- Synthesis of polystyrene-based random copolymers with balanced number of basic or acidic functional groups
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Pairs of polystyrene-based random copolymers with balanced number of pendant basic or acidic groups were synthesized utilizing the template strategy. The same poly[(4hydroxystyrene)-ran-styrene] was used as a template backbone for modification. Two different synthetic approaches for the functionalization were applied. The first one involved direct functionalization of the template backbone through alkylation of the phenolic groups with suitable reagents. The second modification approach was based on "click" chemistry, where the introduction of alkyne groups onto the template backbone was followed by copper-catalyzed 1,3 cycloaddition of aliphatic sulfo-nate- or amine-contaning azides. Both synthetic approaches proved to be highly efficient as evidenced by 1H-NMR analyses. The thermal properties were evaluated by differential scanning calorimetry and thermal gravimetric analyses and were influenced by the type of functionality and the modification method. The ether-linked functional colopymers were thermally more stable than their "clicked" analogues.
- Dimitrov, Ivaylo,Jankova, Katja,Hvilsted, S.. Ren
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- 'Click' synthesized sterol-based cationic lipids as gene carriers, and the effect of skeletons and headgroups on gene delivery
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In this work, we have successfully prepared a series of new sterol-based cationic lipids (1-4) via an efficient 'Click' chemistry approach. The pDNA binding affinity of these lipids was examined by EB displacement and agarose-gel retardant assay. The average particle sizes and surface charges of the sterol-based cationic lipids/pDNA lipoplexes were analyzed by dynamic laser light scattering instrument (DLS), and the morphologies of the lipoplexes were observed by atomic force microscopy (AFM). The cytotoxicity of the lipids were examined by MTT and LDH assay, and the gene transfection efficiencies of these lipid carriers were investigated by luciferase gene transfection assay in various cell lines. In addition, the intracellular uptake and trafficking/localization behavior of the Cy3-DNA loaded lipoplexes were preliminarily studied by fluorescence microscopy. The results demonstrated that the pDNA loading capacity, lipoplex particle size, zeta potential and morphology of the sterol lipids/pDNA lipoplexes depended largely on the molecular structure factors including sterol-skeletons and headgroups. Furthermore, the sterol-based lipids showed quite different cytotoxicity and gene transfection efficacy in A549 and HeLa cells. Interestingly, it was found that the cholesterol-bearing lipids 1 and 2 showed 7-104 times higher transfection capability than their lithocholate-bearing counterparts 3 and 4 in A549 and HeLa cell lines, suggested that the gene transfection capacity strongly relied on the structure of sterol skeletons. Moreover, the study on the structure-activity relationships of these sterol-based cationic lipid gene carriers provided a possible approach for developing low cytotoxic and high efficient lipid gene carriers by selecting suitable sterol hydrophobes and cationic headgroups.
- Sheng, Ruilong,Luo, Ting,Li, Hui,Sun, Jingjing,Wang, Zhao,Cao, Amin
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- Orthogonal functionalisation of α-helix mimetics
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α-Helix mediated protein-protein interactions are of major therapeutic importance. As such, the design of inhibitors of this class of interaction is of significant interest. We present methodology to modify N-alkylated aromatic oligoamide α-helix mimetics using 'click' chemistry. The effect is shown to modulate the binding properties of a series of selective p53/hDM2 inhibitors. This journal is the Partner Organisations 2014.
- Barnard, Anna,Long, Kerya,Yeo, David J.,Miles, Jennifer A.,Azzarito, Valeria,Burslem, George M.,Prabhakaran, Panchami,A. Edwards, Thomas,Wilson, Andrew J.
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- The Mass Spectral Loss of Water from Macrocyclic Amino-ketones
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Macrocyclic oxo-lactams containing an N-alkylamino side chain are stable natural products.Their electronimpact mass spectra are characterized by intensive >M - H2O>(1+) signals, the molecular ion signal itself is missing.Under electospray ionization condi
- Benz, Herbert,Hesse, Manfred
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- 68Ga labeled Erlotinib: A novel PET probe for imaging EGFR over-expressing tumors
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Molecular imaging using radiolabeled Tyrosine Kinase Inhibitors (TKI) is a promising strategy for detection and staging of EGFR-positive cancers. A novel analogue of one such TKI, Erlotinib has been developed for PET imaging by derivatizing the parent Erl
- Jain, Akanksha,Kameswaran, Mythili,Pandey, Usha,Prabhash, Kumar,Sarma, Haladhar Dev,Dash, Ashutosh
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- Synthesis and biological studies of yohimbine derivatives on human α2C-adrenergic receptors
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A series of yohimbine derivatives was synthesized and evaluated for binding affinity at the human α2C-adrenergic receptors expressed in Chinese hamster ovary cells. It has been found that compound 5 shows a higher affinity for α2C-AR than the parent compound yohimbine 1, thereby illustrating that the nature of the linkers affect binding potencies on these receptors.
- Mustafa, Suni M.,Bavadekar, Supriya A.,Ma, Guoyi,Moore, Bob M.,Feller, Dennis R.,Miller, Duane D.
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- PYRROLOBENZODIAZEPINE DIMER PRECURSOR AND LIGAND-LINKER CONJUGATE COMPOUND THEREOF
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The present invention relates to a pyrrolobenzodiazepine dimer prodrug and a ligand-linker conjugate compound thereof, a composition containing these, and therapeutic use thereof particularly as an anticancer drug. The stability of the compounds themselves and the stability thereof in plasma are excellent and the compounds are advantageous in terms of manifestation of toxicity, and thus the compounds are industrially useful in that it is possible to target proliferative diseases such as cancer, to perform a specific treatment, to maximize the drug efficacy, and to minimize the occurrence of side effects.
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- Azido-Desferrioxamine Siderophores as Functional Click-Chemistry Probes Generated in Culture upon Adding a Diazo-Transfer Reagent
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This work aimed to undertake the in situ conversion of the terminal amine groups of bacterial desferrioxamine (DFO) siderophores, including desferrioxamine B (DFOB), to azide groups to enable downstream click chemistry. Initial studies trialed a precursor-directed biosynthesis (PDB) approach. Supplementing Streptomyces pilosus culture with blunt-end azido/amine non-native substrates designed to replace 1,5-diaminopentane as the native diamine substrate in the terminal amine position of DFOB did not produce azido-DFOB. Addition of the diazo-transfer reagent imidazole-1-sulfonyl azide hydrogen sulfate to spent S. pilosus medium that had been cultured in the presence of 1,4-diaminobutane, as a viable native substrate to expand the suite of native DFO-type siderophores, successfully generated the cognate suite of azido-DFO analogues. CuI-mediated or strain-promoted CuI-free click chemistry reactions between this minimally processed mixture and the appropriate alkyne-bearing biotin reagents produced the cognate suite of 1,4-disubstituted triazole-linked DFO-biotin compounds as potential molecular probes, detected as FeIII-loaded species. The amine-to-azide transformation of amine-bearing natural products in complex mixtures by the direct addition of a diazo-transfer reagent to deliver functional click chemistry reagents adds to the toolbox for chemical proteomics, chemical biology, and drug discovery.
- Gotsbacher, Michael P.,Codd, Rachel
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p. 1433 - 1445
(2020/02/27)
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- Modular RNA regulators and methods
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This disclosure describes modular miRNA regulator molecules and methods of using modular miRNA regulator molecules. Generally, the modular miRNA regulator molecules include a recognition module and an inhibition module. Generally, the recognition module includes a polynucleotide in which at least a portion of the polynucleotide recognizes at least a portion of a preselected pre-miRNA. Generally, the inhibition module includes a moiety that inhibits nuclease processing of the preselected pre-RNA to a mature RNA.
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- CONJUGATES COMPRISING SELF-IMMOLATIVE GROUPS AND METHODS RELATED THERETO
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In some aspects, the invention relates to an antibody-drug conjugate, comprising an antibody; a linker; and an active agent. The antibody-drug conjugate may comprise a self- immolative group. The linker may comprise an O-substituted oxime, e.g., wherein the oxygen atom of the oxime is substituted with a group that covalently links the oxime to the active agent; and the carbon atom of the oxime is substituted with a group that covalently links the oxime to the antibody.
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(2017/06/27)
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- COMPOSITIONS AND METHODS RELATED TO ANTI-CD19 ANTIBODY DRUG CONJUGATES
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In some aspects, the invention relates to an antibody-drug conjugate, comprising an anti-CD 19 antibody; a linker; and an active agent. The antibody-drug conjugate may comprise a self-immolative group. The linker may comprise an O-substituted oxime, e.g., wherein the oxygen atom of the oxime is substituted with a group that covalently links the oxime to the active agent; and the carbon atom of the oxime is substituted with a group that covalently links the oxime to the antibody.
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- COMPOSITIONS AND METHODS RELATED TO ANTI-EGFR ANTIBODY DRUG CONJUGATES
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In some aspects, the invention relates to an antibody-drug conjugate, comprising an anti-epidermal growth factor receptor ("EGFR") antibody; a linker; and an active agent. The antibody-drug conjugate may comprise a self-immolative group. The linker may comprise an O-substituted oxime, e.g., wherein the oxygen atom of the oxime is substituted with a group that covalently links the oxime to the drug; and the carbon atom of the oxime is substituted with a group that covalently links the oxime to the antibody.
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- CONJUGATES COMPRISING PEPTIDE GROUPS AND METHODS RELATED THERETO
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In some aspects, the invention relates to an antibody-drug conjugate, comprising an antibody; a linker; and at least two active agents. In preferred embodiments, the linker comprises a peptide sequence of a plurality of amino acids, and at least two of the active agents are covalently coupled to side chains of the amino acids. The antibody-drug conjugate may comprise a self-immolative group, preferably two-self-immolative groups. The linker may comprise an O-substituted oxime, e.g., wherein the oxygen atom of the oxime is substituted with a group that covalently links the oxime to the active agent; and the carbon atom of the oxime is substituted with a group that covalently links the oxime to the antibody.
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- Design and synthesis of dendrimers with facile surface group functionalization, and an evaluation of their bactericidal efficacy
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We report a versatile divergent methodology to construct dendrimers from a tetrafunctional core, utilizing the robust copper(I) catalyzed alkyne-azide cycloaddition (CuAAC, "click") reaction for both dendrimer synthesis and post-synthesis functionalization. Dendrimers of generations 1-3 with 8-32 protected or free OH and acetylene surface groups, were synthesized using building blocks that included acetylene- or azide-terminated molecules with carboxylic acid or diol end groups, respectively. The acetylene surface groups were subsequently used to covalently link cationic amino groups. A preliminary evaluation indicated that the generation one dendrimer with terminal NH3+ groups was the most effective bactericide, and it was more potent than several previously studied dendrimers. Our results suggest that size, functional end groups and hydrophilicity are important parameters to consider in designing efficient antimicrobial dendrimers.
- Ladd, Elizabeth,Sheikhi, Amir,Li, Na,Van De Ven, Theo G.M.,Kakkar, Ashok
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- Structure-based design and synthesis of triazole-based macrocyclic inhibitors of norovirus protease: Structural, biochemical, spectroscopic, and antiviral studies
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Outbreaks of acute gastroenteritis caused by noroviruses constitute a public health concern worldwide. To date, there are no approved drugs or vaccines for the management and prophylaxis of norovirus infections. A potentially effective strategy for the development of norovirus therapeutics entails the discovery of inhibitors of norovirus 3CL protease, an enzyme essential for noroviral replication. We describe herein the structure-based design of the first class of permeable, triazole-based macrocyclic inhibitors of norovirus 3C-like protease, as well as pertinent X-ray crystallographic, biochemical, spectroscopic, and antiviral studies.
- Weerawarna, Pathum M.,Kim, Yunjeong,Kankanamalage, Anushka C. Galasiti,Damalanka, Vishnu C.,Lushington, Gerald H.,Alliston, Kevin R.,Mehzabeen, Nurjahan,Battaile, Kevin P.,Lovell, Scott,Chang, Kyeong-Ok,Groutas, William C.
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p. 300 - 318
(2016/07/06)
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- COMPOUNDS COMPRISING SELF-IMMOLATIVE GROUP
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Provided are compounds comprising a self-immolative group, and the compounds comprising a self-immolative group according to the present invention may include a protein (for example, an oligopeptide, a polypeptide, an antibody, or the like) having substrate-specificity for a target and an active agent (for example, a drug, a toxin, a ligand, a detection probe, or the like) having a specific function or activity.
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- Synthesis, biological activity and structural study of new benzotriazole-based protein kinase CK2 inhibitors
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A new series of 4,5,6,7-tetrabromobenzotriazole (TBB) derivatives was synthesized and characterized as CK2 inhibitors. They were readily synthesized using a click chemistry approach based on a Cu(i)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC). Some of the synthesized compounds present interesting inhibitory activities using an in vitro assay, with Ki values in the low micro molar range and a high degree of selectivity against a panel of 24 kinases. Selected compounds were tested for their antiproliferative effect on several cancer cell lines, and for their proapoptotic activity towards human Jurkat T-leukemia and MCF-7 breast adenocarcinoma cells, showing that they can be proposed as promising anticancer agents. Docking studies as well as crystallographic analysis allowed us to identify ligand-CK2 interactions that account for the molecular recognition process, and can help to further optimize this family of compounds as CK2 inhibitors.
- Swider,Maslyk,Zapico,Coderch,Panchuk,Skorokhyd,Schnitzler,Niefind,De Pascual-Teresa,Ramos
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p. 72482 - 72494
(2015/09/15)
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- Selective and potent proteomimetic inhibitors of intracellular protein-protein interactions
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Inhibition of protein-protein interactions (PPIs) represents a major challenge in chemical biology and drug discovery. α-Helix mediated PPIs may be amenable to modulation using generic chemotypes, termed "proteomimetics", which can be assembled in a modul
- Barnard, Anna,Long, Krya,Martin, Heather L.,Miles, Jennifer A.,Edwards, Thomas A.,Tomlinson, Darren C.,Macdonald, Andrew,Wilson, Andrew J.
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supporting information
p. 2960 - 2965
(2015/06/02)
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- SUBSTITUTED TRIAZOLE AND IMIDAZOLE COMPOUNDS
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The invention is concerned with the compounds of formula (I): and pharmaceutically acceptable salts thereof. In addition, the present invention relates to methods of manufacturing and using the compounds of formula (I) as well as pharmaceutical compositions containing such compounds. The compounds of formula (I) are LMP7 inhibitors and may be useful in treating associated inflammatory diseases and disorders such as, for example, rheumatoid arthritis, lupus and irritable bowel disease.
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Page/Page column 71
(2014/06/24)
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- Macrocyclic inhibitors of 3C and 3C-like proteases of picornavirus, norovirus, and coronavirus
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The design, synthesis, and in vitro evaluation of the first macrocyclic inhibitor of 3C and 3C-like proteases of picornavirus, norovirus, and coronavirus are reported. The in vitro inhibitory activity (50% effective concentration) of the macrocyclic inhibitor toward enterovirus 3C protease (CVB3 Nancy strain), and coronavirus (SARS-CoV) and norovirus 3C-like proteases, was determined to be 1.8, 15.5 and 5.1 μM, respectively.
- Mandadapu, Sivakoteswara Rao,Weerawarna, Pathum M.,Prior, Allan M.,Uy, Roxanne Adeline Z.,Aravapalli, Sridhar,Alliston, Kevin R.,Lushington, Gerald H.,Kim, Yunjeong,Hua, Duy H.,Chang, Kyeong-Ok,Groutas, William C.
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p. 3709 - 3712
(2013/07/27)
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- Regioselective rapid synthesis of fully substituted 1,2,3-triazoles mediated by propargyl cations
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Regioselective rapid triazole syntheses at low temperature are described. Organic azides and propargyl cations generated by acids gave fully substituted 1H-1,2,3-triazoles. Most reactions could be performed in 5 min at not only rt but also -90 C. Both terminal and internal alkynes were acceptable, and the sterically bulky substituents could afford the products smoothly. Various types of three-component coupling reactions were demonstrated, and the presence of allenylaminodiazonium intermediates was indicated.
- Zhang, Huan,Tanimoto, Hiroki,Morimoto, Tsumoru,Nishiyama, Yasuhiro,Kakiuchi, Kiyomi
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p. 5222 - 5225
(2013/11/06)
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- MACROCYCLIC AND PEPTIDOMIMETIC COMPOUNDS AS BROAD-SPECTRUM ANTIVIRALS AGAINST 3C OR 3C-LIKE PROTEASES OF PICORNAVIRUSES, CALICIVIRUSES AND CORONAVIRUSES
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Antiviral protease inhibitors, including macrocylic transition state inhibitors and peptidomimetics are disclosed, along with related antiviral compounds, and methods of using the same to treat or prevent viral infection and disease. The compounds possess broad-spectrum activity against viruses that belong to the picornavirus-like supercluster, which include important human and animal pathogens including noroviruses, sapoviruses, enteroviruses, poliovirus, foot-and-mouth disease virus, hepatitis A virus, human rhinovirus (cause of common cold), human coronavirus (another cause of common cold), transmissible gastroenteritis virus, murine hepatitis virus, feline infectious peritonitis virus, and severe acute respiratory syndrome coronavirus.
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- A bimolecular micelle constructed from amphiphilic pillar[5]arene molecules
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An amphiphilic macrocycle based on pillar[5]arene with polar lysine head groups spontaneously self-assembles into a bimolecular micelle in water. This self-assembled structure was characterized by small angle X-ray scattering (SAXS), field flow fluctuation coupled with multi-angle light scattering (FFF-MALS) and atomic force microscopy (AFM). The self-assembly of amphiphilic pillar[5]arene into dimeric spherical micelles represents a new molecular architecture for micelle formation. The Royal Society of Chemistry.
- Nishimura, Tomoki,Sanada, Yusuke,Matsuo, Takuma,Okobira, Tadashi,Mylonas, Efstratios,Yagi, Naoto,Sakurai, Kazuo
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supporting information
p. 3052 - 3054
(2013/05/23)
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- Tetrahydroquinoline Derivatives And Their Pharmaceutical Use
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Tetrahydroquinoline compounds of formula (I) and salts thereof, pharmaceutical compositions containing such compounds and their use in therapy.
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(2012/08/28)
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- TETRAHYDROQUINOLINE DERIVATIVES AND THEIR PHARMACEUTICAL USE
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Tetrahydroquinoline compounds of Formula (I) and salts thereof, pharmaceutical compositions containing such compounds and their use in therapy.
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Page/Page column 78-79
(2011/06/11)
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- Degradable self-assembling dendrons for gene delivery: Experimental and theoretical insights into the barriers to cellular uptake
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This paper uses a combined experimental and theoretical approach to gain unique insight into gene delivery. We report the synthesis and investigation of a new family of second-generation dendrons with four triamine surface ligands capable of binding to DN
- Barnard, Anna,Posocco, Paola,Pricl, Sabrina,Calderon, Marcelo,Haag, Rainer,Hwang, Mark E.,Shum, Victor W. T.,Pack, Daniel W.,Smith, David K.
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supporting information; scheme or table
p. 20288 - 20300
(2012/02/05)
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- Efficient synthesis of fluorescent squaraine rotaxane dendrimers
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Chemical Equation Presented A squaraine rotaxane scaffold with four alkyne groups is readily converted into a range of dendritic architectures using high-yielding coppercatalyzed alkyne azide cycloaddition (CuAAC) chemistry. A convergent synthesis approach is more efficient than a divergent pathway. Dendritic squaraine rotaxanes with peripheral amine groups can be further functionalized to produce multivalent deep-red fluorescent derivatives that exhibit high brightness and outstanding chemical stability in biological solution. The surface groups on these functionalized fluorescent dendrimers include guanidinium, mannose, and phosphatidylcholine.
- Xiao, Shuzhang,Fu, Na,Peckham, Kaitlin,Smith, Bradley D.
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supporting information; experimental part
p. 140 - 143
(2010/03/05)
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- Yohimbine derivatives and use thereof
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Yohimbine derivatives are disclosed having modification of the C-16 carboxyl group to include a sidechain and where the resulting derivative does not possess a second yohimbine pharmacophore (i.e., the compound is not a yohimbine dimer). The yohimbine derivatives of the present invention are preferably characterized by selective activity as α2c-AR antagonists. Use of the compounds, or pharmaceutical composition containing them, for treating or preventing an α2c adrenergic receptor mediated condition or disorder, and for antagonizing activity of an α2c adrenergic receptor are also disclosed.
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Page/Page column Sheet 1 of 9
(2009/01/24)
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- NOVEL AZALIDE AND AZALACTAM DERIVATIVES AND PROCESS FOR THE PRODUCTION OF THE SAME
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A compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof, which is useful for a prophylactic and/or therapeutic treatment of a microbial infectious disease. [R1 is hydrogen atom, or a linear C1-6 alkylcarbonyl group; R2 is hydrogen atom, or a C1-6 alkylcarbonyl group; R3 is hydrogen atom, a C1-6 alkyl group, a C1-6 alkylcarbonyl group, a C1-6 alkenyl group, a C2-6 alkenylcarbonyl group, a C2-6 alkynyl group, or an Ar-B- group (Ar represents an aryl group, or a heterocyclic group, and B is a C1-6 alkyl group, a C1-6 alkylcarbonyl group, a C2-6 alkenyl group, a C2-6 alkenylcarbonyl group, or a C2-6 alkynyl group); R5, R6, R7, and R8 represent hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, or an Ar-B'- group (B' is a C1-6 alkyl group, a C2-6 alkenyl group, or a C2-6 alkynyl group); X is oxygen atom, or an -NR4- group (R4 is hydrogen atom, a C1-6 alkyl group, or a C1-6 alkyl group which may be substituted with an Ar group); and R4' is hydrogen atom, or a group represented by the aforementioned formula (a) (R3" and R4" represent hydrogen atom, or a linear or branched C1-6 alkylcarbonyl group)]
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Page/Page column 30
(2010/11/08)
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- Curtius rearrangement of ω-azido acid chlorides: Access to the corresponding ω-azido substituted amines and carbamates, useful building blocks for polyamine syntheses
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Treatment of ω-azido acid chlorides with trimethylsilyl azide affords ω-azido isocyanates which can be easily converted in good yields to the corresponding ω-azidoamines or ω-azidocarbamates. 1,3- and 1,4-diamine dihydrochlorides can then be prepared by catalytic hydrogenation or reductive alkylation with an organodichloroborane.
- Khoukhi, Mostafa,Vaultier, Michel,Benalil, Aziza,Carboni, Bertrand
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p. 483 - 487
(2007/10/03)
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- Mono-Protected Diamines. Nα-tert-Butoxycarbonyl α,ω-Alkanediamine Hydrochlorides from Amino alcohols.
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Nα-tert-Butoxycarbonyl α,ω-alkanediamine hydrochlorides 3a-e are prepared from the amino alcohols in yields of 66-87percent.Reaction of the free amine with di-tert-butyl dicarbonate gives the N-tert-Butoxycarbonylamino alcohol 1a-e.One-pot conversion to the azide 2a-e via the mesylate under phase-transfer conditions followed by hydrogenolysis in the presence of chloroform yields the title compounds.
- Mattingly, Phillip G.
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p. 366 - 368
(2007/10/02)
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