- Allosteric Guest Binding in Chiral Zirconium(IV) Double Decker Porphyrin Cages
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Chiral zirconium(IV) double cage sandwich complex Zr(1)2 has been synthesized in one step from porphyrin cage H21. Zr(1)2 was obtained as a racemate, which was resolved by HPLC and the enantiomers were isolated in >99.5 % ee. Their absolute configurations were assigned on the basis of X-ray crystallography and circular dichroism spectroscopy. Vibrational circular dichroism (VCD) experiments on the enantiomers of Zr(1)2 revealed that the chirality around the zirconium center is propagated throughout the whole cage structure. The axial conformational chirality of the double cage complex displayed a VCD fingerprint similar to the one observed previously for a related chiral cage compound with planar and point chirality. Zr(1)2 shows fluorescence, which is quenched when viologen guests bind in its cavities. The binding of viologen and dihydroxybenzene derivatives in the two cavities of Zr(1)2 occurs with negative allostery, the cooperativity factors α (=4 K2/K1) being as low as 0.0076 for the binding of N,N’-dimethylviologen. These allosteric effects are attributed to a pinching of the second cavity as a result of guest binding in the first cavity.
- Bruekers, Jeroen P. J.,Hellinghuizen, Matthijs A.,Vanthuyne, Nicolas,Tinnemans, Paul,Gilissen, Pieter J.,Buma, Wybren Jan,Naubron, Jean-Valère,Crassous, Jeanne,Elemans, Johannes A. A. W.,Nolte, Roeland J. M.
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supporting information
p. 607 - 617
(2021/01/18)
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- Synthesis of the Common Monomeric Unit of Uroleuconaphins and Viridaphins via Hauser-Kraus Annulation
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A stereoselective synthesis of a pyranonaphthoquinone derivative found in aromatic polyketide-derived aphid pigments is reported herein. This approach features the anionic [4+2]-annulation of phthalides with a carbohydrate-derived optically active enone.
- Kitamura, Kei,Kanagawa, Hinano,Ozakai, Chiharu,Nishimura, Taichi,Tokuda, Hayato,Tsunoda, Tetsuto,Kaku, Hiroto
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p. 1629 - 1635
(2021/01/25)
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- Biological Characterization, Mechanistic Investigation and Structure-Activity Relationships of Chemically Stable TLR2 Antagonists
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Toll-like receptors (TLRs) build the first barrier in the innate immune response and therefore represent promising targets for the modulation of inflammatory processes. Recently, the pyrogallol-containing TLR2 antagonists CU-CPT22 and MMG-11 were reported; however, their 1,2,3-triphenol motif renders them highly susceptible to oxidation and excludes them from use in extended experiments under aerobic conditions. Therefore, we have developed a set of novel TLR2 antagonists (1–9) based on the systematic variation of substructures, linker elements, and the hydrogen-bonding pattern of the pyrogallol precursors by using chemically robust building blocks. The novel series of chemically stable and synthetically accessible TLR2 antagonists (1–9) was pharmacologically characterized, and the potential binding modes of the active compounds were evaluated structurally. Our results provide new insights into structure-activity relationships and allow rationalization of structural binding characteristics. Moreover, they support the hypothesis that this class of TLR ligands bind solely to TLR2 and do not directly interact with TLR1 or TLR6 of the functional heterodimer. The most active compound from this series (6), is chemically stable, nontoxic, TLR2-selective, and shows a similar activity with regard to the pyrogallol starting points, thus indicating the variability of the hydrogen bonding pattern.
- Bermudez, Marcel,Grabowski, Maria,Murgueitio, Manuela S.,Rademann, J?rg,Rudolf, Thomas,Tiemann, Markus,Varga, Péter,Weindl, Günther,Wolber, Gerhard
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- Discovery of KLS-13019, a Cannabidiol-Derived Neuroprotective Agent, with Improved Potency, Safety, and Permeability
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Cannabidiol is the nonpsychoactive natural component of C. sativa that has been shown to be neuroprotective in multiple animal models. Our interest is to advance a therapeutic candidate for the orphan indication hepatic encephalopathy (HE). HE is a serious neurological disorder that occurs in patients with cirrhosis or liver failure. Although cannabidiol is effective in models of HE, it has limitations in terms of safety and oral bioavailability. Herein, we describe a series of side chain modified resorcinols that were designed for greater hydrophilicity and "drug likeness", while varying hydrogen bond donors, acceptors, architecture, basicity, neutrality, acidity, and polar surface area within the pendent group. Our primary screen evaluated the ability of the test agents to prevent damage to hippocampal neurons induced by ammonium acetate and ethanol at clinically relevant concentrations. Notably, KLS-13019 was 50-fold more potent and >400-fold safer than cannabidiol and exhibited an in vitro profile consistent with improved oral bioavailability.
- Kinney, William A.,McDonnell, Mark E.,Zhong, Hua Marlon,Liu, Chaomin,Yang, Lanyi,Ling, Wei,Qian, Tao,Chen, Yu,Cai, Zhijie,Petkanas, Dean,Brenneman, Douglas E.
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supporting information
p. 424 - 428
(2016/05/19)
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- NOVEL FUNCTIONALIZED 1,3-BENZENE DIOLS AND THEIR METHOD OF USE FOR THE TREATMENT OF HEPATIC ENCEPHALOPTHY
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Pharmaceutical compositions of the invention include novel functionalized 1,3-benzenediols having a disease-modifying action in the treatment of hepatic encephalopathy and related conditions. Pharmaceutical compositions of the invention further include novel neuroprotective agents.
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Paragraph 0333
(2016/11/14)
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- NOVEL FUNCTIONALIZED 1,3-BENZENE DIOLS AND THEIR METHOD OF USE FOR THE TREATMENT OF HEPATIC ENCEPHALOPATHY
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Pharmaceutical compositions of the invention include novel functionalized 1,3-benzenediols having a disease-modifying action in the treatment of hepatic encephalopathy and related conditions. Pharmaceutical compositions of the invention further include novel neuroprotective agents.
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Paragraph 0295
(2015/07/23)
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- COMPOSITIONS AND METHODS FOR GLUCOSE TRANSPORT INHIBITION
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Glucose deprivation is an attractive strategy in cancer research and treatment. Cancer cells upregulate glucose uptake and metabolism for maintaining accelerated growth and proliferation rates. Specifically blocking these processes is likely to provide new insights to the role of glucose transport and metabolism in tumorigenesis, as well as in apoptosis. As solid tumors outgrow the surrounding vasculature, they encounter microenvironments with a limited supply of nutrients leading to a glucose deprived environment in some regions of the tumor. Cancer cells living in the glucose deprived environment undergo changes to prevent glucose deprivation-induced apoptosis. Knowing how cancer cells evade apoptosis induction is also likely to yield valuable information and knowledge of how to overcome the resistance to apoptosis induction in cancer cells. Disclosed herein are novel anticancer compounds that inhibit basal glucose transport, resulting in tumor suppression and new methods for the study of glucose deprivation in animal cancer research.
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-
Page/Page column 27-28
(2011/10/13)
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- Chemical synthesis and evaluation of 17α-alkylated derivatives of estradiol as inhibitors of steroid sulfatase
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Steroid sulfatase (STS) controls the levels of 3-hydroxysteroids available from circulating steroid sulfates in several normal and malignant tissues. This and the known involvement of active estrogens and androgens in diseases such as breast and prostate cancers thus make STS an interesting therapeutic target. Here we describe the chemical synthesis and characterization of an extended series of 17α-derivatives of estradiol (E2) using different strategies. A variant of the samarium-Barbier reaction with stoichiometric samarium metal and catalytic Kagan reagent formation was used for introducing low reactive benzyl substrates in position 17 of estrone (E1) whereas heterocyclic substrates were metalated and reacted with either the carbonyl or the 17-oxirane of E1. In vitro evaluation of the inhibitory potency of the new compounds against STS identified new inhibitors and allowed a more complete structure-activity relationship study of this family of 17α-derivatives of E2.
- Fournier, Diane,Poirier, Donald
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experimental part
p. 4227 - 4237
(2011/11/12)
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- Studies of microwave-enhanced Suzuki-Miyaura vinylation of electron-rich sterically hindered substrates utilizing potassium vinyltrifluoroborate
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The Suzuki-Miyaura cross-coupling of sterically hindered and electron-rich ortho,ortho′-substituted aryl halides with potassium vinyltrifluoroborate utilizing microwave irradiation has been conducted while adjusting solvent ratio, irradiation time, and catalyst loading to find optimal conditions. Coupling of benzyl 3,5-bis(benzyloxy)-4-bromobenzoate leads to a mixture of the desired styrene derivative and the reduced product. 4-Bromo-1,3,5- trimethoxybenzene, methyl 4-bromo-3,5-dimethoxybenzoate, and mesitylene bromide were also coupled to test the breadth and scope of this methodology. Of these substrates tested only 4-bromo-1,3,5-trimethoxybenzene was not vinylated successfully, which is believed to be due to the electron-rich nature of this system.
- Brooker, Matthew D.,Cooper Jr., Stefan M.,Hodges, Dena R.,Carter, Rhiannon R.,Wyatt, Justin K.
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experimental part
p. 6748 - 6752
(2011/02/25)
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- Novel inhibitors of basal glucose transport as potential anticancer agents
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Cancer cells commonly show increased levels of glucose uptake and dependence. A potential strategy for the treatment of cancer may be the inhibition of basal glucose transport. We report here the synthesis of a small library of polyphenolic esters that inhibit basal glucose transport in H1299 lung and other cancer cells. These basal glucose transport inhibitors also inhibit cancer cell growth in H1299 cells, and these two activities appear to be correlated.
- Zhang, Weihe,Liu, Yi,Chen, Xiaozhuo,Bergmeier, Stephen C.
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scheme or table
p. 2191 - 2194
(2010/06/15)
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- Efficient total synthesis of piceatannol via (e)-selective wittig-horner reaction
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Efficient and practical total synthesis of piceatannol via (E)-selective Wittig-Horner reaction is demonstrated with six steps in overall 40% yield from a commercially available, cheap starting material, 3,5-dihydroxybenzoic acid. Wittig-Horner reaction o
- Young Han, Su,Suck Lee, Hyun,Hye Choi, Da,Woon Hwang, Jung,Mo Yang, Deok,Jun, Jong-Gab
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experimental part
p. 1425 - 1432
(2009/09/30)
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- Initial investigation into the Suzuki-Miyaura vinylation of hindered aryl bromides utilizing potassium vinyltrifluoroborate
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An initial study of the Suzuki-Miyaura cross-coupling of potassium vinyltrifluoroborate (2) and hindered aryl bromides is presented. Coupling of benzyl 3,5-bis(benzyloxy)-4-bromobenzoate (1) leads to a mixture of the desired styrene derivative, and the reduced product.
- Carter, Rhiannon R.,Wyatt, Justin K.
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p. 6091 - 6094
(2007/10/03)
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- Synthesis of a tetrasubstituted arylphosphonate via the anionic phospho-Fries rearrangement
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The anionic phospho-Fries rearrangement of phosphoric acid (3,5-di-isopropoxy)phenyl ester diethyl ester (11) gave rise to (2-hydroxy-4,6-di-isopropoxy-phenyl)phosphonic acid diethyl ester (12) in excellent yield. The phenol functionality of 12 was converted to the corresponding triflate which was coupled with vinyltributylstannane, under Stille conditions, to give a styrene. This molecule is intended to serve as the aromatic fragment in the synthesis of a phosphorus-based transition-state analogue for the hydrolysis of the S-(-)-zearalenone lactone.
- Jayasundera, Krishanthi P.,Watson, Amy J.,Taylor, Carol M.
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p. 4311 - 4313
(2007/10/03)
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- Synthesis of a piceatannol analog: Replacement of hydroxy group with amide functionality
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Polyhydroxylated stilbene analogs of piceatannol are shown to possess protein-tyrosine kinase (PTK) inbibitory activity. We have developed a novel approach to introduce an amide moiety into the structure of piceatannol. The amido substituted stilbene deri
- Venkatachalam,Huang,Yu,Uckun
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p. 1489 - 1497
(2007/10/03)
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- Synthesis of resveratrol using a direct decarbonylative Heck approach from resorcylic acid
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The phytoalexin resveratrol has been made using a decarbonylative Heck reaction. The acid chloride derived from 3,5-dihydroxybenzoic acid was coupled with 4-acetoxystyrene in the presence of palladium acetate and N,N-bis-(2,6-diisopropylphenyl)dihydroimidazolium chloride to give the substituted stilbene in 73% yield as the key step.
- Andrus, Merritt B.,Liu, Jing,Meredith, Erik L.,Nartey, Edward
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p. 4819 - 4822
(2007/10/03)
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- Solid-phase synthesis using (Allyloxy)carbonyl(Alloc) chemistry of a putative heptapeptide intermediate in vancomycin biosynthesis containing m-chloro-3-hydroxytyrosine
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A convenient method for the solid-phase synthesis of putative linear heptapeptide intermediates in vancomycin biosynthesis is described, in particular, the heptapeptide D-Leu-Cyt-L-Asn-Hpg-Hpg-Cyt'-Dhpg (Cyt = (2R,3R)-m-chloro-3-hydroxytyrosine, Hpg = (R)-2-(p-hydroxyphenyl)glycine, Cyt' = (2S,3R)-m-chloro-3-hydroxytyrosine and Dhpg = (S)-2-(3,5-dihydroxyphenyl)glycine). The synthesis was performed on chlorotrityl resin and employed the (allyloxy)carbonyl protecting group for temporary N(α) protection during peptide-chain assembly.
- Freund, Ernst,Vitali, Francesca,Linden, Anthony,Robinson, John A.
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p. 2572 - 2579
(2007/10/03)
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- Synthesis of polyester dendrimers
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Phloroglucinol 4, hydroqulnone 5 and naphthalene-2,6-diol 6 react with the monomer 2, activated either by 1,3-dicyclohexylcarbodiimide (DCC) or as its acid chloride 3. Hydrogenolysis of the benzyl protecting groups, followed by repetition of these procedures leads, divergently, to three series of analytically pure aryl polyester dendrimers in high yields. The de Gennes limit appears to lie between generations three and four with the three-branched initiator core 4 and between generations four and five with the two-branched cores 5 and 6.
- Haddleton, David M.,Sahota, Hardeep S.,Taylor, Paul C.,Yeates, Stephen G.
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p. 649 - 656
(2007/10/03)
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- Monodispersed Dendritic Polyesters with Removable Chain Ends: a Versatile Approach to Globular Macromolecules with Chemically Reversible Polarities
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A versatile approach to dendritic macromolecules with aromatic polyester inner structure and a readily modified hydrophobic/hydrophilic "surface" is described.The polyester fragments are prepared by a convergent growth process involving 3,5-bis(benzyloxy)benzoic acid as the "surface" or chain-ending moiety and trichloroethyl 3,5-dihydroxybenzoate as the monomer unit.The key esterification step is accomplished in high yield using dicyclohexylcarbodiimide and 4-dimethylaminopyridinium toluene-p-sulfonate as condensing agents.The coupling step is followed by activation of the new focal point by removal of the trichloroethyl ester group with zinc-acetic acid.Repetition of this two-step process leads to large dendritic fragments that may be coupled to a polyfunctional core to complete the dendritic macromolecule.The chemistry chosen for this synthesis allows for subsequent selective removal of the numerous benzyl ether chain ends by hydrogenolysis to afford a dendritic macromolecule with phenolic chain ends.Further modification of the chain ends is readily accomplished in processes that effectively transform the initially hydrophobic dendritic molecule into one that is both hydrophilic and water-soluble.These transformations of the "surface" functionalities are also accompanied by drastic changes in glass transition behaviour.
- Hawker, Craig J.,Frechet, Jean M. J.
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p. 2459 - 2470
(2007/10/02)
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- One-Step Synthesis of Hyperbranched Dendritic Polyesters
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The one-step synthesis of a hyperbranched polyester possessing a dendritic structure has been achieved by thermal self-condensation of 3,5-bis(trimethylsiloxy)benzoyl chloride. The hyperbranched polyesters are obtained in yields of 80% or greater and with polystyrene equivalent weight average molecular weights in the range 30 000 to almost 200 000. The polydispersity and the molecular weights of the polyesters were found to vary greatly with the temperature of the polymerization. Characterization of the polymers was readily accomplished by NMR spectroscopy with the help of model compounds. The degree of branching of the polyesters as determined from NMR experiments was between 55 and 60%. The polyesters, which contain reactive functional groups at all chain extremities, are glassy materials that show a very high thermal stability comparable to that of analogous linear materials. In contrast, the excellent solubility properties of the hyperbranched polyesters influenced by their shape and functionalization are at variance with those of their linear polyester analogues.
- Hawker,Lee,Fréchet
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p. 4583 - 4588
(2007/10/02)
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- Synthesis of Bikaverin
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The total synthesis of bikaverin (1b) is described, from everninic acid (5) and 3,5-dihydrobenzoic acid (6).Dieckmann condensation of methyl 2-acetyl-3,5-bis(benzyloxy)phenylacetate (14), synthesised from (6), followed by treatment with protected everninic acid chloride (9) gave 1,3-bisbenzyloxy-6,8-bis(2-benzyloxy-4-methoxy-6-methylbenzyloxy)naphthalene (16).Photoinduced Fries rearrangement of (16) afforded 1,3-bis(benzyloxy)-7-(2-benzyloxy-4-methoxy-6-methylbenzoyl)-6-(2-benzyloxy-4-methoxy-6-methylbenzoyloxy)-8-hydroxynaphthalene (23).Ring closure of (23) with tetramethylammonium hydroxide in pyridine gave the angular benzoxanthene, 1,3-bis(benzyloxy-6-hydroxy)-10-methoxy-8-methylbenzoxanthen-7-one (25), which was oxidized with potassium dichromate to give the orthoquinone, 1,3-bis(benzyloxy)-10-methoxy-8-methylbenzoxanthen-5,6,7-trione (28).By a novel type of rearrangement, (28) was transformed into the linear benzoxanthen, 8,10-bis(benzyloxy)-3-methoxy-1-methylbenzoxanthen-6,11,12-trione (29) by treatment with silica gel.Oxidation and debenzylation of (29) with manganese dioxide in concentrated H2SO4 gave norbikaverin (1a).
- Katagiri, Nobuya,Nakano, Jun,Kato, Tetsuzo
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p. 2710 - 2716
(2007/10/02)
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