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Novel Compounds (novel + compound)
Selected AbstractsTriptowilfolide, a Novel Compound from Tripterygium wilfordii.CHEMINFORM, Issue 52 2003Duqiang Luo No abstract is available for this article. [source] Genetic determinants for activated fluoropyrimidine chemotherapyDRUG DEVELOPMENT RESEARCH, Issue 2 2006William H. GmeinerArticle first published online: 5 JUN 200 Abstract Fluoropyrimidines (FPs) remain widely used for the treatment of diverse malignancies more than four decades following the initial report of 5-fluorouracil (5FU), the archetypal FP, as a novel compound with potential anti-neoplastic activity. Subsequent decades of research have enriched our understanding of the biochemical mechanisms that are important for FP activation as well as the genetic determinants that are predictive of the likely success, or failure, of FP chemotherapy for a particular individual. The concept that chemotherapy should be customized to complement the genetic profiles of cancer patients has become increasingly important as genotyping of tumor samples has become possible and as the number of available anticancer drugs has increased. Significant progress has been made in identifying the gene expression profiles for cancer patients who are likely to benefit from treatment with FPs. In this review, we will summarize the results of retrospective clinical studies correlating response to FP chemotherapy with the expression of specific genes, such as TS and DPD. We will also present a summary of FPs in current clinical use, including orally bioavailable FPs such as capecitabine, as well as FPs that are in pre-clinical development, such as FdUMP[10]. Refinement of a target population through pharmacogenetic analysis and development of novel FPs that evoke very high response rates in this target population will likely result in the use of FP regimens in the coming era when cancer becomes a largely manageable disease. Drug Dev. Res. 67:119,129, 2006. © 2006 Wiley-Liss, Inc. [source] Acetogenins from the Leaves of Rollinia laurifoliaHELVETICA CHIMICA ACTA, Issue 12 2005Lucia From the EtOH extract of the leaves of Rollinia laurifolia Schl. (Annonaceae), a novel acetogenin, rolifolin (=,3-(9-{(2R*,5S*)-5-[(1S*,4S*)-1,4-dihydroxy-4-{(2S*,5R*)-5-[(1S*)-1-hydroxyundecyl]tetrahydrofuran-2-yl}butyl]tetrahydrofuran-2-yl}-2,3-dihydroxynonyl)-5-methylfuran-2(5H)-one; 1) was isolated, together with the known acetogenin annonin-I (2). Also, from the corresponding hexane extract, a mixture of rolilaurin (3, a novel compound), uvariamicin-I (4), and uvariamicin-II (5) was obtained. The structures of compounds 1,5 were elucidated by NMR and MS analysis, and relative configurations were established. Compounds 2 and 5 have never been obtained before from Rollinia. [source] IRC-083864, a novel bis quinone inhibitor of CDC25 phosphatases active against human cancer cellsINTERNATIONAL JOURNAL OF CANCER, Issue 6 2009Marie-Christine Brezak Abstract CDC25 phosphatases are key actors in cyclin-dependent kinases activation whose role is essential at various stages of the cell cycle. CDC25 expression is upregulated in a number of human cancers. CDC25 phosphatases are therefore thought to represent promising novel targets in cancer therapy. Here, we report the identification and the characterization of IRC-083864, an original bis-quinone moiety that is a potent and selective inhibitor of CDC25 phosphatases in the low nanomolar range. IRC-083864 inhibits cell proliferation of a number of cell lines, regardless of their resistance to other drugs. It irreversibly inhibits cell proliferation and cell cycle progression and prevents entry into mitosis. In addition, it inhibits the growth of HCT-116 tumor spheroids with induction of p21 and apoptosis. Finally, IRC-083864 reduced tumor growth in mice with established human prostatic and pancreatic tumor xenografts. This study describes a novel compound, which merits further study as a potential anticancer agent. © 2008 Wiley-Liss, Inc. [source] Synthesis and evaluation of tritium labelled 10-methylgalanthamine iodide: a novel compound to examine the mechanism of interaction of galanthamine derivatives with the nicotinic acetylcholine receptorsJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 12 2003Andreas Schildan Abstract A new promising galanthamine derivative, 10-[3H]methylgalanthamine iodide, was synthesized for binding studies to nicotinic acetylcholine receptors expressed in Torpedo electric ray electroplaques. Galanthamine was reacted with [3H]methyl iodide to yield 10-[3H]methylgalanthamine iodide with a radiochemical yield of >70% and a specific activity of 32 Ci/mmol after purification via solid phase extraction. To test the ligand properties of the radioligand, calcium imaging and electrophysiology of the non-radioactive analogue were performed to obtain an EC50 of 270 nM, a Hill coefficient of 1.9 and the induced cell current. Copyright © 2003 John Wiley & Sons, Ltd. [source] ,-Monoisostearyl glyceryl ether enhances percutaneous penetration of indometacin in-vivoJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 12 2002Atsushi Suzuki ABSTRACT Molecules that reversibly remove the barrier resistance of skin enhance penetration. ,-Monoisostearyl glyceryl ether (GE-IS) is a novel compound that can be used as a non-ionic surfactant and increases percutaneous penetration of indometacin in rat abdominal skin in-vitro. The present study investigated GE-IS-induced enhancement of indometacin penetration in-vivo. When 1% GE-IS in propylene glycol was applied to rat abdominal skin, serum and muscle concentrations of indometacin increased markedly. Anti-inflammatory activities of test solutions containing both indometacin and GE-IS were investigated in experimental models of acute and chronic inflammation. Application of indometacin with GE-IS to the skin produced greater inhibitory effects on carrageenan-induced rat paw oedema, UV-induced erythema in guinea-pigs, and adjuvant arthritis in rats, compared with application of indometacin alone. The results suggest that GE-IS enhances penetration in-vivo and improves the anti-inflammatory effects of indometacin in animal models. Thus, GE-IS might contribute to the development of cosmetic or medical formulations to improve transfer of bioactive substances to hypodermal sites. [source] Vibrational spectral studies and the non-linear optical properties of a novel NLO material L -prolinium tartrateJOURNAL OF RAMAN SPECTROSCOPY, Issue 12 2006L. Padmaja Abstract Vibrational spectral analysis of the novel non-linear optical (NLO) material, L -prolinium tartrate (LPT) was carried out using NIR-FT-Raman and FT-IR spectroscopy. The density functional theoretical (DFT) computations have been performed at B3LYP/6,31G (d) level to derive equilibrium geometry, vibrational wavenumbers, intensities and first hyperpolarizability. The reasonable NLO efficiency, predicted for the first time in this novel compound, has been confirmed by Kurtz,Perry powder second-harmonic generation (SHG) experiments. The charge-transfer interaction between the pyrrolidine ring and the carbonyl group of the tartrate anion through the intramolecular ionic hydrogen bonds is confirmed by the simultaneous activation of ring modes in IR and Raman spectra. The splitting of the ring-breathing mode, pseudo-rotational ring puckering modes and the NH2 modes of the pyrrolidine ring lead to the conclusion that the pyrrolidine ring adopts a conformation intermediate between the envelope (bent) form and the half-chair (twisted) form, resulting in the lowering of symmetry from C2 to Cs. The lowering of the methylenic stretching wavenumbers and the enhancement of the stretching intensities suggest the existence of the electronic effects of back-donation in LPT. The positional disorder of the pyrrolidine ring, the presence of blue-shifting H-bonds as well as other non-bonded interactions in LPT, low frequency H-bond vibrations and the role of intramolecular charge transfer and the hydrogen bonds in making the molecule NLO active have been analysed on the basis of the vibrational spectral features. Copyright © 2006 John Wiley & Sons, Ltd. [source] The tribological properties of (quinazolin-4-ones)-3-methyl-dibutyl borate as a novel additive in liquid paraffinLUBRICATION SCIENCE, Issue 6-7 2010Ping Ouyang Abstract An organic compound containing N, B and O was synthesised by reacting 3-hydroxymethyl-quinazolin-4-ones and formalin in 1, 4-dioxane solution, the resulting product then being reacted with butanol and boric acid in dimethylbenzene solution. The tribological performance of the novel compound when added to liquid paraffin was evaluated using a four-ball tester and a ring-on-block machine. The relationship between performance and concentration was analysed, and the results showed that the compound possesses good anti-wear, friction-reducing and load-carrying properties. The mechanism of action of the additive was investigated using X-ray photoelectron spectroscopy. Surface analysis indicated the formation of a protective film containing borate, Fe3O4, and an organonitrogen compound. This protective film formed during sliding processes contributes to the increase in wear resistance. Copyright © 2010 John Wiley & Sons, Ltd. [source] Complete assignment of the 1H and 13C NMR spectra of four 2-substituted 4a,8a- cis-endo -5,8-methano-4a,5,8,8a-tetrahydronaphthalene-1,4-dionesMAGNETIC RESONANCE IN CHEMISTRY, Issue 1 2003Ivan P. de Arruda Campos Abstract The complete assignment of the 1H and 13C NMR spectra of the title enediones, bearing as substituents N -aziridinyl (a novel compound), methoxy, chloro and methylsulfanyl, is reported. Copyright © 2002 John Wiley & Sons, Ltd. [source] Apoptosis of BGC823 cell line induced by p -hydroxymethoxybenzobijuglone, a novel compound from Juglans mandshuricaPHYTOTHERAPY RESEARCH, Issue 4 2009ZhiBo Li Abstract p -Hydroxymethoxybenzobijuglone (HMBBJ), a new quinone compound isolated from Juglans mandshurica (by bioassay-guided fractionation), showed cytotoxic activity in the gastric carcinoma cell line BGC823. The growth of BGC823 cells was inhibited as demonstrated by MTT assay and several cellular characteristic changes, such as cell shrinkage, chromatin condensation and apoptotic body formation with programmed cell death. Flow cytometry analysis revealed that the BGC823 cell cycle was arrested at G2/M phase by HMBBJ, and the apoptotic rate of BGC823 cells increased with respect to HMBBJ in a dose-dependent manner. HMBBJ also activated caspase-3, decreased the expression of Bcl-2 and caused a decrease in the mitochondrial membrane potential (,,m). These findings suggest that HMBBJ could significantly induce apoptosis in BGC823 cells and should be considered as a potential candidate for a chemotherapeutic drug against cancer. Copyright © 2008 John Wiley & Sons, Ltd. [source] Expression of a celery mannose 6-phosphate reductase in Arabidopsis thaliana enhances salt tolerance and induces biosynthesis of both mannitol and a glucosyl-mannitol dimerPLANT CELL & ENVIRONMENT, Issue 2 2003G. ZHIFANG ABSTRACT Mannitol, a sugar alcohol that may serve as a compatible solute to cope with salt stress, is synthesized via the action of a mannose-6-phosphate reductase (M6PR) in celery (Apium graveolens L). In contrast to previous approaches that have used a bacterial gene to engineer mannitol biosynthesis in plants and other organisms, Arabidopsis thaliana, a non-mannitol producer, was transformed with the celery leaf M6PR gene under control of the CaMV 35S promotor. In all independent Arabidopsis M6PR transformants, mannitol accumulated throughout the plants in amounts ranging from 0·5 to 6 µmol g,1 fresh weight. A novel compound, not found in either celery or Arabidopsis, 1-O- , - d -glucopyranosyl- d -mannitol, also accumulated in vegetative tissues of mature plants in amounts up to 4 µmol g,1 fresh weight, but not in flowers and seeds. In the absence of NaCl, all transformants were phenotypically the same as the wild type; however, in the presence of NaCl, mature transgenic plants showed a high level of salt tolerance, i.e. growing, completing normal development, flowering, and producing seeds in soil irrigated with 300 mm NaCl in the nutrient solution. These results demonstrate a major role in developing salt-tolerant plants by means of introducing mannitol biosynthesis using M6PR. [source] Trigonal structures of ABe2BO3F2 (A = Rb, Cs, Tl) crystalsACTA CRYSTALLOGRAPHICA SECTION B, Issue 4 2009Colin D. McMillen Several interesting fluoroberyllium borates were synthesized hydrothermally and characterized by single-crystal X-ray diffraction. The crystal structures of RbBe2BO3F2 (RBBF; rubidium fluoroberyllium borate) and CsBe2BO3F2 (CBBF; caesium fluoroberyllium borate), previously determined in the space group C2, were reinvestigated for higher symmetry and found to have more suitable solutions in the space group R32. TlBe2BO3F2 (TBBF; thallium fluoroberyllium borate) was synthesized as a novel compound also having this trigonal structure type. Details of the space-group determination and unique structural features are discussed. These crystal structures were compared with that of KBe2BO3F2, revealing interesting structural trends within this family of compounds that are also discussed. A crystallographic explanation of the physical morphology is postulated. [source] A synchrotron radiation study of the one-dimensional complex of sodium with (1S)- N -carboxylato-1-(9-deazaadenin-9-yl)-1,4-dideoxy-1,4-imino- d -ribitol, a member of the 'immucillin' familyACTA CRYSTALLOGRAPHICA SECTION C, Issue 3 2010Graeme J. Gainsford The sodium salt of [immucillin-A,CO2H], (Imm-A), namely catena -poly[[[triaquadisodium(I)](,-aqua)[,-(1S)- N -carboxylato-1-(9-deazaadenin-9-yl)-1,4-dideoxy-1,4-imino- d -ribitol][triaquadisodium(I)][,-(1S)- N -carboxylato-1-(9-deazaadenin-9-yl)-1,4-dideoxy-1,4-imino- d -ribitol]] tetrahydrate], {[Na2(C12H13N4O6)2(H2O)7]·4H2O}n, (I), forms a polymeric chain via Na+,O interactions involving the carboxylate and keto O atoms of two independent Imm-A molecules. Extensive N,O,H...O hydrogen bonding utilizing all water H atoms, including four waters of crystallization, provides crystal packing. The structural definition of this novel compound was made possible through the use of synchrotron radiation utilizing a minute fragment (volume ,2.4 × 10,5,mm,3) on a beamline optimized for protein data collection. A summary of intra-ring conformations for immucillin structures indicates considerable flexibility while retaining similar intra-ring orientations. [source] Disordered structure of ZrW1.8V0.2O7.9 from a combined X-ray and neutron powder diffraction study at 530 KACTA CRYSTALLOGRAPHICA SECTION C, Issue 10 2009Xi Chen A novel compound, vanadium aliovalent substituted zirconium tungstate, ZrW1.8V0.2O7.9, was prepared with vanadium substituting tungsten rather than the common zirconium substitution. The structure of the high-temperature phase was refined from combined neutron and X-ray powder diffraction data gathered at 530,K. This phase is the disordered centric modification (space group Pa) and the average crystal structure is similar to that of ,-ZrW2O8. The V atom occupies only a W2 site and charge compensation is achieved through oxygen vacancy, i.e. the oxygen vacancy occurs at only the O4 site. [Atom names follow the established scheme; Evans et al. (1996). Chem. Mater.8, 2809,2823.] [source] Dispiro[fluorene-9,5,-[1,2,3,4]tetrathiane-6,,9,,-fluorene]ACTA CRYSTALLOGRAPHICA SECTION C, Issue 6 2001Anthony Linden The tetrathiane ring of the title compound, C26H16S4, has a chair conformation and the molecule has approximate C2 symmetry. Each of the two fluorene ring systems is virtually planar, with the ring planes intersecting at an angle of 67.58,(5)°. This novel compound has been formed as a side product from the treatment of 9H -fluorene-9-thione with methyl N -[(benzylidene)phenyl]glycinate in the presence of LiBr and 1,6-diazabicyclo[5.4.0]undecane. [source] NV-128, a novel isoflavone derivative, induces caspase-independent cell death through the Akt/mammalian target of rapamycin pathwayCANCER, Issue 14 2009Ayesha B. Alvero MD Abstract BACKGROUND: Resistance to apoptosis is 1 of the key events that confer chemoresistance and is mediated by the overexpression of antiapoptotic proteins, which inhibit caspase activation. The objective of this study was to evaluate whether the activation of an alternative, caspase-independent cell death pathway could promote death in chemoresistant ovarian cancer cells. The authors report the characterization of NV-128 as an inducer of cell death through a caspase-independent pathway. METHODS: Primary cultures of epithelial ovarian cancer (EOC) cells were treated with increasing concentration of NV-128, and the concentration that caused 50% growth inhibition (GI50) was determined using a proprietary assay. Apoptotic proteins were characterized by Western blot analyses, assays that measured caspase activity, immunohistochemistry, and flow cytometry. Protein-protein interactions were determined using immunoprecipitation. In vivo activity was measured in a xenograft mice model. RESULTS: NV-128 was able to induce significant cell death in both paclitaxel-resistant and carboplatin-resistant EOC cells with a GI50 between 1 ,g/mL and 5 ,g/mL. Cell death was characterized by chromatin condensation but was caspase-independent. The activated pathway involved the down-regulation of phosphorylated AKT, phosphorylated mammalian target of rapamycin (mTOR), and phosphorylated ribosomal p70 S6 kinase, and the mitochondrial translocation of beclin-1 followed by nuclear translocation of endonuclease G. CONCLUSIONS: The authors characterized a novel compound, NV-128, which inhibits mTOR and promotes caspase-independent cell death. The current results indicated that inhibition of mTOR may represent a relevant pathway for the induction of cell death in cells resistant to the classic caspase-dependent apoptosis. These findings demonstrate the possibility of using therapeutic drugs, such as NV-128, which may have beneficial effects in patients with chemoresistant ovarian cancer. Cancer 2009. © 2009 American Cancer Society. [source] The novel ruthenium,, -linolenic complex [Ru2(aGLA)4Cl] inhibits C6 rat glioma cell proliferation and induces changes in mitochondrial membrane potential, increased reactive oxygen species generation and apoptosis in vitroCELL BIOCHEMISTRY AND FUNCTION, Issue 1 2010Geise Ribeiro Abstract The present study reports the synthesis of a novel compound with the formula [Ru2(aGLA)4Cl] according to elemental analyses data, referred to as Ru2GLA. The electronic spectra of Ru2GLA is typical of a mixed valent diruthenium(II,III) carboxylate. Ru2GLA was synthesized with the aim of combining and possibly improving the anti-tumour properties of the two active components ruthenium and , -linolenic acid (GLA). The properties of Ru2GLA were tested in C6 rat glioma cells by analysing cell number, viability, lipid droplet formation, apoptosis, cell cycle distribution, mitochondrial membrane potential and reactive oxygen species. Ru2GLA inhibited cell proliferation in a time and concentration dependent manner. Nile Red staining suggested that Ru2GLA enters the cells and ICP-AES elemental analysis found an increase in ruthenium from <0.02 to 425,mg/Kg in treated cells. The sub-G1 apoptotic cell population was increased by Ru2GLA (22,±,5.2%) when analysed by FACS and this was confirmed by Hoechst staining of nuclei. Mitochondrial membrane potential was decreased in the presence of Ru2GLA (44,±,2.3%). In contrast, the cells which maintained a high mitochondrial membrane potential had an increase (18,±,1.5%) in reactive oxygen species generation. Both decreased mitochondrial membrane potential and increased reactive oxygen species generation may be involved in triggering apoptosis in Ru2GLA exposed cells. The EC50 for Ru2GLA decreased with increasing time of exposure from 285,µM at 24,h, 211,µM at 48,h to 81,µM at 72,h. In conclusion, Ru2GLA is a novel drug with antiproliferative properties in C6 glioma cells and is a potential candidate for novel therapies in gliomas. Copyright © 2009 John Wiley & Sons, Ltd. [source] 2132: Celastrol regulates innate immunity response via NF-kB and HSP70 in ARPE-19 cellsACTA OPHTHALMOLOGICA, Issue 2010T PAIMELA Purpose Chronic inflammation participates in the pathology of age-related macular degeneration (AMD). Recent studies indicate that celastrol, a novel triterpene compound, modulates inflammatory responses, but its effect on the human retinal pigment epithelial cells is poorly understood. In this study, we investigated the potential anti-inflammatory role of celastrol and its effect on nuclear factor kappa B (NF-kB) activity in human retinal pigment epithelial cells (ARPE-19). Methods ARPE-19 cells were exposed to lipopolysaccharide (LPS; TLR 4 agonist) with simultaneous exposure to various concentrations of celastrol and the secretion of IL-6 cytokine was analyzed by ELISA. The effect of celastrol exposure on heat shock protein 70 (HSP70) expression was analyzed by western blotting. In response to celastrol and modulated HSP70 levels NF-kB activity was examined by ELISA. Results Celastrol suppressed the LPS-induced IL-6 expression levels via NF-kB transcription factor in ARPE-19 cells. Celastrol evoked elevated HSP70 levels without cytotoxicity. Interestingly, celastrols capability to inhibit NF-kB activity was diminished when HSP70 response was suppressed by siRNA. This reveals that celastrol has potent anti-inflammatory capacity in ARPE-19 cells, and its effect is modulated through NF-kB and HSP70. Conclusion Our findings reveal that celastrol is a novel compound to suppress innate immunity response in human retinal pigment epithelial cells. [source] THE NOVEL SELECTIVE TOLL-LIKE RECEPTOR 4 SIGNAL TRANSDUCTION INHIBITOR TAK-242 PREVENTS ENDOTOXAEMIA IN CONSCIOUS GUINEA-PIGSCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 5-6 2009Masamune Kuno SUMMARY 1TAK-242 is a novel compound that suppresses nitric oxide and cytokine production by selectively inhibiting intracellular signals from toll-like receptor (TLR)-4. In the present study, we investigated the effectiveness of TAK-242 against sepsis using an endotoxaemia model in conscious and unrestricted guinea-pigs. Measures examined included muscle tension paralysis of the intestine, blood pressure, high morbidity group box (HMGB)-1 levels and survival rate. 2Tension of the longitudinal muscle of the colon was monitored continuously by telemetry. Arterial blood pressure was monitored via a carotid artery catheter. TAK-242 was administered intravenously through a jugular vein catheter. Guinea-pigs were divided into a control group, given vehicle (placebo emulsion), and the experimental group, administered 3 or 10 mg/kg TAK-242, 1 h before administration of 10 mg/kg lipopolysaccharide (LPS). 3In the control group, the tension of the longitudinal muscle of the colon decreased in a time-dependent manner and blood pressure was reduced, with maximal effects observed 1,3 h after administration of LPS. In the TAK-242-treated group, LPS-induced relaxation of the intestine and hypotension were significantly inhibited. In the control group, HMGB-1 levels were increased after LPS administration and this reaction was significantly blocked in the TAK-242-treated group. Importantly, survival rate was increased after TAK-242 treatment. 4In conlusion, the results of the present study show that TAK-242 inhibited the symptoms associated with endotoxaemia in a guinea-pig model of sepsis and that it may, therefore, be an effective treatment for sepsis. [source] Synthesis and Characterisation of Novel Complexes Containing Group 15 Elements and Their Potential Use as Molecular Precursors for the Formation of Transition Metal PnictidesEUROPEAN JOURNAL OF INORGANIC CHEMISTRY, Issue 1 2005Manfred Scheer Abstract The reaction of [{W(CO)5}2PCl] with K[Co(CO)4] yields the novel compounds [{W(CO)4Co2(CO)6}{µ3 -PW(CO)5}2] (3) and [{(CO)4WCo3(CO)6}{µ3 -PW(CO)5}3] (4) along with known derivatives [Co2(CO)6{,,,2 -PW(CO)5}2] (1) and [Co3(CO)9{,3 -PW(CO)5}] (2). The complex [{W2(CO)8(,-CO)}{,,,2:,1:,1 -PW(CO)5}2)] (5) was synthesised by treating Na2[W2(CO)10] with PBr3. Reaction of K[Mn(CO)5] with SbCl3 affords [Sb{Mn(CO)5}3] (6) in high yields. The spectroscopic and structural characterisation of the novel products is discussed, as well as the thermolytic behaviour of 2, 3 and 6 for the potential formation of novel phases of transition metal pnictides. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005) [source] Stereostructural Determination by a Synthetic and NMR-Based Approach of Three Oxazinins Isolated from Adriatic MusselsEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 32 2007Patrizia Ciminiello Abstract Two oxazinins, namely oxazinin-5 and -6, along with a related linear precursor (preoxazinin-7) were isolated from toxic mussels collected along the Northern Adriatic coasts in October 2005. Determination of the planar structure of these novel compounds was achieved through extensive NMR spectroscopic analysis, whereas a synthetic approach was crucial for their absolute stereochemical elucidation.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007) [source] Synthesis of Highly Functionalized Anthraquinones and Evaluation of Their Antitumor Activity,EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 27 2007Lutz F. Tietze Abstract Highly functionalized anthraquinones which derive from the natural products mensacarcin, islandicin, and chrysophanol have been efficiently synthesized using a Diels,Alder reaction as key step. The introduction of the proposed pharmacophoric side chain unit has been achieved by an addition of an aryllithium species onto different aldehydes. Furthermore, the antitumor activity of these novel compounds has been studied by the in vitro growth inhibition of human lung carcinoma cells of line A549.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007) [source] Two Novel 14-Nor-13,14-secopodocarpanes from the Bark of Taiwania cryptomeriodesHELVETICA CHIMICA ACTA, Issue 2 2004Shih-Chang Chien The two novel compounds cryptomelactones A (3) and B (4) were isolated from the bark of Taiwania cryptomeriodes, besides the two known podocarpane derivatives 1,,13,14-trihydroxypodocarpa-8,11,13-trien-7-one (1) and 3,,13,14-trihydroxypodocarpa-8,11,13-trien-7-one (2), and were characterized by spectroscopic means including 2D-NMR techniques. Compounds 3 and 4 are novel-14-nor-13,14-seco-podocarpanes. The absolute configurations of 3 and 4 were determined by the modified Mosher method. The biotransformation mechanism of 3 and 4 is proposed. [source] Synthesis and Biological Evaluation of 14-Alkoxymorphinans.HELVETICA CHIMICA ACTA, Issue 7 2003Part 1 The 14- O -benzylnaltrexones 3,6 were prepared from naltrexone (2) in several steps. The novel compounds were biologically evaluated in radioligand binding and in [35S]GTP,S functional assays in comparison to the reference compound naltrexone. In the binding assay, compounds 3,6 exhibited preference for , opioid receptors, while the parent compound naltrexone shows preference for , receptors. In the functional assay, , antagonist potency of compounds 3,6 was in the range of naltrexone, while , antagonist potency was considerably higher for most novel compounds in comparison to naltrexone. [source] Substituted 1,3,2,4-benzodithiadiazines: Novel derivatives, by-products, and intermediates,HETEROATOM CHEMISTRY, Issue 7 2001Alexander Yu. The synthesis of the title compounds 1 by 1:1 condensation of ArNSNSiMe3 2 with SCl2 followed by intramolecular ortho-cyclization of each [ArNSNSCl] intermediate is complicated by further reaction of 1 with SCl2 to give Herz salts 3. With the 2:SCl2 ratio of 2:1, the formation of by-products 3 is reduced and novel compounds 1 are accessible. With ortho-I containing starting material 2j, the parent compound 1s is obtained as the result of an unexpected I, not H, substitution. The rate of the 1 + SCl2 reaction depends upon a substituent's position, and the minor 8-R isomers 1l,p (R = Br, I) are isolated for the first time from mixtures with the major 6-R isomers due to reduced reactivity toward SCl2. The synthesized compounds 1,3 are characterized by multinuclear (including nitrogen) NMR and X-ray crystallography. According to the X-ray diffraction data, 1j (6-Br) and 1k (7-Br) derivatives are planar, whereas 1i (5-Br) and 1l (8-Br) are bent along the S1···N4 line by ,5° and ,4°, respectively, and the 1r (7-OCH3) derivative is planar in contrast to the known 5-OCH3 isomer, which possesses a significantly folded heterocycle. The distortion of the planar geometry of some compounds 1 is interpreted in terms of a pseudo-Jahn-Teller effect as the result of ,-highest occupied molecular orbital (HOMO) ,*-(LUMO) lowest unoccupied molecular orbital + 1 mixing in a planar conformation. The 2p compound is the first structurally defined Ar,N = S = N,SiMe3 azathiene. The compound Ar,N = S = N,S,NH-Ar 6 modeling the aforementioned intermediate has been isolated and structurally characterized. We describe the attempts to synthesize compounds 1 from 2-aminobenzenethiols and (SN)4 and from salts 3 and Me3SiN3, and we discuss the reaction pathways. © 2001 John Wiley & Sons, Inc. Heteroatom Chem 12:563,576, 2001 [source] How valuable are animal models in defining antidepressant activity?HUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 1 2001M Bourin Abstract Animal models of depression have been utilised to screen novel compounds with antidepressant potential although uncertainty lingers concerning their clinical relevance. In order for a model to be considered of any value, it must possess predictive validity (does drug action in the model correspond to that in the clinic?), face validity (are there phenomenological similarities between the model and the clinic?) and construct validity (does the model possess a strong theoretical rationale?). On the one hand, there are models based on stress such as the learned helplessness model, the forced swimming test and the chronic mild stress model and, on the other hand, models based on neuronal deficits such as the olfactory bulbectomy model. To date, among models more frequently used in depression, none of them meet all these criteria. Moreover, improvements to tests are often poorly validated and estimating time of onset of action of antidepressants remains a major challenge in animal model research. Finally, reproducing the tests outside the laboratory of origin continues to be problematic and leads to variability in results. Although animal models of depression fail to be unequivocally valid, they represent the best tool to define potential antidepressant activity of drugs, to investigate their mechanism of action and, to a greater extent, explore this complex heterogeneous illness. Copyright © 2001 John Wiley & Sons, Ltd. [source] Novel Inhibitors of Alkaline Phosphatase Suppress Vascular Smooth Muscle Cell Calcification,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 11 2007Sonoko Narisawa Abstract We report three novel inhibitors of the physiological pyrophosphatase activity of alkaline phosphatase and show that these compounds are capable of reducing calcification in two models of vascular calcification (i.e., they suppress in vitro calcification by cultured Enpp1,/, VSMCs and they inhibit the increased pyrophosphatase activity in a rat aortic model). Introduction: Genetic ablation of tissue-nonspecific alkaline phosphatase (TNALP) leads to accumulation of the calcification inhibitor inorganic pyrophosphate (PPi). TNALP deficiency ameliorates the hypermineralization phenotype in Enpp1,/, and ank/ank mice, two models of osteoarthritis and soft tissue calcification. We surmised that the pharmacological inhibition of TNALP pyrophosphatase activity could be used to prevent/suppress vascular calcification. Materials and Methods: Comprehensive chemical libraries were screened to identify novel drug-like compounds that could inhibit TNALP pyrophosphatase function at physiological pH. We used these novel compounds to block calcification by cultured vascular smooth muscle cells (VSMCs) and to inhibit the upregulated pyrophosphatase activity in a rat aortic calcification model. Results: Using VSMC cultures, we determined that Enpp1,/, and ank/ank VSMCs express higher TNALP levels and enhanced in vitro calcification compared with wildtype cells. By high-throughput screening, three novel compounds, 5361418, 5923412, and 5804079, were identified that inhibit TNALP pyrophosphatase function through an uncompetitive mechanism, with high affinity and specificity when measured at both pH 9.8 and 7.5. These compounds were shown to reduce the calcification by Enpp1,/, VSMCs. Furthermore, using an ex vivo rat whole aorta PPi hydrolysis assay, we showed that pyrophosphatase activity was inhibited by all three lead compounds, with compound 5804079 being the most potent at pH 7.5. Conclusions: We conclude that TNALP is a druggable target for the treatment and/or prevention of ectopic calcification. The lead compounds identified in this study will serve as scaffolds for medicinal chemistry efforts to develop drugs for the treatment of soft tissue calcification. [source] 1,3-Dipolar cycloaddition reaction: Synthesis of novel 5,6-dehydronorcantharidin derivatives of substituted aromatic amines with potential antitumor activitiesJOURNAL OF HETEROCYCLIC CHEMISTRY, Issue 1 2005Li-Ping Deng Twelve novel compounds were synthesized by the [3+2] 1,3-dipolar cycloaddition reaction of 5,6-dehydronorcantharidin derivatives of substituted aromatic amines with nitrile oxides. The structure and the configuration of all compounds were confirmed by 1H NMR, IR, MS, 1H- 1HCOSY, and NOESY spectral data. Their anti-tumor activities are under way. [source] Insect nicotinic acetylcholine receptor agonists as flea adulticides in small animalsJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 4 2010D. T. VO Vo, D. T., Hsu, W. H., Abu-Basha, E. A., Martin, R. J. Insect nicotinic acetylcholine receptor agonists as flea adulticides in small animals. J. vet. Pharmacol. Therap. doi: 10.1111/j.1365-2885.2010.01160.x. Fleas are significant ectoparasites of small animals. They can be a severe irritant to animals and serve as a vector for a number of infectious diseases. In this article, we discuss the pharmacological characteristics of four insect nicotinic acetylcholine receptor (nAChR) agonists used as flea adulticides in dogs and cats, which include three neonicotinoids (imidacloprid, nitenpyram, and dinotefuran) and a macrocyclic lactone (spinosad). Insect nAChR agonists are one of the most important classes of insecticides, which are used to control sucking insects on both plants and animals. These novel compounds provide a new approach for practitioners to safely and effectively eliminate adult fleas. [source] Characterization of two Pseudomonas putida lipopeptide biosurfactants, putisolvin I and II, which inhibit biofilm formation and break down existing biofilmsMOLECULAR MICROBIOLOGY, Issue 1 2004Irene Kuiper Summary Pseudomonas putida strain PCL1445 was isolated from roots of plants, grown on a site polluted with polycyclic aromatic hydrocarbons. PCL1445 produces biosurfactant activity at the end of the exponential growth phase. High-performance liquid chromatography (HPLC) analysis of supernatant extracts of PCL1445 showed two peaks with surface-tension reducing activity, tentatively assigned as biosurfactants putisolvin I and putisolvin II and was followed by structural analyses. A transposon mutant of PCL1445, strain PCL1436, which lacks the two surface-active peaks appeared to be mutated in an open reading frame (ORF) with amino acid homology to various lipopeptide synthetases. Structural analyses of the two biosurfactants of PCL1445 revealed that both are novel cyclic lipodepsipeptides with a hexanoic lipid chain connected to the N-terminus of a 12-amino-acid peptide moiety, in which the C-terminal carboxylic acid group forms an ester with the hydroxyl side-chain of Ser9. The difference between the two structures is located in the second amino acid from the C-terminus, being valine for putisolvin I, and leucine/isoleucine for putisolvin II. We show that these novel compounds lower the surface tension and influence the biofilm development on polyvinyl chloride (PVC). Biofilm formation of the bio-synthetic mutant PCL1436 was strongly increased containing more cells, which formed aggregates earlier as compared with wild-type PCL1445 biofilms. Using purified putisolvin I and II it was shown that biofilm formation of different Pseudomonas strains was inhibited and most interestingly, that both putisolvins are also able to break down existing Pseudomonas biofilms. [source] | |||||||||||||||||||||||||||||||