- An antibody-catalyzed isomerization reaction
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Monoclonal antibodies (mAbs) were generated against the coplanar transition state (TS(paragraph)) analogue 1 and assayed for their ability to catalyze the isomerization of bridged biphenyls 4, 6, and 7. This is a relatively simple unimolecular reaction whose activation barrier arises from unfavorable steric interactions between the two benzylic methylene groups and strain in the bridging ring system. Seven mAbs were found that catalyzed the isomerization of 4 to 6; the most efficient (mAb 64D8E10) has k(cat) and K(M) values of 4.3 x 10-5 s-1 and 420 μM, respectively. This corresponds to a rate enhancement over the unimolecular uncatalyzed reaction (k(cat)/k(uncat)) of 2900. The dissociation constant for the TS(paragraph) analogue, K(d), was determined to be 210 nM. For both the antibody (64D8E10) catalyzed and uncatalyzed reactions, the free energy of activation (ΔG(paragraph)) is comprised largely of the enthalpy term; the antibody decreases the enthalpy of activation by 5 kcal/mol. Despite relatively large differences in the values of k(cat)/k(uncat) for the five antibodies, the ratios of K(d) to K(M)(4) are very similar. It is likely that the antibodies catalyze this reaction by reducing both ring strain and nonbonded steric interactions in the transition state.
- Uno,Ku,Prudent,Huang,Schultz
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Read Online
- ω-oxidation of α-chlorinated fatty acids: Identification of α-chlorinated dicarboxylic acids
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Myeloperoxidase-derived HOCl targets tissue- and lipoprotein- associated plasmalogens to generate α-chlorinated fatty aldehydes, including 2-chlorohexadecanal. Under physiological conditions, 2-chlorohexadecanal is oxidized to 2-chlorohexadecanoic acid (2-ClHA). This study demonstrates the catabolism of 2-ClHA by ω-oxidation and subsequent β-oxidation from the ω-end. Mass spectrometric analyses revealed that 2-ClHA is ω-oxidized in the presence of liver microsomes with initial ω-hydroxylation of 2-ClHA. Subsequent oxidation steps were examined in a human hepatocellular cell line (HepG2). Three different α-chlorinated dicarboxylic acids, 2-chlorohexadecane-(1,16)- dioic acid, 2-chlorotetradecane- (1,14)-dioic acid, and 2-chloroadipic acid (2-ClAdA), were identified. Levels of 2-chlorohexadecane-( 1,16)-dioic acid, 2-chlorotetradecane-(1,14)-dioic acid, and 2-ClAdA produced by HepG2 cells were dependent on the concentration of 2-ClHA and the incubation time. Synthetic stable isotope-labeled 2-ClHA was used to demonstrate a precursorproduct relationship between 2-ClHA and the α-chlorinated dicarboxylic acids. We also report the identification of endogenous 2-ClAdA in human and rat urine and elevations in stable isotopelabeled urinary 2-ClAdA in rats subjected to intraperitoneal administration of stable isotope-labeled 2-ClHA. Furthermore, urinary 2-ClAdA and plasma 2-ClHA levels are increased in LPStreated rats. Taken together, these data show that 2-ClHA is ω-oxidized to generate α-chlorinated dicarboxylic acids, which include α-chloroadipic acid that is excreted in the urine.
- Brahmbhatt, Viral V.,Albert, Carolyn J.,Anbukumar, Dhanalakshmi S.,Cunningham, Bryce A.,Neumann, William L.,Ford, David A.
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- A synthesis and properties of new 4,4-difluoro-3a,4a- diaza-s-indacene (BODIPY)-labeled lipids
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A series of fluorescently labeled fatty acids of various chain lengths with 4,4-difluoro-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacene-8-yl (Me 4-BODIPY-8) residue in the ω-position were synthesized. These acids were used to prepare new fluorescently labeled phosphatidylcholines, sphingomyelin, and galactosyl ceramide. The symmetry of the Me 4-BODIPY-8-fluorophore suggests that, in most bilayer membrane systems, this fluorophore would be embedded into the bilayer. Pleiades Publishing, Inc., 2006.
- Boldyrev,Molotkovsky, Jul G.
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- BODIPYs revealing lipid droplets as valuable targets for photodynamic theragnosis
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Endowing BODIPY PDT agents with the ability to probe lipid droplets is demonstrated to boost their phototoxicity, allowing the efficient use of highly fluorescent dyes (poor ROS sensitizers) as phototoxic agents. Conversely, this fact opens the way to the development of highly bright ROS photosensitizers for performing photodynamic theragnosis (fluorescence bioimaging and photodynamic therapy) from a single simple agent. On the other hand, the noticeable capability of some of the reported dyes to probe lipid droplets in different cell lines under different conditions reveals their use as privileged probes for advancing the study of interesting lipid droplets by fluorescence microscopy.
- Agarrabeitia, Antonia R.,De La Moya, Santiago,García-Garrido, Fernando,García-Moreno, Inmaculada,Ortiz, María J.,Palao, Eduardo,Prieto-Casta?eda, Alejandro,Tabero, Andrea,Villanueva, Angeles
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Read Online
- Synthesis of the 4-aza cyclopentenone analogue of Δ12,14-15-deoxy-PGJ2 and S-cysteine adducts
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The synthesis of a series of 4-aza cross-conjugated cyclopentenones, inspired by the natural prostaglandin Δ12,14-15-deoxy-PGJ2 (5) is described. Using the 4-aza cyclopentenone 7, the installation of the α-side chain was performed using N-functionalisation, following a Boc-deprotection. The ω-side chain was then installed through a Baylis-Hillman type aldol reaction with trans-2-octenal. This afforded 11, the aza-analogue of 5. With this prostaglandin analogue in hand, a series of thiol adducts (14–16) were prepared. Included are activities for compounds 11 and 14–16 in relation to inhibition of the transcription factor NF-κB.
- Conway, Lorna,Riccio, Anna,Santoro, M. Gabriella,Evans, Paul
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Read Online
- New protoilludane sesquiterpenes from Lactarius violascens
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Violascensol 1 and the corresponding 6-ketostearoyl ester 2 were isolated from the fruiting bodies of Lactarius violascens. Their structures were established by spectroscopic and chemical methods. Compounds 1 and 2 are the first examples of protoilludane sesquiterpenes isolated from a Lactarius species.
- Vidari, Giovanni,Garlaschelli, Luigi,Rossi, Alessandra,Vita-Finzi, Paola
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Read Online
- Neutrophil-Selective Fluorescent Probe Development through Metabolism-Oriented Live-Cell Distinction
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Human neutrophils are the most abundant leukocytes and have been considered as the first line of defence in the innate immune system. Selective imaging of live neutrophils will facilitate the in situ study of neutrophils in infection or inflammation events as well as clinical diagnosis. However, small-molecule-based probes for the discrimination of live neutrophils among different granulocytes in human blood have yet to be reported. Herein, we report the first fluorescent probe NeutropG for the specific distinction and imaging of active neutrophils. The selective staining mechanism of NeutropG is elucidated as metabolism-oriented live-cell distinction (MOLD) through lipid droplet biogenesis with the help of ACSL and DGAT. Finally, NeutropG is applied to accurately quantify neutrophil levels in fresh blood samples by showing a high correlation with the current clinical method.
- Gao, Min,Lee, Sun Hyeok,Park, Sang Hyuk,Ciaramicoli, Larissa Miasiro,Kwon, Haw-Young,Cho, Heewon,Jeong, Joseph,Chang, Young-Tae
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supporting information
p. 23743 - 23749
(2021/10/14)
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- Aziridine-2-carboxylic acid derivatives and its open-ring isomers as a novel PDIA1 inhibitors
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[Figure not available: see fulltext.] Acyl derivatives of aziridine-2-carboxylic acid have been synthesized and tested as PDIA1 inhibitors. Calculations of charge value and distribution in aziridine ring system and some alkylating agents were performed. For the first time was found that acyl derivatives of aziridine-2-carboxylic acid are weak to moderately active PDIA1 inhibitors.
- Leite, Irena,Andrianov, Victor,Zelencova-Gopejenko, Diana,Loza, Einars,Kazhoka-Lapsa, Iveta,Domracheva, Ilona,Stoyak, Marta,Chlopicki, Stefan,Kalvins, Ivars
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p. 1086 - 1106
(2022/01/12)
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- Design, synthesis and biological evaluation of novel indazole-based derivatives as potent HDAC inhibitors via fragment-based virtual screening
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Based on fragment-based virtual screening and bioisoterism strategies, novel indazole and pyrazolo[3,4-b] pyridine derivatives as HDACs inhibitors were designed, synthesized and evaluated. Most of these compounds displayed good to excellent inhibitory activities against HDACs, especially compounds 15k and 15m were identified as potent inhibitors of HDAC1 (IC50 = 2.7 nM and IC50 = 3.1 nM), HDAC2 (IC50 = 4.2 nM and IC50 = 3.6 nM) and HDAC8 (IC50 = 3.6 nM and IC50 = 3.3 nM). Further anti-proliferation assays revealed that compounds 15k and 15m showed better anti-proliferative activities against HCT-116 and HeLa cells than positive control SAHA. The western blot analysis results indicated that compounds 15k and 15m noticeably up-regulated the level of acetylated α-tubulin and histone H3. In addition, the two compounds 15k and 15m could arrest cell cycle in G2/M phase and promote cell apoptosis, which was similar as the reference compound SAHA. Through the molecular docking and dynamic studies, the potent HDAC inhibitory activities mainly caused by van der Waals and electrostatic interactions with the HDACs.
- Gao, Liang,Gao, Lina,He, Fengjun,Hu, Lihong,Kang, Di,Liu, Jian,Wang, Ping,Wen, Yu,Zhou, Jingxian
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- Cationic lipid molecule, and application thereof in nucleic acid delivery
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The present invention discloses a cationic lipid molecule, and an application thereof in nucleic acid delivery. The structural formula of the cationic lipid molecule is represented by formula i. The invention further provides a cationic liposome, a lipid compound, a reagent, a kit, a preparation and a medicinal composition based on the cationic lipid molecule. The cationic lipid molecule has the advantages of simple synthesis process and good stability, and the cationic liposome has a high efficiency (characterized by high transfection efficiency) and a low toxicity, is stable and uniform, is easy to prepare, and can be used for transferring various cell lines. The cationic lipid molecule has excellent transitivity, and can efficiently deliver active substances (such as exemplary siRNA) omto cells (such as exemplary lung cancer cells), tissues and organs to achieve efficient regulation of the active substances. The problem that the toxicity and the transfer efficiency of cationic liposome existing in the prior art are low is solved.
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Paragraph 0149-0152
(2019/10/08)
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- Preparation method of substituted phenylacetic acid derivative
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The invention belongs to the field of drug synthesis and relates to a preparation method of a substituted phenylacetic acid derivative, especially to a preparation method for preparing 2-[4-(2-oxyamylmethyl)phenylpropionic acid]. The preparation method includes a Friedel-Crafts reaction, ring-closure reaction and a coupled reaction which are sequentially exchangeable, and a reduction reaction. Thepreparation method hasn't been enlightened by the prior art and also cannot obtain technical enlightenment from the prior art. The preparation method is suitable for production on a commercial scaleand provides another technical scheme for the industrial production of loxoprofen sodium.
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Paragraph 0082; 0083
(2019/01/08)
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- Primary, Secondary, and Tertiary γ-C(sp3)-H Vinylation of Amides via Organic Photoredox-Catalyzed Hydrogen Atom Transfer
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An efficient strategy for primary, secondary and tertiary aliphatic γ-C(sp3)-H vinylation of amides with alkenylboronic acids is reported. These reactions are catalyzed by visible-light organic photoredox agents. Regioselective γ-C(sp3)-H vinylation of amides is controlled by a 1,5-hydrogen atom transfer of an amidyl radical generated in situ.
- Chen, Hui,Guo, Liangliang,Yu, Shouyun
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supporting information
p. 6255 - 6259
(2018/10/05)
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- A Fluorescence-Lifetime-Based Binding Assay for Class IIa Histone Deacetylases
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Class IIa histone deacetylases (HDACs) show extremely low enzymatic activity and no commonly accepted endogenous substrate is known today. Increasing evidence suggests that these enzymes exert their effect rather through molecular recognition of acetylated proteins and recruiting other proteins like HDAC3 to the desired target location. Accordingly, class IIa HDACs like bromodomains have been suggested to act as “Readers” of acetyl marks, whereas enzymatically active HDACs of class I or IIb are called “Erasers” to highlight their capability to remove acetyl groups from acetylated histones or other proteins. Small-molecule ligands of class IIa histone deacetylases (HDACs) have gained tremendous attention during the last decade and have been suggested as pharmaceutical targets in several indication areas such as cancer, Huntington's disease and muscular atrophy. Up to now, only enzyme activity assays with artificial chemically activated trifluoroacetylated substrates are in use for the identification and characterization of new active compounds against class IIa HDACs. Here, we describe the first binding assay for this class of HDAC enzymes that involves a simple mix-and-measure procedure and an extraordinarily robust fluorescence lifetime readout based on [1,3]dioxolo[4,5-f]benzodioxole-based ligand probes. The principle of the assay is generic and can also be transferred to class I HDAC8.
- Meyners, Christian,Mertens, Monique,Wessig, Pablo,Meyer-Almes, Franz-Josef
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p. 3107 - 3116
(2017/03/13)
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- Pd(II)-catalyzed chelation-assisted cross dehydrogenative coupling between unactivated C(sp3)H bonds in aliphatic amides and benzylic CH bonds in toluene derivatives
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The chelation-assisted cross dehydrogenative coupling of C(sp3)H bonds is achieved by the Pd(II)-catalyzed reaction of aliphatic amides that contain a 5-chloro-8-aminoquinoline moiety as the directing group with toluene derivatives in the presence of heptafluoroisopropyl iodide. A variety of functional groups are tolerated.
- Kubo, Teruhiko,Aihara, Yoshinori,Chatani, Naoto
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supporting information
p. 1365 - 1367
(2015/11/24)
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- Optimization of gefitinib analogues with potent anticancer activity
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The interactions of gefitinib (Iressa) in EGFR are hydrogen bonding and van der Waals forces through quinazoline and aniline rings. However the morpholino group of gefitinib is poorly ordered due to its weak electron density. A series of novel piperazino analogues of gefitinib where morpholino group substituted with various piperazino groups were designed and synthesized. Most of them indicated significant anti-cancer activities against human cancer cell lines. In particular, compounds 52-54 showed excellent potency against cancer cells. Convergent synthetic approach has been developed for the synthesis of gefitinib intermediate which can lead to gefitinib as well as numerous analogues.
- Yin, Kai-Hao,Hsieh, Yi-Han,Sulake, Rohidas S.,Wang, Su-Pei,Chao, Jui-I.,Chen, Chinpiao
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supporting information
p. 5247 - 5250
(2015/01/08)
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- NMR-based molecular ruler for determining the depth of intercalants within the lipid bilayer. Part III: Studies on keto esters and acids
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The development of "molecular rulers" would allow one to quantitatively locate the penetration depth of intercalants within lipid bilayers. To this end, an attempt was made to correlate the 13C NMR chemical shift of polarizable "reporter" carbons (e.g., carbonyls) of intercalants within DMPC liposomal bilayers - with the polarity it experiences, and with its Angstrom distance from the interface. This requires families of molecules with two "reporter carbons" separated by a known distance, residing at various depths/polarities within the bilayer. For this purpose, two homologous series of dicarbonyl compounds, methyl n-oxooctadecanoates and the corresponding n-oxooctadecanoic acids (n = 4-16), were synthesized. To assist in assignment and detection several homologs in each system were prepared 13C-enriched in both carbonyls. Within each family, the number of carbons and functional groups remains the same, with the only difference being the location of the second ketone carbonyl along the fatty acid chain. Surprisingly, the head groups within each family are not anchored near the lipid-water interface, nor are they even all located at the same depth. Nevertheless, using an iterative best fit analysis of the data points enables one to obtain an exponential curve. The latter gives substantial insight into the correlation between polarity (measured in terms of the Reichardt polarity parameter, ET(30)) and penetration depth into the liposomal bilayer. Still missing from this curve are data points in the moderate polarity range.
- Afri, Michal,Alexenberg, Carmit,Aped, Pinchas,Bodner, Efrat,Cohen, Sarit,Ejgenburg, Michal,Eliyahu, Shlomi,Gilinsky-Sharon, Pessia,Harel, Yifat,Naqqash, Miriam E.,Porat, Hani,Ranz, Ayala,Frimer, Aryeh A.
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p. 105 - 118
(2015/02/19)
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- Synthesis of nitrogen-containing derivatives of (18α,19β)-19-Hydroxy-2,3-secooleanane-2,3,28-trioic Acid 28,19-Lactone
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The object of this study is the interaction of the cyclic anhydride 2 of (18α,19β)-19-hydroxy-2,3-secooleanane-2,3,28-trioic acid 28,19-lactone (1) with primary and secondary amines. It was shown that the products of steric control (the corresponding 2-amino-2-oxo-3-oic acids=2-amides) were formed solely upon the opening of the anhydride cycle by secondary amines (Scheme 2), whereas the interaction with primary amines yielded a mixture of isomeric amides (Scheme 10). In the latter case, the solvent provided a noticeable effect on the reaction selectivity, which was demonstrated in the case of 4-methoxybenzylamine. The interaction between the resulting 3-amides and oxalyl chloride yielded the corresponding cyclic imides, whereas under these conditions, 2-amides formed spiropyrrolidinetriones (Scheme 4). Copyright
- Shernyukov, Andrey V.,Mainagashev, Ilya Ya.,Korchagina, Dina V.,Genaev, Alexander M.,Komarova, Nina I.,Salakhutdinov, Nariman F.,Tolstikov, Genrikh A.
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p. 1757 - 1781
(2013/10/21)
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- Insights into soluble guanylyl cyclase activation derived from improved heme-mimetics
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Recently, the structure of BAY 58-2667 bound to the Nostoc sp. H-NOX domain was published. On the basis of this structural information, we designed BAY 58-2667 derivatives and tested their effects on soluble guanylyl cyclase (sGC) activity. Derivative 20 activated sGC 4.8-fold more than BAY 58-2667. Co-crystallization of 20 with the Ns H-NOX domain revealed that the increased conformational distortion at the C-terminal region of αF helix containing 110-114 residues contributes to the higher activation triggered by 20.
- Von Wantoch Rekowski, Margarete,Kumar, Vijay,Zhou, Zongmin,Moschner, Johann,Marazioti, Antonia,Bantzi, Marina,Spyroulias, Georgios A.,Van Den Akker, Focco,Giannis, Athanassios,Papapetropoulos, Andreas
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p. 8948 - 8952
(2013/12/04)
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- Anti-GM1/GD1a complex antibodies in GBS sera specifically recognize the hybrid dimer GM1-GD1a
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It is now emerging the new concept that the antibodies from some patients with Guillain-Barre syndrome (GBS) recognize an antigenic epitope formed by two different gangliosides, a ganglioside complex (GSC). We prepared the dimeric GM1-GD1a hybrid ganglioside derivative that contains two structurally different oligosaccharide chains to mimic the GSC. We use this compound to analyze sera from GBS patients by high-performance thin-layer chromatography immunostaining and enzyme-linked immunosorbent assay. We also synthesized the dimeric GM1-GM1 and GD1a-GD1a compounds that were used in control experiments together with natural gangliosides. The hybrid dimeric GM1-GD1a was specifically recognized by human sera from GBS patients that developed anti-oligosaccharide antibodies specific for grouped complex oligosaccharides, confirming the information that GBS patients developed antibodies against a GSC. High-resolution 1H-13C heteronuclear single-quantum coherence-nuclear overhauser effect spectroscopy nuclear magnetic resonance experiments showed an interaction between the IV Gal-H1 of GM1 and the IV Gal-H2 of GD1a suggesting that the two oligosaccharide chains of the dimeric ganglioside form a single epitope recognized by a single-antibody domain. The availability of a method capable to prepare several hybrid gangliosides, and the availability of simple analytical approaches, opens new perspectives for the understanding and the therapy of several neuropathies. The Author 2011. Published by Oxford University Press. All rights reserved.
- Mauri, Laura,Casellato, Riccardo,Ciampa, Maria G.,Uekusa, Yoshinori,Kato, Koichi,Kaida, Ken-Ichi,Motoyama, Mayumi,Kusunoki, Susumu,Sonnino, Sandro
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experimental part
p. 352 - 360
(2012/04/04)
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- Discovery of LFF571: An investigational agent for Clostridium difficile infection
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Clostridium difficile (C. difficile) is a Gram positive, anaerobic bacterium that infects the lumen of the large intestine and produces toxins. This results in a range of syndromes from mild diarrhea to severe toxic megacolon and death. Alarmingly, the prevalence and severity of C. difficile infection are increasing; thus, associated morbidity and mortality rates are rising. 4-Aminothiazolyl analogues of the antibiotic natural product GE2270 A (1) were designed, synthesized, and optimized for the treatment of C. difficile infection. The medicinal chemistry effort focused on enhancing aqueous solubility relative to that of the natural product and previous development candidates (2, 3) and improving antibacterial activity. Structure-activity relationships, cocrystallographic interactions, pharmacokinetics, and efficacy in animal models of infection were characterized. These studies identified a series of dicarboxylic acid derivatives, which enhanced solubility/efficacy profile by several orders of magnitude compared to previously studied compounds and led to the selection of LFF571 (4) as an investigational new drug for treating C. difficile infection.
- Lamarche, Matthew J.,Leeds, Jennifer A.,Amaral, Adam,Brewer, Jason T.,Bushell, Simon M.,Deng, Gejing,Dewhurst, Janetta M.,Ding, Jian,Dzink-Fox, Joanne,Gamber, Gabriel,Jain, Akash,Lee, Kwangho,Lee, Lac,Lister, Troy,McKenney, David,Mullin, Steve,Osborne, Colin,Palestrant, Deborah,Patane, Michael A.,Rann, Elin M.,Sachdeva, Meena,Shao, Jian,Tiamfook, Stacey,Trzasko, Anna,Whitehead, Lewis,Yifru, Aregahegn,Yu, Donghui,Yan, Wanlin,Zhu, Qingming
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supporting information; experimental part
p. 2376 - 2387
(2012/06/01)
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- Design, synthesis and preliminary bioactivity studies of 1,3,4-thiadiazole hydroxamic acid derivatives as novel histone deacetylase inhibitors
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Histone deacetylase (HDAC) inhibitors have emerged as a new class of anticancer agents, targeting the biological processes including cell cycle, apoptosis and differentiation. In the present study, a series of 1,3,4-thiadiazole based hydroxamic acids were developed as potent HDAC inhibitors. Some of them showed good inhibitory activity in HDAC enzyme assay and potent growth inhibition in some tumor cell lines. Among them, compound 6i (IC50 = 0.089 μM), exhibited better inhibitory effect compared with SAHA (IC50 = 0.15 μM).
- Guan, Peng,Sun, Feng'E,Hou, Xuben,Wang, Feng,Yi, Fan,Xu, Wenfang,Fang, Hao
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experimental part
p. 3865 - 3872
(2012/08/27)
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- A highly efficient macrolactonization method via ethoxyvinyl ester
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We present the highly efficient reaction procedure of the macrolactonization method via ethoxyvinyl esters (EVEs). The following procedure was performed: 1)The EVE was prepared from hydroxycarboxylic acid and ethoxyacetylene in the presence of the Ru catalyst [RuCl2(p-cymene)] 2 in acetone; 2) after filtration of the Ru catalyst through a short-neutral SiO2 pad and evaporation of acetone, the EVE formed was diluted in 1,2-dichloroethane (DCE) and the solution was slowly added by a syringe pump to the highly diluted DCE solution of pTsOH (10mol%) at 80°C. Varioussized lactones could be produced by the method described here. It is note worthy that the method can give 9- to 14-membered macrolactones in good yields. This macrolactonization method via EVEs is useful for acid-/base-sensitive substrates. Furthermore, it was found that EVE formation was possible without loosing activity of the Ru catalyst even for the compounds with nucleophilic amine functions. The characteristic feature of the method was exemplified by the reaction of the compound 14 with many functional groups.
- Ohba, Yusuke,Takatsuji, Mayuko,Nakahara, Kenji,Fujioka, Hiromichi,Kita, Yasuyuki
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experimental part
p. 3526 - 3537
(2009/12/31)
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- Structure-activity relationships of α-ketooxazole inhibitors of fatty acid amide hydrolase
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A systematic study of the structure-activity relationships of 2b (OL-135), a potent inhibitor of fatty acid amide hydrolase (FAAH), is detailed targeting the C2 acyl side chain. A series of aryl replacements or substituents for the terminal phenyl group provided effective inhibitors (e.g., 5c, aryl = 1-napthyl, K, - 2.6 nM), with 5hh (aryl -3-ClPh, Ki = 900 pM) being 5-fold more potent than 2b. Conformationally restricted C2 side chains were examined, and many provided exceptionally potent inhibitors, of which 11j (ethylbiphenyl side chain) was established to be a 750 pM inhibitor. A systematic series of heteroatoms (O, NMe, S), electron-withdrawing groups (SO, SO2), and amides positioned within and hydroxyl substitutions on the linking side chain were investigated, which typically led to a loss in potency. The most tolerant positions provided effective inhibitors (12p, 6-position S, Ki = 3 nM, or 13d, 2-position OH, Ki = 8 nM) comparable in potency to 2b. Proteome-wide screening of selected inhibitors from the systematic series of >100 candidates prepared revealed that they are selective for FAAH over all other mammalian serine proteases.
- Hardouin, Christophe,Kelso, Michael J.,Romero, F. Anthony,Rayl, Thomas J.,Leung, Donmienne,Hwang, Inkyu,Cravatt, Benjamin F.,Boger, Dale L.
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p. 3359 - 3368
(2008/02/13)
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- METHOD OF PREPARING CHIRAL CYCLIC ?-AMINOCARBOXAMIDES
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The present invention encompasses a process for preparing compounds of formula (1), wherein a compound of general formula (2) is reacted in the presence of a catalyst and a solvent under hydrogen pressure to form a compound of general formula (1) and wherein A and R1 - R4 are defined as in claim 1.
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Page/Page column 17-18
(2008/06/13)
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- THERAPEUTIC AMINE-ARYLSULFONAMIDE CONJUGATE COMPOUNDS
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Therapeutic amine-arylsulfonamide conjugate compounds, of the general formula: wherein R′ is [D-W-], hydroxyl, or alkoxyl; R″ is independently [D-W′-], hydrogen, alkoxy, alkyl, cycloalkyl, alkenyl, alkynyl or aryl, or R″ and R″ together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, 7- or 8-membered ring optionally containing one or two further heteroatoms independently selected from nitrogen, oxygen and sulfur; D is independently a therapeutic amine radical comprising at least one nitrogen atom and optionally at least one oxygen atom coupled to W or W′ by a nitrogen or oxygen atom; W and W′ are a chemical bond or linker; wherein either R′ is [D-W-] or at least one R″ is [D-W′-], and pharmaceutically acceptable esters, amides, salts or solvates thereof, pharmaceutical compositions containing same, methods for their preparation, and their use in treating psychiatric, neurologic and metabolic disorders are disclosed.
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Page/Page column 30
(2010/11/27)
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- SUBSTITUTED CYCLOHEXYL-1,4-DIAMINE DERIVATIVES WITH A CHAIN EXTENSION
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The invention relates to substituted cyclohexyl-1,4-diamine derivatives, to a method for their production, to medicaments containing said compounds and to the use of substituted cyclohexyl-1,4-diamine derivatives for producing medicaments.
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Page/Page column 25
(2008/06/13)
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- On the use of nonfluorescent dye labeled ligands in FRET-based receptor binding studies
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The efficiency of fluorescence resonance energy transfer (FRET) is dependent upon donor-acceptor proximity and spectral overlap, whether the acceptor partner is fluorescent or not. We report here on the design, synthesis, and characterization of two novel pirenzepine derivatives that were coupled to patent blue VF and pinacyanol dyes. These nonfluorescent compounds, when added to cells stably expressing enhanced green fluorescent protein (EGFP)-fused muscarinic M1 receptors, promote EGFP fluorescence extinction in a time-, concentration-, and atropine-dependent manner. They display nanomolar affinity for the muscarinic receptor, determined using either FRET or classical radioligand binding conditions. We provide evidence that these compounds behave as potent acceptors of energy from excited EGFP with quenching efficiencies comparable to those of analogous fluorescent bodipy or rhodamine red pirenzepine derivatives. The advantages they offer over fluorescent ligands are illustrated and discussed in terms of reliability, sensitivity, and wider applicability of FRET-based receptor binding assays.
- Tahtaoui, Chouaib,Guillier, Fabrice,Klotz, Philippe,Galzi, Jean-Luc,Hibert, Marcel,Ilien, Brigitte
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p. 7847 - 7859
(2007/10/03)
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- Novel (3,5-di-tert-butyl-2-hydroxy-phenylcarbamoyl)-alkanoic acids as potent antioxidants
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A series of novel phenolic antioxidants of amphiphilic structure has been synthesized. Investigations into the influence of aliphatic spacer length and nature of a hydrophilic anchor on the antioxidant activity allowed elucidating certain structure requirements for the membrane-addressed antioxidant designing.
- Lodyato, Vladimir I.,Yurkova, Irina L.,Sorokin, Viktor L.,Shadyro, Oleg I.,Dolgopalets, Vladimir I.,Kisel, Mikhail A.
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p. 4253 - 4256
(2007/10/03)
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- Phosphorus-based SAHA analogues as histone deacetylase inhibitors
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(Matrix presented) Three analogues of suberoyl anilide hydroxamic acid (SAHA) with phosphorus metal-chelating functionalities were synthesized as inhibitors of histone deacetylases (HDACs). The compounds showed weak activity for HeLa nuclear extracts (IC50 = 0.57-6.1 mM), HDAC8 (IC 50 = 0.28-0.41 mM), and histone-deacetylase-like protein (HDLP, IC50 = 0.33-1.9 mM), suggesting that the transition state of HDAC is not analogous to zinc proteases. Antiproliferative activity against A2780 cancer cells (IC50 = 0.11-0.12 mM), comparable to SAHA (0.15 mM), was observed.
- Kapustin, Galina V.,Fejer, Gyoergy,Gronlund, Jennifer L.,McCafferty, Dewey G.,Seto, Edward,Etzkorn, Felicia A.
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p. 3053 - 3056
(2007/10/03)
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- A facile synthesis of 2-substituted isoflavones for immunoassay: Assembly of the isoflavonoid skeleton by means of a novel cyclisation reaction
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For the purpose of the development of immunoassays for wide-scale screening, isoflavones suitable for attachment to a hapten were prepared. A new cyclisation reaction allowed the direct conversion of 2- (acyloxy)deoxybenzoins to 2-alkylisoflavones by treatment with chlorotrimethylsilane and triethylamine in dimethylformamide.
- Pelter, Andrew,Ward, Robert S.,Whalley, Jacqueline L.
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p. 1793 - 1802
(2007/10/03)
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- Novel synthetic inhibitors of selectin-mediated cell adhesion: Synthesis of 1,6-bis[3-(3-carboxymethylphenyl)-4-(2-α-D-mannopyranosyloxy)phenyl] hexane (TBC1269)
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Reports of a high-affinity ligand for E-selectin, sialyl di-Lewis(x) (sLe(x)Le(x), 1), motivated us to incorporate modifications to previously reported biphenyl-based inhibitors that would provide additional interactions with the protein. These compounds were assayed for the ability to inhibit the binding of sialyl Lewis(x) (sLe(x), 2) bearing HL-60 cells to E-, P-, and L- selectin fusion proteins. We report that dimeric or trimeric compounds containing multiple components of simple nonoligosaccharide selectin antagonists inhibit sLe(x)-dependent binding with significantly enhanced potency over the monomeric compound. The enhanced potency is consistent with additional binding interactions within a single selectin lectin domain; however, multivalent interaction with multiple lectin domains as a possible alternative cannot be ruled out. Compound 15e (TBC1269) showed optimal in vitro activity from this class of antagonists and is currently under development for use in the treatment of asthma.
- Kogan, Timothy P.,Dupré, Brian,Bui, Huong,McAbee, Kathy L.,Kassir, Jamal M.,Scott, Ian L.,Hu, Xin,Vanderslice, Peter,Beck, Pamela J.,Dixon, Richard A. F.
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p. 1099 - 1111
(2007/10/03)
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- A New and Efficient Synthesis of Trifluoromethyl Ketones from Carboxylic Acids. Part I.
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Trifluoromethyl ketones can be prepared in good yield from primary carboxylic acid chlorides by reaction with pyridine and trifluoroacetic anhydride followed by aqueous work up.
- Boivin, Jean,El Kaim, Laurent,Zard, Samir Z.
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p. 2573 - 2584
(2007/10/02)
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- Enzymic Polymerisation of an Unactivated Diol/Diacud System
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The polyesterification of adipic acid and butane-1,4-diol by a commercial lipase (Lipozyme IM-20) has been studied using a two-chamber reactor and molecular sieve as a dehydrating agent.The lower oligomeric products were identified and a low-disperisity polyester averaging 20 repeat units was produced.
- Binns, Falmai,Roberts, Stanley M.,Taylor, Alan,Williams, Charles F.
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p. 899 - 904
(2007/10/02)
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- A New Route to N-Monosubstituted Thioamides Utilizing Phosphoramidothionates as Reagents for the Thioamidation of Carboxylic Acids
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Several N-monosubstituted thioamides have been synthesized from the corresponding carboxylic acid chlorides and primary amines by a new procedure.The procedure utilizes a commercially available and inexpensive organophosphorus reagent (dimethyl chlorothiophosphate) to derivatize the amine, form the carboxamide bond, and accomplish the thionation of the carbonyl by an intramolecular rearrangement.The phosphoryl group is then cleaved from the resulting thiocarbonyl phosphoryl mixed imide by a simple hydrolysis.Thioamides (RCSNHR') containing a variety of functionality(R= simple alkyl, phenyl, bulky alkyl, cycloalkylalkyl, α,β-unsaturated, and alkyl with remote keto, ester, or amide carbonyl groups; R'= methyl, benzyl, allyl) have been prepared by this method in generally high overall yields (50-80 percent).Competing thionation of remote carbonyl groups or epimerization of a chiral center containing a proton α to a ketone group was not observed.
- DeBruin, Kenneth E.,Boros, Eric E.
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p. 6091 - 6098
(2007/10/02)
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- Synthesis and Deprotection of -1-methyl-2-oxobutyl>triphenylphosphonium Chloride: A Key Intermediate in the Wittig Reaction between a Cyclic Anhydride and a Stabilized Ylide
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-1-methyl-2-oxobutyl>triphenylphosphonium chloride (16) has been synthesized as an unstable oil.Removal of the (diphenylmethoxy)carbonyl group gave E enol lactone 5 stereoselectively and without evidence of phosphonium salt 8.When enol lactone formation is not favored as with phosphonium salt 27, loss of triphenylphosphine oxide occurs to yield an allene.Phosphonium salts 16, 17, 18, 20, and 35 have also been shown to yield an allene on treatment with base.The chemistry of these derivatives and the mechanism of enol lactone and allene formation is discussed.Phosphonium salts such as 8 and 27 are postulated as key intermediates in the Wittig reaction between a cyclic anhydride and a stabilized ylide.
- Abell, Andrew D.,Morris, Kathryn B.,Litten, J. Christopher
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p. 5217 - 5221
(2007/10/02)
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- SYNTHESE DANS LA CHIMIE DES PHENANTHRIDINES. II. PREPARATION D'UNE NOUVELLE SERIE D'ω-(PHENANTHRIDINYL-6) ALCANOATES DE METHYLE OU D'ETHYLE
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A new series of methyl and ethyl ω-(6-phenanthridinyl) alkanoates is easily synthesised from the acid chloride - esters ROCO(CH2)nCOCl (n=0, 3 to 8; R=Me or Et).Reaction of these with o-aminobiphenyl leads to the expected amide-esters which are cyclised to phenanthridines quaternised to the corresponding phenanthridinium salts.
- Lion, C.,Boukou-Poba, J. P.,Charvy, C.
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p. 567 - 574
(2007/10/02)
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- Synthesis of Tetrahydrofuranic Acids Substituted in Position 2 and 5
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A synthesis of the 3,6-epoxyalkane diacids 9a-d previously detected in human urine is described.
- Kern, Werner,Spiteller, Gerhard
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p. 1168 - 1174
(2007/10/02)
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- Regioselective Functionalization of Non-Activated CH-bonds, 2. Photochemical Functionalization of the Myristoyl Group in 1,2-Alkanediyl and o-Phenylene 1-(4-Benzoylbenzoate) 2-Myristates
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Myristic acid (1a) was linked with ethylene glycol (2a), trans-1,2-cyclohexanediol (2b), and catechol (2c) to 4-benzoylbencoic acid to form the diesters 4a-c.These cyclize by photolysis to the carbinols 12, which are converted into the methyl 7- to 13-oxomyristates (5a).The ketofunctionalization of the remote CH2-groups in 1a is more selective than in the corresponding benzoylbenzoic esters 13 without the 1,2-alkanediyl or o-phenylene link.Additionally the maximum of the functionalization is shifted from the end towards the middle of the chain.The latter observation can be explained by a higher population of gauche conformations at the beginning of the chain.In CCl4 the selectivity increases slightly from 4a to 4b, c with increasing rigidity of the link.The polarity of the solvent has only a small effect on the selectivity.
- Dors, Bernhard,Luftmann, Heinrich,Schaefer, Hans J.
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p. 761 - 776
(2007/10/02)
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- 1'-(6-Hydroxyoctanoyl)nornicotine and 1'-(7-Hydroxyoctanoyl)nornicotine, Two New Alkaloids from Japanese Domestic Tobacco
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Two new pyridine alkaloids were isolated from an extract of air-cured Japanese domestic tobacco (Nicotiana tabacum L. cv.Ibusuki).The assigned structures of 1'-(6-hydroxyoctanoyl)nornicotine (IIb) and 1'-(7-hydroxyoctanoyl)nornicotine (IIc) were based on spectroscopic properties.In addition, the structure assignments were confirmed by synthesis.
- Miyano, Masashi,Yasumatsu, Norio,Matsushita, Hajime,Nishida, Koh
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p. 1029 - 1033
(2007/10/02)
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- Analogues of 8-amino>-6-methoxy-4-methylquinoline as Candidate Antileishmanial Agents
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8-amino>-6-methoxy-4-methylquinoline (I) has been shown to be highly effective against Leishmania donovani in hamsters, being approximately 475 times as active as the standard meglumine antimoniate.Several nuclear and side-chain analogues of I have been prepared in an attempt to further enhance the antileishmanial activity of this class of compounds.The compounds were tested against L. donovani in the golden hamster.Although several analogues had meglumine antimoniate indexes in excess of 300, none was superior to the model compound.
- LaMontagne, Maurice P.,Dagli, Dinesh,Khan, M. Sami,Blumbergs, Peter
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p. 981 - 985
(2007/10/02)
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- Conjugate, Homoconjugate, and 1,2-Additions of Acetylene Nucleophiles and their Application to Prostaglandin Synthesis
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1-Acylcyclopent-1-enes (10) and (11) undergo 1,4- and 1,2-addition reactions with various alkynylalane reagents at ambient temperatures.Homoconjugate additions of alkynylalanes to endo-3-t-butyldimethylsilyloxytricyclo2,7>heptan-6-one (12) occur to give 7-anti-alkynylbicycloheptanones (24) and (25). 1-Lithioalk-1-ynes can undergo conjugate additions when the reagent is solvated with hexamethylphosphoric triamide. These reactions, designed to provide an approach to prostanoic acid derivatives and their intermediates, avoid the use of low temperatures for conjugate additions.
- Newton, Roger F.,Reynolds, Derek P.,Greenwood, John,Scheinmann, Feodor
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p. 2346 - 2352
(2007/10/02)
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- Covalent Attachment of Arenes to SnO2-Semiconductor Electrodes
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The synthesis and chemical and physical properties of some arene-derivatized tin oxide semiconductor electrodes are described.Several techniques for attachment are employed (esterification, silanation, silanation/amidation, and the use of cyanuric chloride as a linking agent) and the merits of each are evaluated.The relationship between the observed properties of the attached arenes and the potential utility of the derivatized electrodes as anodes in photogalvanic cells is discussed.
- Fox, Marye Anne,Nobs, Frederic J.,Voynick, Tamara A.
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p. 4029 - 4036
(2007/10/02)
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