activity with transfected human embryonic kidney cells 293. Compounds 4-7 inhibited TNF-α-induced NF-κB activity with IC50 values in the range of 0.04-5.6μM.

NAD(P)H:quinone reductase 1 (QR1) belongs to a class of enzymes called cytoprotective enzymes. It exhibits its cancer protective activity mainly by inhibiting the formation of intracellular semiquinone radicals, and by generating α-tocopherolhydroquinone, which acts as a free radical scavenger. It is therefore believed that QR1 inducers can act as cancer chemopreventive agents. Resveratrol (1) is a naturally occurring stilbene derivative that requires a concentration of 21 μM to double QR1 activity (CD = 21 μM). The stilbene double bond of resveratrol was replaced with a thiadiazole ring and the phenols were eliminated to provide a more potent and selective derivative 2 (CD = 2.1 μM). Optimizing the substitution pattern of the two phenyl rings and the central heterocyclic linker led to a highly potent and selective QR1 inducer 9o with a CD value of 0.087 μM.

Natural products are a very productive source of leads for the development of medicines. Six Pakistani plants were chosen for study based on ethnobotanical data.Exploration of important medicinal plants of Pakistan for cancer treatment.The crude extracts of the six plants and their fractions were tested for inhibition of nuclear factor κB (NFκB), aromatase, and nitric oxide (NO) production in lipopolysaccharide (LPS)-activated murine macrophage RAW 264.7 cells, induction of quinone reductase 1 (QR1), agonism of retinoid X receptor, and growth inhibition with MCF-7, LU-1 and MDA-MB-231 cancer cells.Two samples of Withania coagulans (Stocks) Dunal (Solanaceae) demonstrated inhibition of TNF-α induced activity of NFκB with IC₅₀ values of 2.6 and 4.3 µg/mL, respectively. Two fractions from W. coagulans and Euphorbia wallichii Hook F. (Euphorbiaceae) aerial parts inhibited aromatase with IC₅₀ values of 17.0 and 17.7 µg/mL, respectively. A total of 13 samples (five from E. wallichii, one from Acer oblongifolium Hort. ex Dippel (Aceraceae), one from Aster thomsonii C. B. Clarke (Asteraceae) and six from W. coagulans aerial parts with fruits) inhibited NO production with IC₅₀ values ranging from 1.3 to 15.6 µg/mL. Fourteen samples demonstrated induction of QR1 with CD ranging from 1.0 to 20.6 µg/mL, and a total of eight extracts and fractions inhibited the proliferation of cancer cells in culture with IC₅₀ values ranging from 1.2 to 7.8 µg/mL.Selected plants can be a valuable source of chemopreventive and anticancer products. W. coagulans aerial parts showed the strongest activity.

Several lactone- and lactam-based neoflavonoids and tetrahydroquinolones were synthesized and evaluated for cancer chemopreventive studies using cell and molecular target-based in vitro bioassays, namely NFκB, aromatase, and quinone reductase 1. These analogs blocked TNF-α-induced NFκB activation in a dose-dependent manner with IC₅₀ values in the range of 0.11-3.2 μM. In addition, compound 8 inhibited aromatase activity with an IC₅₀ value of 12.12 μM, and compound 10 affected quinone reductase 1 induction (IR, 3.6; CD, 19.57 μM). Neoflavonoids 8 and 10 exhibiting good results can further be optimized for improved therapeutic profiles. However, investigations into the actions of neoflavonoids and tetrahydroquinolones, especially those related to the NFκB signaling pathway, aromatase inhibition, induction of quinone reductase 1 expression, and in vivo studies could provide new insights into the cancer chemopreventive ability of these molecules.

Three new kaempferol glycosides, named palmatosides A (1), B (2) and C (3), together with three known kaempferol glycosides, multiflorins A (4) and B (5), and afzelin (6), were isolated from the roots of the fern Neocheiropteris palmatopedata. Palmatosides A (1) and B (2) were determined to be novel kaempferol glycosides, each possessing an unusual sugar moiety containing a 4, 4-dimethyl-3-oxo-butoxy substituent group. The isolated compounds were evaluated for their cancer chemopreventive potential based on their ability to inhibit tumor necrosis factor alpha (TNF-α)-induced NF-κB activity, nitric oxide (NO) production, aromatase, quinone reductase 2 (QR-2) and COX-1/-2 activities. Palmatosides B (2) and C (3) inhibited TNF-α-induced NF-κB activity with IC50 values of 15.7 and 24.1 μM, respectively; multiflorin A (4) inhibited aromatase enzyme with an IC50 value of 15.5 μM; afzelin (6) showed 68.3% inhibition against QR2 at a concentration of 11.5 μg/ml; palmatoside A (1) showed 52 % inhibition against COX-1 enzyme at a concentration of 10 μg/ml; and multiflorin B (5) showed 52 % inhibition against nitric oxide production at a concentration of 20 μg/ml. In addition, compounds 3-6 were shown to bind QR2 enzyme using LC-MS ultrafiltration binding assay.

The western Himalayas in the northern areas of Pakistan have significant potential for ethnomedicinal research. In the current study, indigenous informants were interviewed using open-ended questionnaires and a free-listing of knowledge related to native medicinal plants. Information patterns indicated that over 100 local plant species were in frequent medicinal use for a variety of conditions, including inflammation and cancer. Several field surveys were conducted in community forests and meadows, with the aim of exploration, collection, taxonomic identification, and finally, in vitro analysis. Organic extracts of eight species were tested for inhibition of nuclear factor-kappaB (NF-κB), activation of retinoic acid X receptor alpha (RXR), induction of quinone reductase (QR), and inhibition of aromatase, along with assessment of cytotoxicity with four human cancer cell lines. Mellia azedarach, Ajuga bractiosa, Figonia cretica and Swertia chirata inhibited both tetradecanoylphorbol-13-acetate (TPA) and tum...

Two new sulfated sesterterpene alkaloids, 19-oxofasciospongine A (3) and fasciospongine C (4), and a new sesterterpene sulfate, 25-hydroxyhalisulfate 9 (5), along with two known sesterterpene sulfates, halisulfates 7 (6) and 9 (7), were isolated from an organic extract of the marine sponge Fasciospongia sp. The structures of the new compounds were established on the basis of one- and two-dimensional NMR spectroscopic studies as well as by HRESIMS analysis. Compounds 1-7 exhibited inhibitory activity against Streptomyces 85E in the hyphae-formation inhibition assay. Compounds 1, 2, and 4-7 were not cytotoxic when tested at 20 microg/mL with MCF-7, LNCaP, and LU cell lines. Only compound 3 demonstrated a moderate cytotoxic effect on the MCF-7 (IC(50) 13.4 microM), LNCaP (IC(50) 21.8 microM), and LU-1 cells (IC(50) 5.0 microM), respectively.

Three new cyclohexadepsipeptides, arenamides A-C (1-3), were isolated from the fermentation broth of a marine bacterial strain identified as Salinispora arenicola. The planar structures of these compounds were assigned by detailed interpretation of NMR and MS/MS spectroscopic data. The absolute configurations of the amino acids, and those of the chiral centers on the side chain, were established by application of the Marfey and modified Mosher methods. The effect of arenamides A and B on NFkappaB activity was studied with stably transfected 293/NFkappaB-Luc human embryonic kidney cells induced by treatment with tumor necrosis factor (TNF). Arenamides A (1) and B (2) blocked TNF-induced activation in a dose- and time-dependent manner with IC(50) values of 3.7 and 1.7 microM, respectively. In addition, the compounds inhibited nitric oxide (NO) and prostaglandin E(2) (PGE(2)) production with lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. Moderate cytotoxicity was observed with the human colon carcinoma cell line HCT-116, but no cytotoxic effect was noted with cultured RAW cells. Taken together, these data suggest that the chemoprevention and anti-inflammatory characteristics of arenamides A and B warrant further investigation.

A new plant species, Barringtonia maunwongyathiae. W. Chuakul (Lecythidaceae), was recently discovered in Khuan Thon Forest, Ao Luek District, Krabi Province, Thailand. Chemical investigation of th...

The synthesis of new imidazo[2,1-b]thiazoles bearing phenolic groups is reported. These compounds and some previously described analogs were evaluated as antioxidant agents with three chemical model systems, and cancer chemopreventive potential was examined by inhibition of NO production, TNF-a activated NFkB activity, and aromatase activity, as well as induction of QR1 and RXRE binding. Two of the test compounds, 9 and 12, displayed promising activity by inhibiting iNOS, NFkB and aromatase in dose edependent manner, with IC50 values in low micromolar range. The same compounds activated QR1 in a bifunctional manner. When incubated with human liver microsomes, the active compounds were further hydroxylated on the parent ring system, suggesting the next logical step in the development of these promising leads will entail synthetic production of metabolites followed by additional assessment of biological activity.

Chemical investigation of an endophytic fungus Chaetomium globosum isolated from leaves of Wikstroemia uva-ursi led to the isolation of two new azaphilones, chaetoviridins J and K (1 and 3), along with five known derivatives (2 and 4-7). The structures of azaphilones were determined by NMR, X-ray diffraction, Mosher's method, and CD analysis. The isolated compounds were evaluated for their cancer chemopreventive-potential based on their abilities to inhibit tumor necrosis factor alpha (TNF-α)-induced nuclear factor-kappa B (NF-κB). Compounds 4, 5, 7, and synthetic 8 and 9 inhibit nitric oxide (NO) production with IC50 values in the range of 0.3-5.8 μM. Compounds 4, 5, and 9 also displayed (TNF-α)-induced NF-κB activity with IC50 values in the range of 0.9-5.1 μM.

For a compound to be a best chemopreventive agent it should be a descent DNA binder and at the same time should be active against any of the three stages of carcinogenesis i.e. cancer initiation, cancer propagation and tumor growth. Most of the problems associated with chemotherapy can be overcome if the chemopreventive agent is active against all the three stages of cancer development. Cancer may be initiated by higher concentration of free radicals, inflammating agents and phase I enzymes (Cytochrome P450) in the body. Cancer propagation can be very efficiently controlled by inducing the phase II enzymes (glutathione S-transferases (GSTs), UDP-glucuronosyl transferases, and quinone reductases) in the body and cancer termination depends on the killing of the faulty cells i.e. cytotoxic actions. This article reports comprehensively the comparative DNA binding studies (with, cyclic voltammetry, UV–vis spectroscopy and viscometry), antioxidant activities (DPPH scavenging), anti-inflammatory activities (nitrite inhibition), phase I enzyme inhibition activities (aromatase inhibition), phase II enzyme induction studies (quinone reductase induction) and cytotoxic studies against neuroblastoma (MYCN2 and SK-N-SH), liver cancer (Hepa 1c1c7) and breast cancer (MCF-7) of seventeen ferrocene incorporated selenoureas.

A new cyclic 4-hydroxy-dithiosulfonate, bruguiesulfurol (1), as well as two known 4-hydroxydithiolane 1-oxides, brugierol (2) and isobrugierol (3) were isolated from the flowers of Bruguiera gymnorrhiza. With stably-transfected HepG2 cells, the three isolates activated antioxidant response element (ARE) luciferase activation with (EC(50)) values of 56.7, 3.7 and 1.8 microM, respectively. Compounds 2 and 3 also inhibited phorbol ester-induced NF-kappaB (nuclear factor-kappaB) luciferase activity with IC (50) values of 85.0 and 14.5 microM, respectively. In addition, compound 2 inhibited enzyme cyclooxygenase-2 (COX-2) activity with an IC(50) value of 6.1 microM. The structures of these isolates were determined by spectral data, and that of compound 1 was confirmed by X-ray crystallographic analysis.

Objectives: We studied the expression of cytokines and inflammatory cells in normal and inflamed esophageal mucosa of children with the aim of furthering our understanding of the pathophysiology of allergic eosinophilic esophagitis (AEE). Methods: Controls and AEE patients (≥15 eosinophils/highpower field on esophageal mucosal biopsies) between the ages of 1 and 18 years were recruited. Esophageal biopsies were obtained for histologic examination, immunohistochemical studies, and cytokine analysis. Results: Eight controls (4 males; mean age 9.99 years) and 11 AEE patients (8 males; mean age 7.15 years) were studied. mRNA expression ofinterferon (IFN)-γ, interleukin (IL)-4, IL-5. IL-13, eotaxin-1, eotaxin-2, eotaxin-3, and RANTES was studied. IFN-γ and IL-5 expressions were significantly up-regulated in AEE patients compared with controls. Expressions of IL-4 and IL-13 were similar between AEE patients and controls. Eotaxin-1 expression was significantly up-regulated in AEE patients, whereas eotaxin-2 was up-regulated in controls. Expression of RANTES and eotaxin-3 was similar between the two groups. There was increased staining for mast cells in AEE patients compared with controls. Conclusions: Our data suggests that AEE is primarily an IL-5 selective TH2 response, with a possible TH1 component, and a differential role of eosinophilic chemoattractants. The role of mast cells in the pathogenesis of AEE needs additional study.

Polyphenols are widely distributed in the plant kingdom and represent an abundant antioxidant component of the human diet. The review offers a brief description of the chemistry and occurrence in plant food of four important groups of polyphenols: phenolic acids, flavonoids, stilbenes, and lignans. Interest in the possible health benefits of polyphenols has increased due to corresponding antioxidant capacity. Considerable evidence is now available showing anticarcinogenic effects of polyphenolic compounds, as well as potential to prevent cardiovascular and cerebrovascular diseases. The use of botanicals has received a large amount of attention in recent years. Epidemiological studies have shown that a reduced risk of cancer is associated with diets rich in vegetables and fruits, and methods for the discovery and characterization of active compounds from plant sources are available. These results are promising, but additional research on the molecular mechanism of action of polyphenols and their application to human health is required.

Four new undecose nucleosides (herbicidin congeners), three known herbicidins, and 9-(β-d-arabinofuranosyl)hypoxanthine (Ara-H) were isolated from the organic extract of a fermentation culture of Streptomyces sp. L-9-10 using proton NMR-guided fractionation. Their structures were elucidated on the basis of comprehensive 1D and 2D NMR and mass spectrometry analyses. These structures included 2′-O-demethylherbicidin F (1), 9′-deoxy-8′,8′-dihydroxyherbicidin B (2), 9′-deoxy-8′-oxoherbicidin B (2a), and the 8′-epimer of herbicidin B (3). This is the first detailed assignment of proton and carbon chemical shifts for herbicidins A, B, and F. The isolated compounds were evaluated for cancer chemopreventive potential based on inhibition of tumor necrosis factor alpha (TNF-α)-induced nuclear factor-kappa B (NF-κB) activity.