- 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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Read Online
- Synthesis of alternating polystyrene/poly(ethyleneoxide) branched polymacromonomers
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Newly designed PS/PEO alternating branched polymacromonomers have been obtained by polycondensation of α-dicarboxy-functionalized polystyrene and α-dihydroxy-functionalized polyethyleneoxide. 4-[3,5-Bis-(methoxycarbonyl)phenoxymethyl]benzyl bromide was used as atom-transfer radical polymerization (ATRP) initiator for the synthesis of α-dicarboxy functionalized polystyrenes. These macromonomers possess low polydispersities and molecular weights in the range of 7000 to 100000, as proved by gel permeation chromatography (GPC) and 1H NMR. α-Dihydroxy functionalized polyethyleneoxide (PEO) was synthesized by treatment of monofunctionalized PEO with 3,5-bis(benzyloxy)benzoyl chloride. Polycondensation of the α-dicarboxy PS with the α-dihydroxy PEO in solution or in bulk resulted in alternating PS/PEO polymacromonomers, which were effectively purified from the unreacted macromonomers and characterized by using 1H NMR, GPC, thermal analysis, and optical microscopy. Light-scattering measurements in organic solvents like THF or dioxane have shown that these polymacromonomers form stable micelles.
- Deimede, Valadoula,Kallitsis, Joannis K.
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Read Online
- 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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- Synthesis and comparative structure-activity study of carbohydrate-based phenolic compounds as α-glucosidase inhibitors and antioxidants
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Twenty-one natural and unnatural phenolic compounds containing a carbohydrate moiety were synthesized and their structure-activity relationship (SAR) was evaluated for α-glucosidase inhibition and antioxidative activity. Varying the position of the galloyl unit on the 1,5-anhydro -D-glucitol (1,5-AG) core resulted in changes in the α-glucosidase inhibitory activity and notably, particularly strong activity was demonstrated when the galloyl unit was present at the C-2 position. Furthermore, increasing the number of the galloyl units significantly affected the α-glucosidase inhibition, and 2,3,4,6-tetra-galloyl-1,5-AG (54) and 2,3,4,6-tetra-galloyl-d-glucopyranose (61) exhibited excellent activities, which were more than 13-fold higher than the α-glucosidase inhibitory activity of acertannin (37). Moreover, a comparative structure-activity study suggested that a hemiacetal hydroxyl functionality in the carbohydrate core and a biaryl bond of the 4,6-O-hexahydroxydiphenoyl (HHDP) group, which are components of ellagitannins including tellimagrandin I, are not necessary for the α-glucosidase inhibitory activity. Lastly, the antioxidant activity increased proportionally with the number of galloyl units.
- MacHida, Shota,Mukai, Saki,Kono, Rina,Funato, Megumi,Saito, Hiroaki,Uchiyama, Taketo
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- Synthesis, structure activity relationship and in vitro anti-influenza virus activity of novel polyphenol-pentacyclic triterpene conjugates
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It is urgently necessary to develop more effective anti-influenza agents due to the continuous emergence of drug-resistant strains of influenza virus. Our earlier studies have identified that certain pentacyclic triterpene derivatives are effective inhibitors of influenza virus infection. In the present study, a series of C-28 modified pentacyclic triterpene derivatives via conjugation with a series of polyphenols were synthesized, and their antiviral activities against influenza A/WSN/33 (H1N1) virus in MDCK (Madin-Darby canine kidney) cells were evaluated. Four compounds 23m, 23o, 23q and 23s displayed robust anti-influenza potency with averaged IC50 values at the low-micromole level, surpassing the potency of oseltamivir. In addition, the in vitro cytotoxic activity of the four conjugates against MDCK cells showed no toxicity at 100 μM. Further mechanism studies of compound 23s, one of the best representative conjugates with IC50 value of 5.80 μM and a selective index (SI) value of over 17.2, by hemagglutination inhibition (HI), surface plasmon resonance and molecular modeling indicated that this conjugate bound tightly to the viral envelope hemagglutinin (KD = 15.6 μM), thus blocking the invasion of influenza viruses into host cells.
- Li, Haiwei,Li, Man,Xu, Renyang,Wang, Shouxin,Zhang, Yongmin,Zhang, Lihe,Zhou, Demin,Xiao, Sulong
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p. 560 - 568
(2019/01/03)
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- Dendritic architectures by orthogonal thiol-maleimide "click" and furan-maleimide dynamic covalent chemistries
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A set of dendrons and dendrimers is synthesized divergently using an orthogonal combination of kinetically-driven thiol-maleimide "click" chemistry and thermodynamically reversible furan-maleimide cycloaddition/retrocycloaddition reactions. Growth is controlled by taking advantage of the selective thiol-ene addition of thiols to the electron withdrawn alkene of maleimide in the presence of electron rich alkene of oxanorbornene. Subsequent activation of growing dendrons/dendrimers requires only heat to induce the dynamic covalent liberation of peripheral furan protecting groups. The methodology introduced provides a new route to multifunctional dendrimers that could, in principle, be synthesized by introducing different branched monomers at any stage of dendrimer growth, allowing dendrimer architectures and properties to be better tailored to their intended applications.
- Frayne, Stephen H.,Stolz, Robert M.,Northrop, Brian H.
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supporting information
p. 7878 - 7883
(2019/09/06)
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- NON-PEPTIDE OXYTOCIN RECEPTOR AGONISTS
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Disclosed herein are compounds according to Formula I; a pharmaceutical composition including, consisting essentially of, or consisting of: a pharmaceutically acceptable compound of Formula I and a pharmaceutically acceptable carrier, diluent, or excipient; the use of compounds of Formula I in the preparation of a medicament; and a method including administering a pharmaceutical compositions comprising the compound of Formula I to a patient. The compounds, compositions, use, and methods are directed to the treatment of neurological, psychiatric disorders which are characterised by a fundamental disruption of social behaviour, and substance use disorders.
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Page/Page column 31; 32
(2018/07/05)
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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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- Benzoic hydroxamate-based iron complexes as model compounds for humic substances: Synthesis, characterization and algal growth experiments
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A series of monomeric and dimeric FeIII complexes bearing benzoic hydroxamates as O,O-chelates has been prepared and characterized by elemental analysis, IR spectroscopy, UV-Vis spectroscopy, electrospray ionization mass spectrometry (ESI-MS), cyclic voltammetry, EPR spectroscopy and for some examples by X-ray diffraction analysis. The stability of the synthesized complexes in pure water and seawater was monitored over 24 h by means of UV-Vis spectrometry. The ability to release iron from the synthesized model complexes has been investigated with algae growth experiments.
- Orlowska, Ewelina,Roller, Alexander,Wiesinger, Hubert,Pignitter, Marc,Jirsa, Franz,Krachler, Regina,Kandioller, Wolfgang,Keppler, Bernhard K.
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p. 40238 - 40249
(2016/05/24)
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- Effect of the bulkiness of the end functional amide groups on the optical, gelation, and morphological properties of oligo(p-phenylenevinylene) π-gelators
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Herein, we describe the role of end functional groups in the self-assembly of amide-functionalized oligo(p-phenylenevinylene) (OPV) gelators with different end-groups. The interplay between hydrogen-bonding and π-stacking interactions was controlled by the bulkiness of the end functional groups, thereby resulting in aggregates of different types, which led to the gelation of a wide range of solvents. The variable-temperature UV/Vis absorption and fluorescence spectroscopic features of gelators with small end-groups revealed the formation of 1D H-type aggregates in CHCl3. However, under fast cooling in toluene, 1D H-type aggregates were formed, whereas slow cooling resulted in 2D H-type aggregates. OPV amide with bulky dendritic end-group formed hydrogen-bonded random aggregates in toluene and a morphology transition from vesicles into fibrous aggregates was observed in THF. Interestingly, the presence of bulky end-group enhanced fluorescence in the xerogel state and aggregation in polar solvents. The difference between the aggregation properties of OPV amides with small and bulky end-groups allowed the preparation of self-assembled structures with distinct morphological and optical features. Buying in bulk: OPV amides with small end-groups self-assemble into 2D/1D aggregates in toluene and 1D aggregates in CHCl3. Bulky end-groups impede fluorescence quenching in the self-assembled state by blocking π-stacking and facilitate morphological transition in THF.
- Babu, Sukumaran Santhosh,Praveen, Vakayil K.,Kartha, Kalathil K.,Mahesh, Sankarapillai,Ajayaghosh, Ayyappanpillai
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supporting information
p. 1830 - 1840
(2014/07/08)
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- Structure-activity relationships for vitamin D3-based aromatic a-ring analogues as hedgehog pathway inhibitors
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A structure-activity relationship study for a series of vitamin D3-based (VD3) analogues that incorporate aromatic A-ring mimics with varying functionality has provided key insight into scaffold features that result in potent, selective Hedgehog (Hh) pathway inhibition. Three analogue subclasses containing (1) a single substitution at the ortho or para position of the aromatic A-ring, (2) a heteroaryl or biaryl moiety, or (3) multiple substituents on the aromatic A-ring were prepared and evaluated. Aromatic A-ring mimics incorporating either single or multiple hydrophilic moieties on a six-membered ring inhibited the Hh pathway in both Hh-dependent mouse embryonic fibroblasts and cultured cancer cells (IC50 values 0.74-10 μM). Preliminary studies were conducted to probe the cellular mechanisms through which VD3 and 5, the most active analogue, inhibit Hh signaling. These studies suggested that the anti-Hh activity of VD3 is primarily attributed to the vitamin D receptor, whereas 5 affects Hh inhibition through a separate mechanism.
- Deberardinis, Albert M.,Madden, Daniel J.,Banerjee, Upasana,Sail, Vibhavari,Raccuia, Daniel S.,De Carlo, Daniel,Lemieux, Steven M.,Meares, Adam,Hadden, M. Kyle
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p. 3724 - 3736
(2014/05/20)
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- A new synthesis of 4′-resveratrol esters and evaluation of the potential for anti-depressant activity
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The 4′-ester analog of the disease preventative resveratrol 1 (RV), 4′-acetyl-RV 2 along with 4′-pivaloate 13 and benzoate 14 RV were synthesized. The previously developed palladium catalyzed decarbonylative Heck coupling was used to assemble the stilbene core together with 3,5-dibenzyl protected phenol intermediates that allowed for efficient coupling and deprotection using boron trifluoride etherate. Studies with Long-Evans rats were performed to establish safety, toxicity, and behavioral parameters. In addition, the Porsalt forced-swim test was used to demonstrate anti-depressant activity.
- Acerson, Mark J.,Fabick, Kimberly M.,Wong, Yong,Blake, Crystal,Lephart, Edwin D.,Andrus, Merritt B.
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p. 2941 - 2944
(2013/06/27)
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- Functionalization of pristine graphene with conjugated polymers through diradical addition and propagation
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Hanging on: Pristine graphene was grafted with conjugated polymers through addition and propagation of diradicals generated from Bergman cyclization of enediyne-containing dendrimers. The surface functionalization was confirmed with TGA, FTIR and Raman spectroscopy, and AFM analysis. The sp2 network of graphene is only slightly destroyed, as revealed by conductivity measurements. Copyright
- Ma, Xiaowei,Li, Fei,Wang, Youfu,Hu, Aiguo
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p. 2547 - 2550,4
(2020/09/02)
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- Lanthanide-based coordination polymers assembled from derivatives of 3,5-dihydroxy benzoates: Syntheses, crystal structures, and photophysical properties
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Two new aromatic carboxylic acids, namely, 3,5-bis(benzyloxy)- benzoic acid (HL1) and 3,5-bis(pyridine-2-ylmethoxy)benzoic acid (HL2), have been prepared by replacing the hydroxyl hydrogens of 3,5-dihydroxy benzoic acid with benzyl and pyridyl moieties, respectively. The anions derived fromHL1 and HL2 have been used for the support of a series of lanthanide coordination compounds [Eu 3+ = 1-2; Tb3+ = 3-4; Gd3+ = 5-6]. The new lanthanide complexes have been characterized on the basis of a variety of spectroscopic techniques in conjunction with an assessment of their photophysical properties. Lanthanide complexes 2, 4, and 6, which were synthesized from 3,5-bis(pyridine- 2-ylmethoxy)benzoic acid, were structurally authenticated by single-crystal X-ray diffraction. All three complexes were found to exist as infinite one-dimensional (1-D) coordination polymers with the general formula {[Ln(L2)3- (H2O)2] xH2O}n Scrutiny of the packing diagrams for 2, 4, and 6 revealed the existence of interesting two-dimensional molecular arrays held together by intermolecular hydrogen-bonding interactions. Furthermore, the coordinated benzoate ligands serve as efficient light harvesting chromophores. In the cases of 1-4, the lowest energy maxima fall in the range 280-340 nm [molar absorption coefficient (ε) = (0.39-1.01) × 104 M-1 cm-1]. Moreover, the Tb3+ complexes 3 and 4 exhibit bright green luminescence efficiencies in the solid state (φoverall = 60% for 3; 27% for 4) and possess longer excited state lifetimes than the other complexes (t = 1.16 ms for 3; 1.38 ms for 4). In contrast to the foregoing, the Eu3+ complexes 1 and 2 feature poor luminescence efficiencies.
- Sivakumar, Sarika,Reddy,Cowley, Alan H.,Butorac, Rachel R.
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experimental part
p. 4882 - 4891
(2011/08/03)
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- Luminescent micro and nanogel formation from AB3 type poly(aryl ether) dendron derivatives without conventional multi-interactive gelation motifs
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We report the synthesis, gelation and photophysical properties of luminescent AB3 type poly(aryl ether) dendron derivatives in the absence of conventional multi-interactive gelation motifs. The gelation process is controlled through employing partial polar solvent milieu, which significantly enhances the propensity of π-π interaction between the aryl units present in the system. The self-assembly leads to unprecedented gelation through entrapping solvent molecules in the fibrillar arrangement of poly(aryl ether) units. The strategy was further utilized to prepare an excimer based photoluminescent gel through incorporating anthracene units in the dendrons. The close proximity between the anthracene units in the gel renders the formation of anthracene excimers at room temperature, resulting in the emission of bright green light from the gel, upon UV excitation. The study suggests that the size and packing of the self-assembled fibre can be controlled by the generation and functional groups present in the dendron. Furthermore, the strategy envisages an easy approach to generate fluorescent Low Molecular-mass Organic Gelator (LMOG) through incorporating poly cyclic aromatic hydrocarbon units to the poly(aryl ether) dendrons, since the self-assembly is largely guided by π-π interactions. The Royal Society of Chemistry and the Centre National de la Recherche Scientifique.
- Rajamalli,Prasad, Edamana
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experimental part
p. 1541 - 1548
(2011/09/20)
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- Synthesis of dendronized polymers through bergman cyclization of enediyne-containing Frechet-type dendrimers
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In this article, dendronized polymers with rigid backbones were synthesized from enediyne-containing Frechet-type dendrimers. Two generations of dendrimers were conically incorporated with 3-(2-(2-(trimethylsilyl)ethynyl)phenyl)prop-2- yn-1-ol. The trimethylsilyl protection groups of enediyne units were subsequently removed, and two types of brush polymers with rigid conjugated backbone were prepared through Bergman cyclization polymerization at elevated temperature under vacuum. The dendronized polymers were characterized with GPC, IR, UV-vis, and NMR spectroscopy. Furthermore, the morphology of the dendronized polymer was revealed by atomic force microscopy.
- Ma, Jianguo,Ma, Xiaowei,Deng, Sheng,Li, Fei,Hu, Aiguo
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experimental part
p. 1368 - 1375
(2012/02/14)
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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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- A simple method for the alkaline hydrolysis of esters
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A very mild and rapid procedure for the efficient alkaline hydrolysis of esters in non-aqueous conditions has been developed, by the use of dichloromethane/methanol (9:1) as solvent. This method conveniently provides both carboxylic acids and alcohols from the corresponding esters and sodium hydroxide in a few minutes at room temperature. A plausible reaction mechanism is proposed.
- Theodorou, Vassiliki,Skobridis, Konstantinos,Tzakos, Andreas G.,Ragoussis, Valentine
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p. 8230 - 8233
(2008/03/14)
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- Self-assembly of chiral depsipeptide dendrimers
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The self-assembly of chiral depsipeptide dendrons 4, which contain a cyanuric acid building block at their focal point, with the homotritopic Hamilton receptor 1 is reported. The 1:3 compositions of the resulting chiral supramolecular dendrimers, the association constants Kn, and the cooperativity of binding expressed by Scatchard plots and the Hill coefficients nH was determined by NMR titration experiments. The most pronounced positive cooperativity was found for the complexes 1L3 with L being the second-generation dendrons 4c-e. The least stable complexes are formed with the bulky third-generation dendrons 4f-h. Similar results are obtained by the corresponding complexation of the achiral Frechet-type first- to third-generation dendrons 3 with 1. Chiroptical investigations of 1:3 complexes of 1 and 4 reveal chirality transfer from the dendron to the Hamilton receptor as demonstrated by the appearance of new CD absorption bands at 310 nm.
- Hager, Kristine,Franz, Alexander,Hirsch, Andreas
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p. 2663 - 2679
(2008/02/03)
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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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- Structural and thermodynamic studies on cation-II interactions in lectin-ligand complexes: High-affinity galectin-3 inhibitors through fine-tuning of an arginine-arene interaction
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The high-resolution X-ray crystal structures of the carbohydrate recognition domain of human galectin-3 were solved in complex with N-acetyllactosamine (LacNAc) and the high-affinity inhibitor, methyl 2-acetamido-2-deoxy-4-O-(3-deoxy-3-[4-methoxy-2,3,5,6-tetrafluorobenzamido] -β-D-galactopyranose)-β-D-glucopyranoside, to gain insight into the basis for the affinity-enhancing effect of the 4-methoxy-2,3,5,6- tetrafluorobenzamido moiety. The structures show that the side chain of Arg144 stacks against the aromatic moiety of the inhibitor, an interaction made possible by a reorientation of the side chain relative to that seen in the LacNAc complex. Based on these structures, synthesis of second generation LacNAc derivatives carrying aromatic amides at 3′-C, followed by screening with a novel fluorescence polarization assay, has led to the identification of inhibitors with further enhanced affinity for galectin-3 (Kd ≥ 320 nM). The thermodynamic parameters describing the binding of the galectin-3 C-terminal to selected inhibitors were determined by isothermal titration calorimetry and showed that the affinity enhancements were due to favorable enthalpic contributions. These enhancements could be rationalized by the combined effects of the inhibitor aromatic structure on a cation-Π interaction and of direct interactions between the aromatic substituents and the protein. The results demonstrate that protein-ligand interactions can be significantly enhanced by the fine-tuning of arginine-arene interactions.
- Soerme, Pernilla,Arnoux, Pascal,Kahl-Knutsson, Barbro,Leffler, Hakon,Rini, James M.,Nilsson, Ulf J.
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p. 1737 - 1743
(2007/10/03)
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- Synthesis of new unsymmetrical polyarylester dendrimers
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Preparation of polyarylester dendrimers containing 2-(hydroxymethyl)-1,4- butanediol and 2,2-bis(hydroxymethyl)-1,4-butanediol cores is described. These polyarylester dendrimers are unsymmetrical with respect to chain lengths and function as model systems for studying in vitro controlled drug release systems. Reaction conditions for deprotection of trichloroethyl group of the dendritic wedges have been improved.
- Potluri, Srinagesh Kumar,Ramulu, A. Raghu,Pardhasaradhi
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p. 3739 - 3744
(2007/10/03)
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- The first total synthesis of SB87-Cl and pestalone, novel bioactive benzophenone natural products
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SB87-Cl 1, an inhibitor of testosterone-5α-reductase, and pestalone 2 exhibiting effective antimicrobial activity against MRSA (MIC=37ng/mL) and VRE (MIC=78ng/mL), were novel bioactive benzophenone natural products. Total synthesis of 1 and 2 has been successfully accomplished. The common synthetic precursor 18 of 1 and 2, was successfully obtained by the coupling of 8 with 12.
- Iijima, Daisuke,Tanaka, Daisuke,Hamada, Motoko,Ogamino, Takahisa,Ishikawa, Yuichi,Nishiyama, Shigeru
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p. 5469 - 5471
(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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- Trisubstituted carbocyclic cyclophilin binding compounds and their use
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The present invention relates to novel, non-peptidic small organic compounds having an affinity for cyclophilin (CyP)-type immunophilin proteins, and to pharmaceutical compositions comprising one or more of the said compounds. The invention further relates to the uses of these compounds and compositions for binding CyP-type proteins, inhibiting their peptidyl-prolyl isomerase activity, and for research, development, and therapeutic applications in a variety of medical disorders.
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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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- Phenylglycine derivatives useful for treating disorders of the central nervous system
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A pharmaceutical compound of the formula: STR1 in which R1 is hydrogen, hydroxy or C1-6 alkoxy, R2 is hydrogen, carboxy, tetrazolyl, --SO2 H, --SO3 H, --OSO3 H, --CONHOH, or --P(OH)OR', --PO(OH)OR', --OP(OH)OR' or --OPO(OH)OR' where R' is hydrogen, C1-6 alkyl, C2-6 alkenyl or aryl C1-6 alkyl, R3 is hydrogen, hydroxy or C1-4 alkoxy, and R4 is fluoro, trifluoromethyl, nitro, C1-6 alkyl, C3-7 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkylthio, heteroaryl, optionally substituted aryl, optionally substituted aryl C1-6 alkyl, optionally substituted aryl C2-6 alkenyl, optionally substituted aryl C2-6 alkynyl, optionally substituted aryloxy, optionally substituted aryl C1-6 alkoxy, optionally substituted arylthio, optionally substituted aryl C1-6 alkylthio or --CONR"R'", --SO2 NR"R"", --NR"R'", --OCONR"R"' or --SONR"R'" where R" and R'" are each hydrogen, C1-6 alkyl or aryl C1-6 alkyl, or R" and R'" together form a C3-7 alkylene ring; provided that (i) R1, R2 and R3 are not all hydrogen,and (ii) when R2 and R3 are hydrogen and R1 is hydroxy, R4 is not fluoro; or a salt or ester thereof.
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- Induction of liquid crystallinity by host-guest interactions
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A molecular clip is described which binds aromatic guests by an induced fit mechanism. It contains twelve long aliphatic chains and can evoke liquid-crystalline properties in a variety of molecules, including polymers and porphyrins, by a process of molecular recognition.
- Van Nunen, Johanna L. M.,Folmer, Brigitte F. B.,Nolte, Roeland J. M.
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p. 283 - 291
(2007/10/03)
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- Selective endothelin A receptor ligands. 1. Discovery and structure-activity of 2,4-disubstituted benzoic acid derivatives
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This paper describes the discovery of a new non-peptide endothelin A (ET(A)) selective ligand, 2,4-dibenzyloxybenzoic acid 3, which inhibits the binding of [125I]ET-1 to ET(A) receptors with an IC50 of 9 μM (ET-1 = endothelin-1). Optimisation of 3 resulted in compound 52 which had an IC50 of 1 μM. One of the analogues of 3, compound 15, was examined in a functional assay and shown to antagonise ET-1-induced contraction of rat aorta. The identification of 3 was made through the application of ChemDBS-3D searching of our corporate database. The 3D query, using an aromatic ring to a carboxylic acid group separated by 10.2 ± 1.1 A, was derived from an examination of common pharmacophoric distances found in the low energy conformations of two known ET(A) antagonists, the cyclic pentapeptide BQ 123 1 and myriceron caffeoyl ester 2.
- Astles,Brown,Handscombe,Harper,Harris,Lewis,Lockey,McCarthy,McLay,Porter,Roach,Smith,Walsh
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p. 409 - 423
(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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- Radical-mediated cyclisation of δ-aryl-β-dicarbonyl compounds to β-tetralones [3,4-dihydronaphthalen-2(1H)-ones]
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δ-Aryl-β-dicarbonyl compounds carrying electron-releasing groups in the aromatic ring undergo efficient radical-mediated oxidative cyclisation to β-tetralones in the presence of four equivalents of manganese(III) acetate in acetic acid. Secondary oxidation invariably results in acetoxylation at the benzylic α-position of the initially-formed β-tetralones. Use of the oxidant cerium(IV) ammonium nitrate in methanol affords the corresponding α-methoxylated β-tetralones. The α-acetoxy-α-acyl-β-tetralones, but not their α-acetoxy-α-alkoxycarbonyl analogues, are aromatised in high yield on treatment with alkaline silica gel, providing an effective synthetic entry to appropriately substituted β-naphthols. The possible involvement of such radical-mediated intramolecular annulations of δ-aryl β-diketone intermediates in the biosynthetic formation of the second carbocyclic ring of the naphthalenoid ansamycin antibiotics is discussed in relation to the previously proposed Michael addition mechanism.
- Jamie, Joanne F.,Rickards, Rodney W.
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p. 2603 - 2613
(2007/10/03)
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- A urinary metabolite of Δ1-tetrahydrocannabinol. The first synthesis of 4''-hydroxy-Δ1-tetrahydrocannabinol-7-oic acid labelled with deuterium
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The first synthesis of 4''-hydroxy-Δ1-THC-7-oic acid, one of the three major metabolites of Δ1-THC identified in human urine is discussed. Methyl 4-(3,5-dihydroxyphenyl)butanoate (8) was prepared from 3,5-dihydroxybenzoic acid in an overall yield of 15%. 8 was condensed with a terpene synthon (9) under acidic conditions followed by hydrolysis and conversion of the 4''-carboxylic acid function to the corresponding methyl ketone using methyllithium. Reduction with NaBH4 afforded the secondary alcohol in the side-chain. Acetylation and removal of the 1,3-dithiane masking group gave the aldehyde in C-7-position which was further oxidized using NaClO2 followed by deacetylation to give the desired metabolite 14. The same procedure may be used for the synthesis of unlabelled 4''-hydroxy-Δ1-THC-7-oic acid.
- Szirmai,Odqvist,Halldin
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p. 309 - 324
(2007/10/03)
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- N-SUBSTTTUTED ANILINES, INHIBITORS OF PHOSPHOLIPASES A2
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Compounds of the formula wherein R1, R2, R3, R4, Rs, Re, R7, R8, n, m, o, p and q are as hereinafter set forth, and, when R2 is hydrogen, pharmaceutically acceptable salts thereof with bases,are described. The compounds of formula 1 are potent inhibitors of phospholipases A2 (PLA2's) and are therefore useful in the treatment of inflammatory diseases, such as psosiasis, inflammatory bowel disease, asthma, allergy, arthritis, dermatitis, gout, pulmonary disease, myocardial ischemia/reperfusion, and trauma induced inflammation, such as spinal cord injury
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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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- Biosynthesis of Fungal Metabolites. Terrein, a Metabolite of Aspergillus terreus Thom
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Terrein, a metabolite of Aspergillus terreus Thom, is biosynthesised from 3,4-dihydro-6,8-dihydroxy-3-methylisocoumarin by contraction of an aryl ring.The direction of the ring contraction has been investigated using acetate as precursor.
- Hill, Robert A.,Carter, Rachel H.,Staunton, James
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p. 2570 - 2576
(2007/10/02)
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- Orally active bronchospasmolytic compounds and their preparation
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Novel compounds are disclosed having useful activity as bronchodilators of improved longevity of action and reduced incidence of side effects. These compounds are described by the formula: EQU1 wherein R1 is a member of the class consisting of tertiary butyl and cyclobutyl, and R2 is a hydrogen or 2 to 5 carbon atom acyl radical, and pharmaceutically acceptable salts thereof. The activity of these compounds is compared to previously known bronchodilators such as 1-(3', 5'-dihydroxyphenyl)-2-(isopropylamino)-ethanol, having the common name orciprenaline, and 1-(3', 4'-dihydroxyphenyl-2-isoproplyamino-ethanol, having the common name isoprenaline.
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