- Bromo-spiroisoxazoline Alkaloids, including an Isoserine Peptide, from the Caribbean Marine Sponge Aplysina lacunosa
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Three new bromotyrosine spiroisoxazoline alkaloids, lacunosins A and B (1 and 2) and desaminopurealin (3), were isolated from a MeOH extract of the marine sponge Aplysina lacunosa that showed modest α-chymotrypsin inhibitory activity. The structures of 1-3 share the spirocyclohexadienyl-isoxazoline ring system found in purealidin-R and several other Verongid sponge secondary metabolites. Compounds 1 and 2 are coupled to a glycine and an isoserine methyl ester, respectively. Alkaloid 3 is linked, contiguously, to an O-1-aminopropyl 3,5-dibromotyrosyl ether and, finally, to histamine through an amide bond. The planar structures of all three compounds were obtained from analysis of MS and 1D and 2D NMR data. The absolute configuration of the SIO unit of 1-3 was assigned by electronic circular dichroism (ECD). The isoserine amino acid residue in 2 was found to be a 1:1 mixture of epimers using a new Marfey's type reagent, derived from Trp-NH2. Allylic O-naphthoylation of the SIO subunit enhances the ECD spectrum of SIOs and improves discrimination of enantiomorphs. A unifying hypothesis is proposed that links the biosynthesis of several of the new compounds with previously reported analogues.
- Salib, Mariam N.,Jamison, Matthew T.,Molinski, Tadeusz F.
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- Isolation, Structural Identification, Synthesis, and Pharmacological Profiling of 1,2- trans-Dihydro-1,2-diol Metabolites of the Utrophin Modulator Ezutromid
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5-(Ethylsulfonyl)-2-(naphthalen-2-yl)benzo[d]oxazole (ezutromid, 1) is a first-in-class utrophin modulator that has been evaluated in a phase 2 clinical study for the treatment of Duchenne muscular dystrophy (DMD). Ezutromid was found to undergo hepatic oxidation of its 2-naphthyl substituent to produce two regioisomeric 1,2-dihydronaphthalene-1,2-diols, DHD1 and DHD3, as the major metabolites after oral administration in humans and rodents. In many patients, plasma levels of the DHD metabolites were found to exceed those of ezutromid. Herein, we describe the structural elucidation of the main metabolites of ezutromid, the regio- and relative stereochemical assignments of DHD1 and DHD3, their de novo chemical synthesis, and their production in systems in vitro. We further elucidate the likely metabolic pathway and CYP isoforms responsible for DHD1 and DHD3 production and characterize their physicochemical, ADME, and pharmacological properties and their preliminary toxicological profiles.
- Chatzopoulou, Maria,Claridge, Tim D. W.,Davies, Kay E.,Davies, Stephen G.,Elsey, David J.,Emer, Enrico,Fletcher, Ai M.,Harriman, Shawn,Robinson, Neil,Rowley, Jessica A.,Russell, Angela J.,Tinsley, Jonathon M.,Weaver, Richard,Wilkinson, Isabel V. L.,Willis, Nicky J.,Wilson, Francis X.,Wynne, Graham M.
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- About the use of an amide group as a linker in fluoroionophores: Competition between linker and ionophore acting as chelating groups
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The photophysical and complexing properties of a series of aza-crown fluoroionophores based on coumarin 343 and on 3- and 6-methoxynaphthoic amides in acetonitrile are reported. The goal of the work was to probe the participation of the amide bridge linking the fluorophore and the ionophore in the metal chelation. The use of 3- and 6-methoxy substituents in the naphthoic amide fluorophores allowed us to maintain the charge transfer character of the system and to probe the participation of the methoxy group as ancillary ligand. The aza-crown unit is no longer complexing when the amide linker is included in a β-dicarbonyl sub-structure. The amide function itself is still able to form complexes, even if weaker, with the cations. The Royal Society of Chemistry 2005.
- Maton, Laetitia,Taziaux, Dorothee,Soumillion, Jean-Philippe,Habib Jiwan, Jean-Louis
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- Discovery of methoxy-naphthyl linked N-(1-benzylpiperidine) benzamide as a blood-brain permeable dual inhibitor of acetylcholinesterase and butyrylcholinesterase
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The cholinesterase enzymes play a vital role in maintaining balanced levels of the neurotransmitter acetylcholine in the central nervous system. However, the overexpression of these enzymes results in hampered neurotransmission. Both the major forms of cholinesterase enzymes viz. acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) play a crucial role in blocking neurotransmission; therefore, in recent years, a strategy of dual cholinesterase inhibition is being explored. Herein, we developed an energy-optimized e-pharmacophore hypothesis AHHPRR from AChE-donepezil complex and screened a set of 15 scaffolds that were designed imaginarily. The ligand with N-(1-benzylpyridinium) benzamide framework has shown the highest fitness and volume score, which was chosen for synthesis and validation. A series of pyridinium benzamides were synthesized and screened for cholinesterase inhibition that led to the identification of 7b, a naphthalene containing N-(1-benzylpiperidine) benzamide as a potent dual AChE and BChE inhibitor with IC50 values of 0.176, and 0.47 μM, respectively. The kinetic study indicated that 7b inhibits AChE in a non-competitive manner with Ki value of 0.21 μM, and BChE in a mixed-fashion with Ki of 0.15 μM. The observed mode of inhibition was corroborated with molecular docking studies. The MD simulation studies pointed out that both AChE and BChE undergo low conformational changes in complex with 7b. The benzamide 7b displayed high BBB permeability in PAMPA assay, which indicates its potential for further exploration in preclinical studies for Alzheimer's disease.
- Abdullaha, Mohd,Bharate, Sandip B.,Nuthakki, Vijay K.
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- Naphthalenyl derivatives for hitting P-gp/MRP1/BCRP transporters
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Substituted naphthalenyl derivatives bearing oxazole, or thiazole or furyl heteronuclei have been carried out as bioisosters of aryl-oxazoles and -thiazoles derivatives previously reported in order to investigate the role of the hindrance on the activity towards P-gp/BCRP/and MRP1 transporters. In addition, the role of naphthalenyl group to modulate P-gp intrinsic activity of these compounds was ascertained. The results demonstrated that all naphthalenyl derivatives displayed comparable P-gp activity with respect to lead compounds previously characterized in our SAR studies but were less active towards BCRP and MRP1 pumps. In terms of intrinsic activity, the replacement of aryl with naphthalenyl moiety led to P-gp inhibitors, unambiguous or ambiguous substrates on the base of the heteronucleus and the substituent on the naphthalenyl fragment. Indeed, oxazole derivatives were: inhibitors (R = H, F, OH), unambiguous substrates (R = OCH3), or ambiguous substrate (R = Br); thiazole derivatives were: unambiguous substrates (R = OCH3, Br), or ambiguous substrates (R = H, F). Finally furyl derivatives were ambiguous substrates.
- Colabufo, Nicola A.,Contino, Marialessandra,Cantore, Mariangela,Capparelli, Elena,Perrone, Maria Grazia,Cassano, Giuseppe,Gasparre, Giuseppe,Leopoldo, Marcello,Berardi, Francesco,Perrone, Roberto
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p. 1324 - 1332
(2013/03/14)
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- Synthesis and structure - Activity relationships of N -(2-Oxo-3-oxetanyl) amides as N -acylethanolamine-hydrolyzing acid amidase inhibitors
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The fatty acid ethanolamides (FAEs) are a family of bioactive lipid mediators that include the endogenous agonist of peroxisome proliferator- activated receptor-α, palmitoylethanolamide (PEA). FAEs are hydrolyzed intracellularly by either fatty acid amide hydrolase or N-acylethanolamine- hydrolyzing acid amidase (NAAA). Selective inhibition of NAAA by (S)-N-(2-oxo-3-oxetanyl)-3-phenylpropionamide [(S)-OOPP, 7a] prevents PEA degradation in mouse leukocytes and attenuates responses to proinflammatory stimuli. Starting from the structure of 7a, a series of β-lactones was prepared and tested on recombinant rat NAAA to explore structure-activity relationships (SARs) for this class of inhibitors and improve their in vitro potency. Following the hypothesis that these compounds inhibit NAAA by acylation of the catalytic cysteine, we identified several requirements for recognition at the active site and obtained new potent inhibitors. In particular, (S)-N-(2-oxo-3-oxetanyl)biphenyl-4-carboxamide (7h) was more potent than 7a at inhibiting recombinant rat NAAA activity (7a, IC50 = 420 nM; 7h, IC50 = 115 nM) in vitro and at reducing carrageenan-induced leukocyte infiltration in vivo.
- Solorzano, Carlos,Antonietti, Francesca,Duranti, Andrea,Tontini, Andrea,Rivara, Silvia,Lodola, Alessio,Vacondio, Federica,Tarzia, Giorgio,Piomelli, Daniele,Mor, Marco
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experimental part
p. 5770 - 5781
(2010/10/20)
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- Modulation on C- and N-terminal moieties of a series of potent and selective linear tachykinin NK2 receptor antagonists
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Herein we describe the synthesis of a series of new potent tachykinin NK2 receptor antagonists by the modulation of the Cand N-terminal moieties of ibodutant (MEN 15596, 1). The Nterminal benzo[b]thiophene ring was replaced by different substituted naphthalenes and benzofurans, while further modifications were evaluated at the C-terminal tetrahydropyran moiety. Most compounds demonstrated a high affinity for the human NK2 receptor and high in vitro antagonist potency, indicating that a wide range of substituents at both termini can be incorporated in the molecule without detrimental effects on the interactions with the NK2 receptor. Selected compounds were tested in vivo confirming their activity as NK2 antagonists. In particular, after both iv and id administration to guinea pig, compound 61b was able to antagonize NK2-induced colonic contractions with a potency and duration-of-action fully comparable to the reference compound 1 (MEN 15596, ibodutant).
- Gensini, Martina,Altamura, Maria,Dimoulas, Tula,Fedi, Valentina,Giannotti, Danilo,Giuliani, Sandro,Guidi, Antonio,Harmat, Nicholas J. S.,Meini, Stefania,Nannicini, Rossano,Pasqui, Franco,Tramontana, Manuela,Triolo, Antonio,Maggi, Carlo Alberto
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experimental part
p. 65 - 78
(2010/11/16)
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- Novel and potent inhibitors of stearoyl-CoA desaturase-1. Part I: Discovery of 3-(2-hydroxyethoxy)-4-methoxy-N-[5-(3-trifluoromethylbenzyl)thiazol-2-yl]benzamide
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A series of structurally novel stearoyl-CoA desaturase-1 (SCD-1) inhibitors has been identified by optimizing a hit from our corporate library. Preliminary structure-activity relationship (SAR) studies led to the discovery of the highly potent and orally bioavailable thiazole-based SCD-1 inhibitor, 3-(2-hydroxyethoxy)-4-methoxy-N-[5-(3-trifluoromethylbenzyl)thiazol-2-yl]benzamide (23a).
- Uto, Yoshikazu,Ogata, Tsuneaki,Harada, Jun,Kiyotsuka, Yohei,Ueno, Yuko,Miyazawa, Yuriko,Kurata, Hitoshi,Deguchi, Tsuneo,Watanabe, Nobuaki,Takagi, Toshiyuki,Wakimoto, Satoko,Okuyama, Ryo,Abe, Manabu,Kurikawa, Nobuya,Kawamura, Sayako,Yamato, Michiko,Osumi, Jun
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scheme or table
p. 4151 - 4158
(2010/04/29)
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- Synthesis and evaluation of novel N-substituted-6-methoxynaphthalene-2- carboxamides as potential chemosensitizing agents for cancer
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A novel class of molecules with structure N-[3-(heteroaryl)propyl]-6- methoxynaphthalene-2-carboxamides 8-13 were synthesized by condensing 6-methoxy-2-naphthoyl chloride 1 with 3-(heteroaryl)propyl amines 2-7. Compounds 8-12 were evaluated in vitro, in P388 murine lymphocytic leukemia cell line (P388) using SRB assay for cytotoxicity and in adriamycin resistant P388 murine lymphocytic leukemia cell line (P388/ADR) using MTT assay for resistant reversal activity. Compounds 8-12 were non-toxic at lower dose of 20 μg/ml, and effectively reversed adriamycin resistance. However, at higher doses (40, 80 μg/ml) they showed significant cytotxicity and hence reversal potency was not determined at these concentrations.
- Lokhande, Tushar Narendra,Viswanathan, Chelakara Lakshmann,Juvekar, Aarti Shashikant
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body text
p. 894 - 896
(2009/08/15)
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- SMMR (small molecule metabolite reporters) for use as in vivo glucose biosensors
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Small Molecule Metabolite Reporters (SMMRs) for use as in vivo glucose biosensors, sensor compositions, and methods of use, are described. The SMMRs include boronic acid-containing xanthene, coumarin, carbostyril and phenalene-based small molecules which are used for monitoring glucose in vivo, advantageously on the skin.
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(2008/06/13)
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- Pyridinylimidazole inhibitors of Tie2 kinase
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This communication details the evolution of the screening lead SB-203580, a known CSBP/p38 kinase inhibitor, into a potent and selective Tie2 tyrosine kinase inhibitor. The optimized compound 5 showed efficacy in an in vivo model of angiogenesis and a MOP
- Semones, Marcus,Feng, Yanhong,Johnson, Neil,Adams, Jerry L.,Winkler, Jim,Hansbury, Michael
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p. 4756 - 4760
(2008/12/21)
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- BENZIMIDAZOLE OR INDOLE AMIDES AS INHIBITORS OF PIN1
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The invention relates to compounds of the formula (1) and to pharmaceutically acceptable salts and solvates thereof, wherein the variables are defined herein. The invention also relates to methods of treating abnormal cell growth in mammals by administering the compounds of formula (1) and to pharmaceutical compositions for treating such disorders that contain the compounds of formula (1). The invention also relates to methods of preparing the compounds of formula (1).
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(2010/11/08)
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- Surface modification of silica nanoparticles: A new strategy for the realization of self-organized fluorescence chemosensorst
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The self-organization of the proper subunits of a fluorescence chemosensor on the surface of silica nanoparticles allows the easy design and realization of new effective sensing systems. Commercially available silica particles (20 nm diameter) were functionalized with triethoxysilane derivatives of selective Cu(II) ligands and fluorescent dyes. Grafting of the sensor components to the particle surface ensures the spatial proximity between the sensor components and, as a consequence, binding of Cu(II) ions by the ligand subunits leads to quenching of the fluorescent units emission. In 9:1 DMSO-water solution, the coated silica nanoparticles (CSNs) selectively detect copper ions down to nanomolar concentrations. The operative range of the sensors can be tuned either by switching the ligand units or by modification of the components ratio. Sensors with the desired photophysical properties can be easily prepared by using different fluorescent dyes. Moreover, the organization of the network of sensor components gives rise to cooperative and collective effects: on one hand, the ligand subunits bound to the particle surfaces cooperate to form multivalent binding sites with an increased affinity for the Cu(II) ions; on the other hand, binding of a single metal ion leads to the quenching of several fluorescent groups producing a remarkable signal amplification. The Royal Society of Chemistry 2005.
- Rampazzo, Enrico,Brasola, Elena,Marcuz, Silvia,Mancin, Fabrizio,Tecilla, Paolo,Tonellato, Umberto
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p. 2687 - 2696
(2007/10/03)
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- Monitoring of microenvironmental changes in the major and minor grooves of DNA by dan-modified oligonucleotides
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(Graph Presented) We describe the synthesis of new environmentally sensitive fluorescence probes to elucidate DNA structures. DNA oligonucleotides containing fluorophore dan (6-(dimethylamino)-2-acylnaphthalene)-modified dC or dG were able to monitor the
- Kimura, Takumi,Kawai, Kiyohiko,Majima, Tetsuro
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p. 5829 - 5832
(2007/10/03)
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- Structures of cribochalines A and B, branched-chain methoxylaminoalkyl pyridines from the micronesian sponge, Cribochalina sp. absolute configuration and enantiomeric purity of related O-methyl oximes
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Two new 3-alkyl pyridines, cribochalines A (2) and B (3), were isolated from the North Pacific sponge Cribochalina sp. The known related oxime, ikimine A, was shown to be a 2.8:1 mixture of the (S)- and (R)-enantiomers. Cribochaline A exhibited antifungal activity against Candida albicans ATCC and Fluconazole-resistant strains C. albicans 96-489, C. krusei and C. glabrata. (C) 2000 Elsevier Science Ltd.
- Nicholas, Gillian M.,Molinski, Tadeusz F.
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p. 2921 - 2927
(2007/10/03)
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- Asymmetric Diastereoselective Conjugate Additions of Lithium Amides to Chiral Naphthyloxazolines Leading to Novel β-Amino Acids
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The functionalization of the naphthalene ring system by a direct amination-alkylation reaction of chiral nonracemic naphthyloxazolines is described.Chiral 1-naphthyl- and 2-naphthyloxazoline were treated with a variety of lithium amides followed by several different electrophilic quenches.The solvent and additives were varied in order to achieve optimum conditions.The combination of HMPA and THF at -78 deg C gave the best yield with excellent stereoselectivity.The present methology provides a stereospecific synthesis of novel, nonracemic, rigid β-amino acides after hydrolytic removal of the chiral oxazoline.
- Shimano, Masanao,Meyers, A. I.
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p. 7445 - 7455
(2007/10/03)
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- Steric Factors in Amide-Directed Metalations of N,N-Dialkyl-6-methoxynaphthalene-2-carboxamides: Synthesis of a Sterically Perturbed Acylnaphthol
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The powerful ortho-metalating directive effect of the N,N-dialkylcarboxamide group can be used for the preparation of C-1 alkyl-substituted 2,6-acylnaphthols.The alternative reaction pathways of C-1 metalation vs. acylation (carbonyl addition) in the reaction of alkyllithium reagents with N,N-dialkyl-6-methoxy-naphthalenecarboxamides depends upon the cumulative steric nature of the N-alkyl and lithium alkyl groups: The N,N-dimethylamide 7 undergoes carbonyl addition with n-BuLi and t-BuLi; the N,N-diethylamide 8, carbonyl addition with n-BuLi, but metalation with t-BuLi; and the N,N-diisopropylamide 9 only C-1 metalation with n-BuLi.Subsequent reaction of the N,N-diethyl-1-ethyl-6-methoxynaphhtalene-2-carboxamide (13) with n-BuLi gives the desired 2,6-acylnaphthyl methyl ether, whereas the corresponding ethylated diisopropylamide 14 undergoes additional metalation on the ethyl group.These 1-ethyl-2-carboxamidonaphthalenes are very sterically crowded and show evidence in the proton NMR of hindered rotation about both the amide bond and the ethyl group.The UV and fluorescence spectra of the acylnaphthols 17 and 18 show the consequences of this steric crowding through reduced conjugation between the acyl group and the naphthalene group.The more hindered 1-ethylated acylnaphthol 18 shows lower molar absorptivity, and it fluoresces only in basic solution.
- Bindal, Rajeshwar D.,Katzenellenbogen, John A.
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p. 3181 - 3185
(2007/10/02)
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- Organic reactions in liquid crystalline solvents. 1. The thermal cis-trans isomerization of a bulky olefin in cholesteric liquid crystalline solvents
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The effect of cholesteric liquid crystalline solvents on the energetics of rotational thermal cis-trans isomerization of olefins has been examined.Rate constants have been obtained over a 70-degree temperature range for isomerization of trans-1,2-di-(4-cyanophenyl)-1,2-diphenyl-ethylene in two isotropic solvents and three cholesteric liquid crystals and the Arrhenius parameters determined.The rates of isomerization are found to be consistently slower in the liquid crystalline phases compared to the isotropic solvents.The Arrhenius parameters for isomerization of the olefin in the isotropic solvents (Ea = 34.8 +/- 0.3 kcal/mol; ΔS+ = - 1.5 +/- 0.5 e.u.) compare favourably with reported values for its isomerization in benzene solution.In the cholesteric phases, Ea is consistently 1-1.5 kcal/mol higher and ΔS+ slightly more positive than the corresponding values for the isotropic solvents.The results are tentatively rationalized in terms of disruption of liquid crystalline orders as the olefin twists from its pseudo-planar, ground state geometry through the globular, twisted transition state.The magnitude of this effect is proposed to depend on both the difference in steric bulk of the ground and transition states and the "tightness" of the solvation shell seen by the isomerizing molecule.It is believed that in the present case the observed effects are somewhat truncated as a result of rather poor solvation of the bulky olefin in the liquid crystalline phases.
- Leigh, William J.,Frendo, Debbie T.,Klawunn, Paul J.
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p. 2131 - 2138
(2007/10/02)
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