- Phosphate-modified analogues of m7GTP and m7Gppppm7G - Synthesis and biochemical properties
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The synthesis and biochemical properties of 17 new mRNA cap analogues are reported. Six of these nucleotides are m7GTP derivatives, whereas 11 are 'two headed' tetraphosphate dinucleotides based on a m7Gppppm7G structure. The compounds contain either a boranophosphate or phosphorothioate moiety in the nucleoside neighbouring position(s) and some of them possess an additional methylene group between β and γ phosphorus atoms. The compounds were prepared by divalent metal chloride-mediated coupling of an appropriate m7GMP analogue with a given P1,P2-di(1-imidazolyl) derivative. The analogues were evaluated as tools for studying cap-dependent processes in a number of biochemical assays, including determination of affinity to eukaryotic initiation factor eIF4E, susceptibility to enzymatic hydrolysis, and translational efficiency in vitro. The results indicate that modification in the phosphate chain can increase binding to cap-interacting proteins and provides higher resistance to degradation. Furthermore, modified derivatives of m7GTP were found to be potent inhibitors of cap-dependent translation in cell free systems.
- Ziemniak, Marcin,Kowalska, Joanna,Lukaszewicz, Maciej,Zuberek, Joanna,Wnek, Katarzyna,Darzynkiewicz, Edward,Jemielity, Jacek
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- Synthesis of 5'-deoxy-5'-thioguanosine-5'-monophosphorothioate and its incorporation into RNA 5'-termini.
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[figure: see text] 5'-Deoxy-5'-thioguanosine-5'-monophosphorothioate (GSMP) was synthesized in four steps with 35% overall yield. GSMP serves as a good substrate for in vitro transcription with T7 RNA polymerase to yield 5'-GSMP-RNA, which was converted to 5'-HS-RNA by dephosphorylation with alkaline phosphatase. The thiol-reactive agents can be efficiently introduced into the 5'-terminus of RNA.
- Zhang,Cui,Sun
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- Release of bioactive volatiles from supramolecular hydrogels: Influence of reversible acylhydrazone formation on gel stability and volatile compound evaporation
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In the presence of alkali metal cations, guanosine-5′-hydrazide (1) forms stable supramolecular hydrogels by selective self-assembly into a G-quartet structure. Besides being physically trapped inside the gel structure, biologically active aldehydes or ketones can also reversibly react with the free hydrazide functions at the periphery of the G-quartet to form acylhydrazones. This particularity makes the hydrogels interesting as delivery systems for the slow release of bioactive carbonyl derivatives. Hydrogels formed from 1 were found to be significantly more stable than those obtained from guanosine. Both physical inclusion of bioactive volatiles and reversible hydrazone formation could be demonstrated by indirect methods. Gel stabilities were measured by oscillating disk rheology measurements, which showed that thermodynamic equilibration of the gel is slow and requires several cooling and heating cycles. Furthermore, combining the rheology data with dynamic headspace analysis of fragrance evaporation suggested that reversible hydrazone formation of some carbonyl compounds influences the release of volatiles, whereas the absolute stability of the gel seemed to have no influence on the evaporation rates.
- Buchsnee Levrand, Barbara,Fieber, Wolfgang,Vigouroux-Elie, Florence,Sreenivasachary, Nampally,Lehn, Jean-Marie,Herrmann, Andreas
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- Design, synthesis and evaluation of N6-substituted 2-aminoadenosine-5′-N-methylcarboxamides as A3 adenosine receptor agonists
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A series of N6-substituted 2-aminoadenosine-5′-N- methylcarboxamides were synthesized from the versatile intermediate, O 6-(benzotriazol-1-yl)-2-amino-2′,3′-O- isopropylideneinosine-5′-N-methylcarboxamide (1). These compounds were evaluated as A3 adenosine receptor agonists in terms of their potency and receptor sub-type selectivity in a cAMP accumulation assay and a number of potent and selective compounds were identified. One such compound, 2-amino-N6-(3-chlorobenzyl)adenosine-5′-N-methylcarboxamide (3i), was over 500-fold selective for the A3AR over the other three adenosine receptor subtypes. This represents a significantly greater selectivity profile compared with the prototypical IB-MECA.
- Devine, Shane M.,May, Lauren T.,Scammells, Peter J.
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- Synthesis of three regioisomeric (7-methoxychromenonyl)methyl guanosine 5′-phosphates
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Herein we describe the synthesis of three new (7-methoxychromenonyl)methyl 2-N-propionyl-2′,3′-isopropylideneguanosine 5′-phosphate diesters, potentially photolabile nucleotides, via an H-phosphonate strategy. The stability of these compounds toward acidic and basic conditions was evaluated during the nucleoside moiety deprotection. Copyright Taylor & Francis Group, LLC.
- Faurel-Paul, Elodie,Yoshida, Kenta,Sepulcre, Magali,Dhimane, Hamid,Merrer, Yves Le
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- Modified GSMP synthesis greatly improves the disulfide crosslink of T7 run-off siRNAs with cell penetrating peptides
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Preventing intramolecular cyclization greatly improves 5′-deoxy- 5′-thioguanosine monophosphorothioate (GSMP) synthesis and its application as a potent initiator nucleotide for T7 run-off transcription of noncoding RNAs. GSMP was efficiently incorporated into the 5′-end of siRNA sense strands and the resulting thiol-modified siRNA was crosslinked with a free cysteine of cell penetrating peptide Penetratin as monitored by mass spectrometry. Cellular uptake and the knockdown potential of the peptide-coupled siRNA (pepsiRNA) were evaluated in primary cells. Georg Thieme Verlag Stuttgart - New York.
- Schmitz, Katja,Hahn, Frank,Schepers, Ute
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- The synthesis of isopropylidene mRNA cap analogs modified with phosphorothioate moiety and their evaluation as promoters of mRNA translation
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Synthetic mRNA cap analogs are valuable tools in the preparation of modified mRNA transcripts with improved translational activity and increased cellular stability, and have recently attracted more attention because of their great potential in therapeutic applications. We have synthesized and tested isopropylidene dinucleotide cap analogs bearing a phosphorothioate group at the β position of the 5′,5′-triphosphate bridge (two diastereomers of 2′,3′-iPr-m7GppSpG), as synthetically simpler alternatives to previously obtained phosphorothioate cap analogs. To evaluate the utility of the new compounds in biological systems we determined their affinity to translation initiation factor 4E (eIF4E), and tested their translational properties in rabbit reticulocyte lysates (RRL) and in human immature dendritic cells (hiDCs). In order to explain the properties of isopropylidene analogs we performed 1H NMR conformational analysis and correlated the absolute configuration at the β-phosphorous atom with previously synthesized m7GppSpG.
- Warminski, Marcin,Kowalska, Joanna,Buck, Janina,Zuberek, Joanna,Lukaszewicz, Maciej,Nicola, Corina,Kuhn, Andreas N.,Sahin, Ugur,Darzynkiewicz, Edward,Jemielity, Jacek
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- Nucleotide substrate specificity of anti-hepatitis C virus nucleoside analogs for human mitochondrial RNA polymerase
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Nucleoside analog inhibitors (NAIs) are an important class of antiviral agents. Although highly effective, some NAIs with activity against hepatitis C virus (HCV) can cause toxicity, presumably due to off-target inhibition of host mitochondrial RNA polymerase (POLRMT). The in vitro nucleotide substrate specificity of POLRMT was studied in order to explore structure-activity relationships that can facilitate the identification of nontoxic NAIs. These findings have important implications for the development of all anti-RNA virus NAIs.
- Ehteshami, Maryam,Zhou, Longhu,Amiralaei, Sheida,Shelton, Jadd R.,Cho, Jong Hyun,Zhang, Hongwang,Li, Hao,Lu, Xiao,Ozturk, Tugba,Stanton, Richard,Amblard, Franck,McBrayer, Tamara R.,Coats, Steven J.,Schinazi, Raymond F.
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- Persistent, well-defined, monodisperse, π-conjugated organic nanoparticles via G-quadruplex self-assembly
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Several oligo(p-phenylene-vinylene) oligomers capped with a guanosine or a guanine moiety have been prepared via a palladium-catalyzed cross-coupling reaction. Their self-assembly, in both the absence and presence of alkaline salts, has been studied by means of different techniques in solution (NMR, MS, UV-vis, CD, fluorescence), solid state (X-ray diffraction), and on surfaces (STM, AFM). When no salt is added, these --conjugated molecules self-associate in a mixture of hydrogen-bonded oligomers, among which the G-quartet structure may be predominant if the steric hindrance around the guanine base becomes important. In contrast, in the presence of sodium or potassium salts, well-defined assemblies of eight functional molecules (8mers) can be formed selectively and quantitatively. In these assemblies, the --conjugated oligomers are maintained in a chirally tilted (J-type) stacking arrangement, which is manifested by negative Cotton effects, small bathochromic absorption and emission shifts, and fluorescence enhancements. Furthermore, these self-assembled organic nanostructures, ～1.5-2.0 nm high and 8.5 nm wide, exhibit an extraordinary stability to temperature or concentration changes in apolar media, and they can be transferred and imaged over solid substrates as individual nanoparticles, showing no significant dissociation or further aggregation.
- Gonzalez-Rodriguez, David,Janssen, Pim G. A.,Martin-Rapn, Rafael,Cat, Inge De,Feyter, Steven De,Schenning, Albertus P. H. J.,Meijer
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- Synthesis and evaluation of potential inhibitors of eIF4E cap binding to 7-methyl GTP
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Cap-dependent translation is initiated by the binding of eIF4E to capped mRNA (m7GpppN). We have prepared a small library of 7-methyl guanosine nucleoside and nucleotide analogs and evaluated their ability to inhibit eIF4E binding to 7-methyl GTP with a competitive eIF4E binding immunoassay. 5′-H-Phosphonate derivatives in which the 2′- and 3′-riboside hydroxyls were tethered together by an isopropylidene group were shown to be a new class of inhibitors of eIF4E binding to capped mRNA.
- Ghosh, Phalguni,Park, Chunkyung,Peterson, Mark S.,Bitterman, Peter B.,Polunovsky, Vitaly A.,Wagner, Carston R.
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- Enhancing the mechanical properties of guanosine-based supramolecular hydrogels with guanosine-containing polymers
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We demonstrate that multivalent, polymeric 8-methoxyguanosine derivatives based on poly(dimethylacrylamide) can enhance the mechanical properties of the low molecular weight hydrogelator 8-methoxy-2′,3′,5′-tri-O- acetylguanosine at biologically relevant salt concentrations. It is proposed that these nongelling polymeric derivatives, under the conditions studied, can result in a significant enhancement of these supramolecular gels (e.g., for gels containing 1 wt % gelator G′ can be increased from ca. 2000 Pa with no additive to 80 000 Pa) by acting as supramolecular cross-linking units. Two competing mechanisms appear to play a role in these cogels. At low polymer concentrations the guanosine-containing polymers tend to act more as solubilizing agents for the gelator, thus weakening the gels, while at high guanosine-containing polymer concentrations the gels show a marked enhancement in mechanical properties consistent with them acting as supramolecular cross-linking agents. As such, the thermomechanical properties of these cogels depend on both the polymer:low molecular weight gelator ratio and the number of 8-methoxyguanosine repeat units present in the polymer additive. Thus, these polymeric guanosine-based additives impart the ability to tailor both the modulus and shear sensitivity of the gels. For example, cogels with a modulus ranging between ca. 95 and 80 000 Pa can be obtained through judicious selection of the type and amount of polymer additive.
- Way, Amanda E.,Korpusik, Angie B.,Dorsey, Taylor B.,Buerkle, Lauren E.,Von Recum, Horst A.,Rowan, Stuart J.
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- From G-quartets to G-ribbon gel by concentration and sonication control
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Two guanosine analogues have been designed and synthesized by connecting one (1) or three adamantane branches (2). The compound containing a single adamantane branch formed G-quartets in acetonitrile solution, and was then transformed into a G-ribbon gel at concentrations higher than the critical gelation concentration. In contrast, the compound with three adamantane branches precipitated after a heating-cooling process. By means of circular dichroism and UV/visible spectra, NMR, SEM, and structural studies, the mechanism of the formation of the G-quartets and G-ribbon gel, as well as the difference in the self-assembly modes of the two compounds, have been fully elucidated. Compound 1 firstly self-assembled into G-quartets in solutions in the concentration range 5.0 × 10-4 to 1.0 × 10-2 M, and these G-quartets were transformed into a G-ribbon on further increasing the concentration. Gelation occurred when the G-ribbon self-assembled into a hexagonal columnar structure with the help of intermolecular hydrogen-bonding and hydrophobic interactions. This gel was sensitive to sonication and underwent a morphology change from a columnar structure to a flower-like structure composed of flakes. In contrast, due to steric hindrance, compound 2 only assembled into a spherical structure based on hydrophobic interactions.
- Meng, Luyan,Liu, Keyin,Mo, Shuli,Mao, Yueyuan,Yi, Tao
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- A fluorescent guanosine dinucleoside as a selective switch-on sensor for c-myc G-quadruplex DNA with potent anticancer activities
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Like likes like! A novel fluorescent C2-symmetric guanosine-based dinucleoside has been engineered by chemical ligation of two guanosine units with a biocompatible dansyl tag. The nucleoside exhibits high selectivity for c-myc G-quadruplex DNA through fluorescence enhancement over duplex DNA and other promoter G-quadruplexes (see scheme). It stains the nucleus preferentially, arrests the cell cycle at the G2/M phase, inhibits cell growth, and induces apoptosis in A375 cancer cells. Copyright
- Kumar, Y. Pavan,Bhowmik, Sudipta,Das, Rabindra Nath,Bessi, Irene,Paladhi, Sushovan,Ghosh, Rita,Schwalbe, Harald,Dash, Jyotirmayee
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- Kinase-Inhibitory Nucleoside Derivatives from the Pacific Bryozoan Nelliella nelliiformis
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Marine organisms are a valuable source of bioactive natural products, yet bryozoan invertebrates have been relatively understudied. Herein, we report nelliellosides A and B, new secondary metabolites of the Pacific bryozoan Nelliella nelliiformis, found using NMR-guided isolation. Their structures, including absolute configurations, were elucidated using spectroscopic and chromatographic techniques. Total synthesis of the natural products and four analogues was also achieved, in addition to an assessment of their biological activity, especially kinase inhibition.
- Bracegirdle, Joe,Gordon, Dennis P.,Harvey, Joanne E.,Keyzers, Robert A.
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p. 547 - 551
(2020/03/19)
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- Compositions and Methods for Reverse Automated Nucleic Acid Synthesis
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Methods for reverse automated nucleic acid synthesis, and 5′-H-phosphonates suitable for use in the same, as well as methods for making 5′-H-phosphonates, are described.
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Paragraph 0117-0118
(2019/10/29)
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- Corroboration of Zn(ii)-Mg(ii)-tertiary structure interplays essential for the optimal catalysis of a phosphorothiolate thiolesterase ribozyme
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The TW17 ribozyme, a catalytic RNA selected from a pool of artificial RNA, is specific for the Zn2+-dependent hydrolysis of a phosphorothiolate thiolester bond. Here, we describe the organic synthesis of both guanosine α-thio-monophosphate and the substrates required for selecting and characterizing the TW17 ribozyme, and for deciphering the catalytic mechanism of the ribozyme. By successively substituting the substrate originally conjugated to the RNA pool with structurally modified substrates, we demonstrated that the TW17 ribozyme specifically catalyzes phosphorothiolate thiolester hydrolysis. Metal titration studies of TW17 ribozyme catalysis in the presence of Zn2+ alone, Zn2+ and Mg2+, and Zn2+ and [Co(NH3)6]3+ supported our findings that Zn2+ is absolutely required for ribozyme catalysis, and indicated that optimal ribozyme catalysis involves the presence of outer-sphere and one inner-sphere Mg2+. A survey of the TW17 ribozyme activity at various pHs revealed that the activity of the ribozyme critically depends on the alkaline conditions. Moreover, a GNRA tetraloop-containing ribozyme constructed with active catalysis in trans provided catalysis and multiple substrate turnover efficiencies significantly higher than ribozymes lacking a GNRA tetraloop. This research supports the essential roles of Zn2+, Mg2+, and a GNRA tetraloop in modulating the TW17 ribozyme structure for optimal ribozyme catalysis, leading also to the formulation of a proposed reaction mechanism for TW17 ribozyme catalysis.
- Wang, Tzu-Pin,Su, Yu-Chih,Chen, Yi,Severance, Scott,Hwang, Chi-Ching,Liou, Yi-Ming,Lu, Chia-Hui,Lin, Kun-Liang,Zhu, Rui Jing,Wang, Eng-Chi
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p. 32775 - 32793
(2018/10/15)
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- Hierarchical self-assembly of a new guanosine derivative to quadruplex structure in presence of potassium and ytterbium ions
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Substituted guanosine molecules can form nanostructures through self-assembly in presence of alkali metal ions in lipophilic solvents. Most of the cases the assembly is directed by the H-bonding interaction as well as the interaction of alkali metal ion with the guanosine molecules. Herein we report the synthesis of a new bipyridyl substituted guanosine molecule G5 which forms a tris bipyridyl ruthenium complex G5-Ru which has been characterized by ESI-MS as well as NMR spectroscopy. This ruthenium complex G5-Ru forms a quadruplex self-assembly in presence of potassium picrate and ytterbium triflate in acetone which has been detected by CD spectroscopy as well as ESI-MS studies in case of ytterbium triflate.
- Kundu, Arunangshu,Ghosh, Sushobhan
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p. 1191 - 1197
(2020/06/27)
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- SULFAMIDE AND SULFAMATE INHIBITORS OF hHint1
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Embodiments provide, among things, compounds of the formula I and methods for using such compounds to reduce pain (e.g., neuronal pain), treat a mammal's addiction to nicotine or anti-pain drugs, and increase a mammal's sensitivity to drugs that bind MOR or NMDAR.
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Page/Page column 0126
(2018/03/25)
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- COMPOUNDS
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The invention provides compounds for use in a method of treating and/or preventing a bacterial infection in a human or non-human mammal, said method comprising administration of said compound in combination with (either simultaneously, separately, or sequentially) a β-lactam antibiotic, wherein said compound has the general formula I: (I) (wherein: Q is a lipophilic, zinc chelating moiety which is selective for Zn2+ ions and which comprises at least one, preferably two or more (e.g 2, 3 or 4), optionally substituted, unsaturated heterocyclic rings, e.g. 5 or 6-membered heterocyclic rings (such rings preferably include at least one heteroatom selected from N, S and O, preferably N); wherein any optional substituents may be selected from C1-6 alkyl, C1-6 alkoxy, halogen, nitro, cyano, amine, and substituted amine; each L, which may be the same or different, is a covalent bond or a linker; each W, which may be the same or different, is a non-peptidic hydrophilic group which comprises one or more hydroxy groups; and x is an integer from 1 to 3) or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof.
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Page/Page column 115
(2018/03/09)
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- Exploring the potential of phosphotriazole 5′ mRNA cap analogues as efficient translation initiators
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Augmenting the mRNA translation efficiency and stability by replacing the standard 7-methylguanosine 5′-cap with properly designed analogues is a viable strategy for increasing the in vivo expression of proteins from exogenously delivered mRNA. However, the development of novel cap analogues with superior biological properties is hampered by the challenges associated with the synthesis of such highly modified nucleotides. To provide a simpler alternative to traditional methods for cap analogue preparation, we have recently proposed a click-chemistry-based strategy for the synthesis of dinucleotide cap analogues and identified several triazole-containing compounds with promising biochemical properties. Here, we further explored the concept of CuAAC-mediated cap synthesis by designing and studying ‘second generation' triazole-modified caps, which were derived from the most promising ‘first generation' compounds by modifying the oligophosphate chain length, altering the position of the triazole moiety, or replacing chemically labile P-N bonds with P-O bonds. The biochemical properties of the new analogues were evaluated by determining their affinity for eIF4E, susceptibility to hDcp2-catalysed decapping, and translation efficiencies in vitro and in cultured cells. The results led to identification of cap analogues that have superior translational properties compared to standard caps and the parent triazole-modified compounds as well as provided directions for future improvements.
- Walczak, Sylwia,Sikorski, Pawel J.,Kasprzyk, Renata,Kowalska, Joanna,Jemielity, Jacek
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supporting information
p. 6741 - 6748
(2018/09/29)
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- Design, Synthesis, and Characterization of Sulfamide and Sulfamate Nucleotidomimetic Inhibitors of hHint1
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Hint1 has recently emerged to be an important target of interest due to its involvement in the regulation of a broad range of CNS functions including opioid signaling, tolerance, neuropathic pain, and nicotine dependence. A series of inhibitors were rationally designed, synthesized, and tested for their inhibitory activity against hHint1 using isothermal titration calorimetry (ITC). The studies resulted in the development of the first small-molecule inhibitors of hHint1 with submicromolar binding affinities. A combination of thermodynamic and high-resolution X-ray crystallographic studies provides an insight into the biomolecular recognition of ligands by hHint1. These novel inhibitors have potential utility as molecular probes to better understand the role and function of hHint1 in the CNS.
- Shah, Rachit,Strom, Alexander,Zhou, Andrew,Maize, Kimberly M.,Finzel, Barry C.,Wagner, Carston R.
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supporting information
p. 780 - 784
(2016/08/24)
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- Amphiphilicity guanosine derivative, and preparation method therefor and application thereof in cytidine triphosphate sensing and recognition
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The present invention discloses an amphiphilicity guanosine derivative, a preparation method therefor and an application thereof in cytidine triphosphate sensing and recognition. The amphiphilicity guanosine derivative takes a hexadecyl chain as a tail group and a guanosine derivative as a head group, and has the features of biocompatibility and nontoxicity; the amphiphilicity guanosine derivative can be assembled with an amphiphilicity Tb (III) complex to form a vesicle type nano interface; characteristic fluorescence of the Tb (III) complex is greatly sensitized by an energy transfer process between a guanosine construction unit assembled on the interface and the Tb (III) complex; and when cytidine triphosphate which can be in complementary pairing with guanosine is added in the system, the energy transfer process between the guanosine derivative and the Tb (III) complex can be blocked drastically, thereby quenching the characteristic fluorescence of the Tb (III) complex and achieving selective recognition for the cytidine triphosphate. The amphiphilicity guanosine derivative provided by the present invention is simple in preparation method and mild in reaction condition, and can be used for cytidine triphosphate detection.
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Paragraph 0042; 0043; 0044; 0045
(2017/01/02)
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- A DNA-inspired synthetic ion channel based on G-C base pairing
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A dinucleoside containing guanosine and cytidine at the end groups has been prepared using a modular one-pot azide-alkyne cycloaddition. Single channel analysis showed that this dinucleoside predominantly forms large channels with 2.9 nS conductance for the transport of potassium ions across a phospholipid bilayer. Transmission electron microscopy, atomic force microscopy, and circular dichroism spectroscopy studies reveal that this dinucleoside can spontaneously associate through Watson-Crick canonical H-bonding and π-π stacking to form stable supramolecular nanostructures. Most importantly, the ion channel activity of this G-C dinucleoside can be inhibited using the nucleobase cytosine.
- Das, Rabindra Nath,Kumar, Y. Pavan,Schütte, Ole Mathis,Steinem, Claudia,Dash, Jyotirmayee
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supporting information
p. 34 - 37
(2015/01/30)
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- Synthesis and complementary self-association of novel lipophilic π-conjugated nucleoside oligomers
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A series of lipophilic nucleosides comprising natural and non-natural bases that are π-conjugated to a short oligophenylene-ethynylene fragment has been synthesized. These bases comprise guanosine, isoguanosine, and 2-aminoadenosine as purine heterocycles, and cytidine, isocytosine and uridine as complementary pyrimidine bases. The hydrogen-bonding dimerization and association processes between complementary bases were also studied by 1H NMR and absorption spectroscopy in order to obtain the relevant association constants.
- Camacho-García,Montoro-García,López-Pérez,Bilbao,Romero-Pérez,González-Rodríguez
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p. 4506 - 4513
(2015/04/14)
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- Triazole-tailored guanosine dinucleosides as biomimetic ion channels to modulate transmembrane potential
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A click ion channel platform has been established by employing a clickable guanosine azide or alkyne with covalent spacers. The resulting guanosine derivatives modulated the traffic of ions across the phospholipid bilayer, exhibiting a variation in conductance spanning three orders of magnitude (pS to nS). F?rster resonance energy transfer studies of the dansyl fluorophore with the membrane binding fluorophore Nile red revealed that the dansyl fluorophore is deeply embedded in the phospholipid bilayer. Complementary cytosine can inhibit the conductance of the supramolecular guanosine channels in the phospholipid bilayers. Coming through: A click ion-channel platform was established by employing a clickable guanosine azide or alkyne with covalent spacers. The guanosine derivatives modulated the traffic of ions across the phospholipid bilayer. FRET studies of the dansyl fluorophore with the membrane-binding fluorophore Nile red revealed that the dansyl fluorophore is deeply embedded in the phospholipid bilayer (see figure).
- Kumar, Y. Pavan,Das, Rabindra Nath,Kumar, Sonu,Schütte, Ole Mathis,Steinem, Claudia,Dash, Jyotirmayee
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supporting information
p. 3023 - 3028
(2014/03/21)
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- Modular construction of dynamic nucleodendrimers
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Isoguanosine-containing dendritic small molecules self-assemble into decameric nucleodendrimers as observed by 1D NMR spectroscopy, 2D DOSY, and mass spectrometry. In particular, apolar building blocks readily form pentameric structures in acetonitrile while the presence of alkali metals promotes the formation of stable decameric assemblies with a preference for cesium ions. Remarkably, co-incubation of guanosine and isoguanosine-containing nucleodendrons results in the formation of decameric structures in absence of added salts. Further analysis of the mixture indicated that guanosine derivatives facilitate the formation, but are not involved in decameric structures; a process reminiscent of molecular crowding. This molecular system provides a powerful canvas for the rapid and modular assembly of polyfunctional dendritic macromolecules.
- Abet, Valentina,Evans, Robert,Guibbal, Florian,Caldarelli, Stefano,Rodriguez, Raphael
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supporting information
p. 4862 - 4866
(2014/05/20)
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- A chemo-enzymatic approach to specifically click-modified RNA
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The growing interest in single-molecule analysis of RNA calls for programmable enzymatic labeling strategies beyond the horizon of solid-phase synthesized RNAs. Herein we describe an easy and versatile chemo-enzymatic approach to label RNA at its termini or defined internal positions via click-chemistry.
- Dojahn, Claudine M.,Hesse, Marlen,Arenz, Christoph
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p. 3128 - 3130
(2013/06/05)
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- Synthesis and in vitro stability of nucleoside 5′-phosphonate derivatives
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Nucleoside derivatives are largely synthesized and tested to investigate their influence on platelet aggregation. It's well known that P2Y receptors play an important role in the regulation of platelet function and, as consequence, in controlling atherothrombotic events. The research of compounds that antagonize P2Y1 and, in particular, P2Y12 receptors is of great interest in the aim to obtain platelet aggregation inhibitors that are effective in the prevention and treatment of arterial thrombosis. In this study we present the synthesis and in vitro metabolic stability in human blood and rat liver homogenate of a new class of nucleoside derivatives, in particular 5′-phosphonate adenosine, inosine, guanosine and thioadenosine analogues also modified at the ribose moiety. On the basis of the results obtained we can hypothesize compounds 4 and 18 to have in vivo a relatively high stability.
- Vertuani, Silvia,Baldisserotto, Anna,Varani, Katia,Borea, Pier Andrea,De Marcos Maria Cruz, Bonache,Ferraro, Luca,Manfredini, Stefano,Dalpiaz, Alessandro
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supporting information; experimental part
p. 202 - 209
(2012/09/07)
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- COMPOUNDS FOR TREATING BACTERIAL INFECTIONS
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The present invention relates to a novel class of guanine nucleotide analogs which inhibit RelA and Relseq synthetic activity and which possess anti-bacterial activity. The present invention also relates to pharmaceutical compositions that include such compounds, and to methods of use of such compounds or compositions for combating bacteria and treating bacterial infections.
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Page/Page column 47-48
(2011/04/25)
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- Evidence for the existence of a specific gprotein-coupled receptor activated by guanosine
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Guanosine, released extracellularly from neurons and glial cells, plays important roles in the central nervous system, including neuroprotection. The innovative DELFIA Eu-GTP binding assay was optimized for characterization of the putative guanosine receptor binding site at rat brain membranes by using a series of novel and known guanosine derivatives. These nucleosides were prepared by modifying the purine and sugar moieties of guanosine at the 6- and 5'-positions, respectively. Results of these experiments prove that guanosine, 6-thioguanosine, and their derivatives activate a Gprotein-coupled receptor that is different from the well-characterized adenosine receptors. Catching the elusive guanosine receptor: The innovative DELFIA Eu-GTP binding assay was applied to characterize the guanosine binding site by using novel and known guanosine derivatives. Some of the tested compounds, which proved to be full agonists with EC50 values in the low nanomolar range, could be useful tools for further characterization of the putative guanosine receptor.
- Volpini, Rosaria,Marucci, Gabriella,Buccioni, Michela,DalBen, Diego,Lambertucci, Catia,Lammi, Carmen,Mishra, Ram C.,Thomas, Ajiroghene,Cristalli, Gloria
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scheme or table
p. 1074 - 1080
(2012/01/06)
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- ppGpp analogues inhibit synthetase activity of Rel proteins from Gram-negative and Gram-positive bacteria
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A prominent feature of the stringent response is the accumulation of two unusual phosphorylated derivatives of GTP and GDP (pppGpp: 5′-triphosphate-3′-diphosphate, and ppGpp: 5′-3′-bis-diphosphate), collectively called (p)ppGpp, within a few seconds after the onset of amino-acid starvation. The synthesis of these 'alarmone' compounds is catalyzed by RelA homologues. Other features of the stringent response include inhibition of stable RNA synthesis and modulation of transcription, replication, and translation. (p)ppGpp accumulation is important for virulence induction, differentiation and antibiotic resistance. We have synthesized a group of (p)ppGpp analogues and tested them as competitive inhibitors of Rel proteins in vitro. 2′-Deoxyguanosine-3′-5′-di(methylene bisphosphonate) [compound (10)] was found as an inhibitor that reduces ppGpp formation in both Gram-negative and Gram-positive bacteria. In silico docking together with competitive inhibition analysis suggests that compound (10) inhibits activity of Rel proteins by competing with GTP/GDP for its binding site. As Rel proteins are completely absent in mammalians, this appears to be a very attractive approach for the development of novel antibacterial agents.
- Wexselblatt, Ezequiel,Katzhendler, Jehoshua,Saleem-Batcha, Raspudin,Hansen, Guido,Hilgenfeld, Rolf,Glaser, Gad,Vidavski, Roee R.
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experimental part
p. 4485 - 4497
(2010/08/22)
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- Simple method for fast deprotection of nucleosides by triethylamine- catalyzed methanolysis of acetates in aqueous medium
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A straightforward methodology for deacetylation of protected ribonucleosides was developed based on triethylamine-catalyzed solvolysis in aqueous methanol. Reactions are completed in a few minutes under microwave irradiation and the free nucleosides are obtained in high yield after simple evaporation of volatiles. Other important features include the involvement of readily available reagents and the compatibility with diverse functional groups, which make this process very attractive for broad application.
- Meier, Lidiane,Monteiro, Gustavo C.,Baldissera, Rodrigo A.M.,Sa?, Marcus Mandolesi
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experimental part
p. 859 - 866
(2010/09/11)
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- Synthesis and biological evaluation of novel neamine-nucleoside conjugates potentially targeting to RNAs
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Eighteen novel neamine-nucleoside conjugates with ethylenediamine-lysine or ethylenediamine-arginine as the linker were synthesized and their potential binding to A site of 16S RNA and TAR RNA was evaluated using SPR (surface plasmon resonance). Compared with neamine, compounds 10i and 10q show 6.3 and 4.8 times potential in binding to A site of 16S RNA and eight and six times potential in binding to TAR RNA, respectively. According to the data of SPR, it indicates that amino acid residue and nucleobase moieties of the designed neamine-nucleosides conjugates exhibit the important contributions for the binding to A site of 16S RNA and TAR RNA. The molecular docking study on the interaction between the ligands and A site of 16S RNA is in agreement with the experimental data. The novel type of modification may provide a promising way for the development of neamine derivatives effectively targeting to RNAs.
- Xu, Yanli,Jin, Hongwei,Yang, Zhenjun,Zhang, Liangren,Zhang, Lihe
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experimental part
p. 5228 - 5239
(2009/12/04)
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- Linear and convergent approaches to 2-substituted adenosine-5′-N-alkylcarboxamides
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Herein we report both linear and convergent pathways for the preparation of 2-alkynyl substituted adenosine-5′-N-ethylcarboxamides via the versatile synthetic intermediate, 2-iodoadenosine-5′-N-ethylcarboxamide (13). The linear approach afforded 13 in an overall yield of 30% from guanosine over eight synthetic steps. The convergent approach was shorter, but proceeded in lower yield (five steps, 20% yield). Both approaches compare favourably with previously reported syntheses of 13, which has been prepared in 15% yield from guanosine over nine steps. 2-Iodoadenosine-5′-N-ethylcarboxamide (13) was subsequently converted to HENECA (2) and PHPNECA (3) to exemplify the utility of this approach for the preparation of?potent A2A adenosine receptor agonists. The linear approach was also amenable to the synthesis of 2-fluoropurine ribosides, which were subsequently elaborated into 2-alkylaminoadenosine-5′-N-ethylcarboxamides. Furthermore, both of these synthetic approaches are readily amenable to the synthesis of adenosine analogues with varied 2-, 6- and 5′-substitution patterns.
- Foitzik, Richard C.,Devine, Shane M.,Hausler, Nicholas E.,Scammells, Peter J.
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experimental part
p. 8851 - 8857
(2009/12/26)
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- Studies on umami taste. Synthesis of new guanosine 5′-phosphate derivatives and their synergistic effect with monosodium glutamate
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A number of N2-alkyl and N2-acyl derivatives of guanosine 5′-phosphate (GMP) have been synthesized and tested for their synergistic effect with monosodium L-glutamate (MSG), the prototypical substance imparting umami taste to savory-based foods. Capacities to enhance the taste intensity of MSG (γ values) were estimated through subjective comparisons of MSG/nucleotide mixtures in water with appropriate solutions of MSG alone. Assuming β = γ[nucleotide]/γ[IMP], β values of the N 2-substituted GMPs were found in the range 1.2-5.7. Such values appear to be related to the chain length of the substituent in the 2-position of the purine nucleus and dependent on the replacement of a CH2 group with an S atom and/or with an α-CO group. These findings indicate that the exocyclic NHR group of the guanine moiety is actively implicated in the synergism between GMP derivatives and MSG. Theoretical calculations suggest that an anti conformation is probably assumed by ribonucleotide molecules interacting with umami receptors.
- Cairoli, Paola,Morelli, Carlo F.,Speranza, Giovanna,Manitto, Paolo,Pieraccini, Stefano,Sironi, Maurizio
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scheme or table
p. 1043 - 1050
(2009/05/08)
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- THERAPEUTIC COMPOUNDS DERIVED FROM SPIDER VENOM AND THEIR METHOD OF USE
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The present invention is directed to new therapeutic compounds isolated from spider venom and methods of using these new compounds. The compounds are sulfated nucleoside derivatives including ribonucleoside mono- and disulfates derived from guanine, adenosine, and cytidine. Some of these compounds are glycosylated or fucosylated bearing one or more sugar residues.
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Page/Page column 29
(2008/06/13)
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Model compound 3 in which the protected guanosine moiety is linked to the carcinogen (N-acetyl-N-hydroxy)-2-aminofluorene has been prepared and studied in various solvolytic conditions. The intramolecular reaction leads notably to the arylamidation of the
- Defrancq, Eric,Leterme, Anne,Pelloux, Nadia,Lhomme, Marie-France,Lhomme, Jean
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p. 5725 - 5736
(2007/10/02)
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- Reactions Between Ribonucleoside Derivatives and Formaldehyde in Ethanol Solution
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2',3'-O-Isopropylidene-adenosine, -cytidine, and -guanosine, (2a), (3a), and (4a), respectively react with formaldehyde in ethanol solution to give the corresponding N-ethoxymethyl derivatives, (2b), (3b), and (4b), respectively in good yields.
- Bridson, Peter K.,Jiricny, Josef,Kemal, Oeznur,Reese, Colin B.
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p. 208 - 209
(2007/10/02)
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