- Bivalent HIV-1 fusion inhibitors based on peptidomimetics
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Membrane fusion is a valid target for inhibition of HIV-1 replication. A 34-mer fragment peptide (C34), which is contained in the HIV-1 envelope protein gp41, has significant anti-HIV activity. Previously, a dimeric derivative of C34 linked by a disulfide bridge at its C-terminus was found to have more potent anti-HIV activity than the C34 peptide monomer. To date, several peptidomimetic small inhibitors have been reported, but most have lower potency than peptide derivatives related to C34. In the present study we applied this dimerization concept to these peptidomimetic small inhibitors and designed several bivalent peptidomimetic HIV-1 fusion inhibitors. The importance of the length of linkers crosslinking two peptidomimetic compounds was demonstrated and several potent bivalent inhibitors containing tethered peptidomimetics were produced.
- Kobayakawa, Takuya,Ebihara, Kento,Tsuji, Kohei,Kawada, Takuma,Fujino, Masayuki,Honda, Yuzuna,Ohashi, Nami,Murakami, Tsutomu,Tamamura, Hirokazu
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- Assisted enzyme replacement therapy
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Reagents and methods useful for the synthesis of conjugates comprising guanidinylated cyclic acetals are provided. Also provided are methods for increasing the cellular uptake of various therapeutic compounds and treatment modalities using these conjugates.
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Page/Page column 93; 95; 96; 97; 98
(2018/03/07)
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- Discovery of Macrocyclic Pyrimidines as MerTK-Specific Inhibitors
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Macrocycles have attracted significant attention in drug discovery recently. In fact, a few de novo designed macrocyclic kinase inhibitors are currently in clinical trials with good potency and selectivity for their intended target. In this study, we successfully engaged a structure-based drug design approach to discover macrocyclic pyrimidines as potent Mer tyrosine kinase (MerTK)-specific inhibitors. An enzyme-linked immunosorbent assay (ELISA) in 384-well format was employed to evaluate the inhibitory activity of macrocycles in a cell-based assay assessing tyrosine phosphorylation of MerTK. Through structure–activity relationship (SAR) studies, analogue 11 [UNC2541; (S)-7-amino-N-(4-fluorobenzyl)-8-oxo-2,9,16-triaza-1(2,4)-pyrimidinacyclohexadecaphane-1-carboxamide] was identified as a potent and MerTK-specific inhibitor that exhibits sub-micromolar inhibitory activity in the cell-based ELISA. In addition, an X-ray structure of MerTK protein in complex with 11 was resolved to show that these macrocycles bind in the MerTK ATP pocket.
- McIver, Andrew L.,Zhang, Weihe,Liu, Qingyang,Jiang, Xinpeng,Stashko, Michael A.,Nichols, James,Miley, Michael J.,Norris-Drouin, Jacqueline,Machius, Mischa,DeRyckere, Deborah,Wood, Edgar,Graham, Douglas K.,Earp, H. Shelton,Kireev, Dmitri,Frye, Stephen V.,Wang, Xiaodong
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supporting information
p. 207 - 213
(2017/02/15)
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- Polyacrylamide pseudo crown ethers via hydrogen bond-assisted cyclopolymerization
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Polyacrylamide pseudo crown ethers with large in-chain rings (15–24 membered) were synthesized by hydrogen bond-mediated cyclopolymerization of bisacrylamides comprising poly(ethylene oxide) spacers (PEGnDAAm, ethylene oxide units: n = 3–6). The monomers undergo the intramolecular hydrogen bonding of the bisacrylamide units in halogenated solvents to dynamically place the two olefins adjacently. As a result, the bisacrylamides homogeneously allowed controlled radical cyclopolymerization without any macroscopic gelation in 1,2-dichloroethane, even at relatively high concentration of monomers (200 mM), to directly provide precision cyclopolyacrylamides and the related copolymers with high cyclization efficiency (84–98%). Owing to the in-chain ring pendants, a cyclopolyacrylamide had glass transition temperature higher than a corresponding polyacrylamide with linear pendants.
- Kimura, Yoshihiko,Miyabara, Yuichiro,Terashima, Takaya,Sawamoto, Mitsuo
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p. 3294 - 3302
(2016/09/09)
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- Optimization of the Sensitization Process and Stability of Octadentate Eu(III) 1,2-HOPO Complexes
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The synthesis of a series of octadentate ligands containing the 1-hydroxypyridin-2-one (1,2-HOPO) group in complex with europium(III) is reported. Within this series, the central bridge connecting two diethylenetriamine units linked to two 1,2-HOPO chromophores at the extremities (5-LIN-1,2-HOPO) is varied from a short ethylene chain (H(2,2)-1,2-HOPO) to a long pentaethylene oxide chain (H(17O5,2)-1,2-HOPO). The thermodynamic stability of the europium complexes has been studied and reveals these complexes may be effective for biological measurements. Extension of the central bridge results in exclusion of the inner-sphere water molecule observed for [Eu(H(2,2)-1,2-HOPO)]- going from a nonacoordinated to an octacoordinated Eu(III) ion. With the longer chain length ligands, the complexes display increased luminescence properties in aqueous medium with an optimum of 20% luminescence quantum yield for the [Eu(H(17O5,2)-1,2-HOPO)]- complex. The luminescence properties for [Eu(H(14O4,2)-1,2-HOPO)]- and [Eu(H(17O5,2)-1,2-HOPO)]- are better than that of the model bis-tetradentate [Eu(5LINMe-1,2-HOPO)2]- complex, suggesting a different geometry around the metal center despite the geometric freedom allowed by the longer central chain in the H(mOn,2) scaffold. These differences are also evidenced by examining the luminescence spectra at room temperature and at 77 K and by calculating the luminescence kinetic parameters of the europium complexes. (Graph Presented).
- D'Aléo, Anthony,Moore, Evan G.,Xu, Jide,Daumann, Lena J.,Raymond, Kenneth N.
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p. 6807 - 6820
(2015/08/03)
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- Multimeric Near IR-MR Contrast Agent for Multimodal in Vivo Imaging
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Multiple imaging modalities are often required for in vivo imaging applications that require both high probe sensitivity and excellent spatial and temporal resolution. In particular, MR and optical imaging are an attractive combination that can be used to determine both molecular and anatomical information. Herein, we describe the synthesis and in vivo testing of two multimeric NIR-MR contrast agents that contain three Gd(III) chelates and an IR-783 dye moiety. One agent contains a PEG linker and the other a short alkyl linker. These agents label cells with extraordinary efficacy and can be detected in vivo using both imaging modalities. Biodistribution of the PEGylated agent shows observable fluorescence in xenograft MCF7 tumors and renal clearance by MR imaging. (Figure Presented).
- Harrison, Victoria S. R.,Carney, Christiane E.,MacRenaris, Keith W.,Waters, Emily A.,Meade, Thomas J.
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supporting information
p. 9108 - 9116
(2015/08/03)
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- Strain-Induced Reactivity in the Dynamic Covalent Chemistry of Macrocyclic Imines
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The displacement of molecular structures from their thermodynamically most stable state by imposition of various types of electronic and conformational constraints generates highly strained entities that tend to release the accumulated strain energy by undergoing either structural changes or chemical reactions. The latter case amounts to strain-induced reactivity (SIR) that may enforce specific chemical transformations. A particular case concerns dynamic covalent chemistry which may present SIR, whereby reversible reactions are activated by coupling to a high-energy state. We herewith describe such a dynamic covalent chemical (DCC) system involving the reversible imine formation reaction. It is based on the formation of strained macrocyclic bis-imine metal complexes in which the macrocyclic ligand is in a high energy form enforced by the coordination of the metal cation. Subsequent demetallation generates a highly strained free macrocycle that releases its accumulated strain energy by hydrolysis and reassembly into a resting state. Specifically, the metal-templated condensation of a dialdehyde with a linear diamine leads to a bis-imine [1+1]-macrocyclic complex in which the macrocyclic ligand is in a coordination-enforced strained conformation. Removal of the metal cation by a competing ligand yields a highly reactive [1+1]-macrocycle, which then undergoes hydrolysis to transient non-cyclic aminoaldehyde species, which then recondense to a strain-free [2+2]-macrocyclic resting state. The process can be monitored by 1H NMR spectroscopy. Energy differences between different conformational states have been evaluated by Hartree-Fock (HF) computations. One may note that the stabilisation of high-energy molecular forms by metal ion coordination followed by removal of the latter, offers a general procedure for producing out-of-equilibrium molecular states, the fate of which may then be examined, in particular when coupled to dynamic covalent chemical processes.
- Ratjen, Lars,Vantomme, Ghislaine,Lehn, Jean-Marie
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supporting information
p. 10070 - 10081
(2015/07/07)
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- Living ring-opening metathesis-polymerization synthesis and redox-sensing properties of norbornene polymers and copolymers containing ferrocenyl and tetraethylene glycol groups
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The controlled synthesis of monodisperse, redox-active metallopolymers and their redox properties and functions, including robust electrode derivatization and sensing, remains a challenge. Here a series of polynorbornene homopolymers and block copolymers containing side-chain amidoferrocenyl groups and tetraethylene glycol linkers were prepared via living ring-opening metathesis polymerization initiated by Grubbs' third-generation catalyst (1). Their molecular weights were determined using MALDI-TOF mass spectra, size exclusion chromatography (SEC), end-group analysis, and the empirical Bard-Anson electrochemical equation. All polymerizations followed a living and controlled manner, and the number of amidoferrocenyl units varied from 5 to 332. These homopolymers and block copolymers were successfully used to prepare modified Pt electrodes that showed excellent stability. The modified Pt electrodes show excellent qualitative sensing of ATP2- anions, in particular those prepared with the block copolymers. The quantitative recognition and titration of [n-Bu4N]2[ATP] was carried out using the CH 2Cl2 solution of the homopolymers, showing that two amidoferrocenyl groups of the homopolymers interacted with each ATP2- molecule. This stoichiometry led us to propose the H-bonding modes in the supramolecular polymeric network.
- Gu, Haibin,Rapakousiou, Amalia,Castel, Patricia,Guidolin, Nicolas,Pinaud, Noeel,Ruiz, Jaime,Astruc, Didier
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supporting information
p. 4323 - 4335
(2014/12/09)
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- PROCESS FOR THE DIRECT AMINATION OF ALCOHOLS USING AMMONIA TO FORM PRIMARY AMINES BY MEANS OF A XANTPHOS CATALYST SYSTEM
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The present invention relates to a chemocatalytic liquid-phase process for the direct one-stage amination of alcohols to primary amines by means of ammonia in high yields using a catalyst system containing at least one transition metal compound and a xantphos ligand.
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Paragraph 0063
(2014/01/08)
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- Synthesis of novel dansyl-labeled Celecoxib derivatives
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Four novel dansyl-labeled derivatives of Celecoxib, a cyclooxygenase-2 (COX-2) selective inhibitor, were designed and synthesized. To realize the fluorophore-linker-approach divergent and convergent synthetic strategies were applied. Therefore Celecoxib p-benzoic acid, 8, was synthesized in a new and convenient way. The yield and the synthetic route to Celecoxib, 1, its pyrazolylic acid, 7, and its pyrazolylic methyl ester, 6, were improved. Through a convenient synthesis 1,11-diamino-3,6,9-trioxundecane, 19, was obtained in high yield and purity and used as a linker for the dansyl moiety.
- Lill, Andreas,Scholich, Klaus,Stark, Holger
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supporting information
p. 6682 - 6686
(2013/11/19)
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- Improved ruthenium-catalyzed amination of alcohols with ammonia: Synthesis of diamines and amino esters
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Diamination of diols: The first homogeneously catalyzed diaminations of primary and secondary diols with ammonia give the corresponding diamines. Other primary as well as secondary alcohols including hydroxy-substituted esters can also be efficiently converted to primary amines. This atom-efficient and selective amination method proceeds in an ammonia atmosphere without additional hydrogen sources. Copyright
- Imm, Sebastian,Baehn, Sebastian,Zhang, Min,Neubert, Lorenz,Neumann, Helfried,Klasovsky, Florian,Pfeffer, Jan,Haas, Thomas,Beller, Matthias
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supporting information; experimental part
p. 7599 - 7603
(2011/10/01)
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- GALACTOSE DERIVATIVE, DRUG CARRIER AND MEDICINAL COMPOSITION
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The object of the invention is to provide a novel and useful galactose derivative constituting a drug carrier by which a medicine can be efficiently transferred into the liver, a drug carrier comprising the derivative, and a pharmaceutical composition comprising the carrier and a medicine. The present invention relates to a galactose derivative made up of galactose, a suitable spacer and a certain lipid, a drug carrier comprising the derivative and a cationic lipid, and a pharmaceutical composition comprising the carrier and a medicine (preferably a double strand RNA, a double strand DNA, an oligo nucleic acid) .
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Page/Page column 24
(2010/11/27)
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- Methods and reagents for oligonucleotide synthesis
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The present invention features novel compositions, linkers, derivatized solid supports, and methods for the efficient solid phase synthesis of oligonucleotides, including RNA, DNA, RNA-DNA chimeras, and analogs thereof.
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- Method for the chemical synthesis of oligonucleotides
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The present invention features novel compositions, linkers, derivatized solid supports, and methods for the efficient solid phase synthesis of oligonucleotides, including RNA, DNA, RNA-DNA chimeras, and analogs thereof.
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- Parallel vs. anti-parallel orientation in a curdlan/oligo(dA) complex as estimated by a FRET technique
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We already found that β-1,3-glucan polysaccharides form polymeric complexes with certain polynucleotides, but the parallel vs. anti-parallel orientation in those complexes had remained unsolved. In this paper, this controversial problem has been discussed for curdlan/oligo(dA) complexes utilizing two different energy transfer techniques. The first system consists of a combination of fiuorescein-labeled curdlan and 3′-(or 5′-)tetramethyl-rhodamine (TAMRA)-labeled oligo(dA). The second system utilizes gold nanoparticles: that is, two curdlan chains were linked by a disulfide bond and after complexation with oligo(dA), the complex was immobilized on gold nanoparticles. In this system, TAMRA was attached to the 3′ (or 5′) end of oligo(dA) and the gold particle acted as a fluorescence quencher (energy acceptor). These experiments have led us to conclude that in the curdlan/oligo(dA) complex, parallel orientation is more favourable than anti-parallel orientation. These findings have enabled us to envision a clearer image for the complexation mode between ss-1,3-glucan polysaccharides and polynucleotides. The Royal Society of Chemistry 2005.
- Numata, Munenori,Koumoto, Kazuya,Mizu, Masami,Sakurai, Kazuo,Shinkal, Seiji
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p. 2255 - 2261
(2007/10/03)
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- Tetraethylene glycol-derived spacer for oligonucleotide synthesis
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3,6,9-Trioxaundecane-1,11-diisocyanate (6) was synthesised from tetraethylene glycol in 5 steps and 48 % overall yield. Spacer 6 was monofunctionalised with the fully protected adenosyl-3'-O-succinate derivative 7 and linked to aminomethyl polystyrene affording a solid support suitable for oligoribonucleotide synthesis (loading: ~20 μmol/g). The HPLC analysis of a crude oligoribonucleotide synthesis and the yield of the full- length product show that this spacer compares well to hexamethylene diamine.
- Gunzenhauser,Biala,Strazewski
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p. 1223 - 1224
(2007/10/03)
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- Tetraethylene glycol-derived spacer for oligonucleotide synthesis
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3,6,9-Trioxaundecane-1,11-diisocyanate (6) was synthesised from tetraethylene glycol in 5 steps and 48 % overall yield. Spacer 6 was monofunctionalised with the fully protected adenosyl-3'-O-succinate derivative 7 and linked to aminomethyl polystyrene (50 % crosslinked with divinylbenzene) affording a solid support suitable for oligoribonucleotide synthesis (loading: ~20 μmol/g). The HPLC analysis of a crude oligoribonucleotide synthesis and the isolated yield of purified oligomer show that this spacer compares well to hexamethylene diamine.
- Gunzenhauser, Sigmund,Biala, Ewa,Strazewski, Peter
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p. 6277 - 6280
(2007/10/03)
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- A convenient preparation of diamino oligoethylene glycols and amino polyethylene glycols
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Diamino oligoethylene glycols and amino polyethylene glycols were prepared in good yields by using the reaction of sodium diformamide with oligoethylene glycol or polyethylene glycol dichlorides or ditosylates followed by hydrolysis using ethanolic hydrochloride.
- Yinglin,Tianbao,Hongwen,Xiao
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- Synthesis, Basicity, and Conformation of New Concave Pyridines
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Eight new bimacrocyclic concave pyridines 9 and six monomacrocyclic and open-chain analogues 10-12 were synthesized in overall yields up to 40percent (up to 75percent for nonmacrocyclic pyridines) starting from 2,6-pyridinedicarbaldehydes 1, diamines 2 and diacyl dichlorides 7.Their basicities cover a range of more than three orders of magnitude.They are determined not only by the substitution pattern of the pyridine ring, but also by the overall structure of the whole molecule and by its ability to stabilize the positive charge of a proton intramolecularly.The conformations ofthe bimacrocyclic bislactams 9 in solution and in the solid state were investigated spectroscopically, the structure of 9b could be determined by X-ray analysis.
- Luening, Ulrich,Baumstark, Roland,Peters, Karl,Schnering, Hans Georg von
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p. 129 - 143
(2007/10/02)
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- Precursor to nucleic acid probe
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Nucleic acids may be labeled by intercalating the alkylating intercalation moiety of a labeling reagent into a partially double-stranded nucleic acid to form a complex and activating the complex to cause covalent bonding between the reagent and the nucleic acid. Preferably, the labeled nucleic acid is a hybridization probe for detecting nucleic acid sequences capable of hybridizing with a hybridizing region of the nucleic acid. Also preferably the label moiety is non-radioactive. The labeling reagent is of the formula: where A is an alkylating intercalation moiety, B is a divalent organic moiety of the formula: STR1 where Y is O, NH or N--CHO, x is a number from 1 to 4, y is a number from 2 to 4, and L is a monovalent label moiety, wherein B is exclusive of any portion of the intercalation and label moieties. Preferably A is a 4-methylene-substituted psoralen moiety, and most preferably A is a 4'-methylene-substituted-4,5', 8-trimethylpsoralen moiety and L is biotin. This patent application is a divisional application of copending U.S. Ser. No. 791,332 filed Oct. 25, 1985, now U.S. Pat. No. 4,617,261, which is a continuation-in-part application (CIP) of copending U.S. Ser. No. 683,263 filed Dec. 18, 1984, now U.S. Pat. No. 4,582,789 which is a CIP of copending U.S. Ser. No. 591,811 filed Mar. 21, 1984, now abandoned. This patent application is also related to copending U.S. application Ser. No. 791,323 filed Oct. 25, 1985.
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- Macroheterocycles. III. Synthesis, properties, and tautomeric transformations of macrocyclic thioureas
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Macrocyclic thioureas of the and types, where R=CH2(CH2OCH2)nCH2 and (CH2)m (n=1, 2, 3, m=8), were obtained for the first time by the reaction of diamines with carbon bisulfide.The UV, IR, and PMR spectra of the compounds were studied.It was shown that they exist in the thione form in the crystalline state and in protic solvents.Thione - thiol isomerization is observed in nonpolar solvents.
- Bogatskii, A.V.,Luk'yanenko, N. G.,Kirichenko, T. I.
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p. 1124 - 1129
(2007/10/02)
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- Complexes of macrocyclic compounds
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Novel macrocyclic (monocyclic and bicyclic) compounds having nitrogen bridgehead atoms and having in the hydrocarbon bridging chains at least two additional hetero atoms selected from the group consisting of sulfur, oxygen, and nitrogen, when admixed with a compatible cation-donor compound form stable cation-containing macrocyclic complexes which, in turn, can be conveniently dissociated by addition of acid or a quaternizing agent. The novel macrocyclics are valuable for use in the same way and for the same purposes as chelating agents.
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