- Structure-Activity Studies of Truncated Latrunculin Analogues with Antimalarial Activity
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Malarial parasites employ actin dynamics for motility, and any disruption to these dynamics renders the parasites unable to effectively establish infection. Therefore, actin presents a potential target for malarial drug discovery, and naturally occurring actin inhibitors such as latrunculins are a promising starting point. However, the limited availability of the natural product and the laborious route for synthesis of latrunculins have hindered their potential development as drug candidates. In this regard, we recently described novel truncated latrunculins, with superior actin binding potency and selectivity towards P. falciparum actin than the canonical latrunculin B. In this paper, we further explore the truncated latrunculin core to summarize the SAR for inhibition of malaria motility. This study helps further understand the binding pattern of these analogues in order to develop them as drug candidates for malaria.
- Varghese, Swapna,Rahmani, Rapha?l,Drew, Damien R.,Beeson, James G.,Baum, Jake,Smith, Brian J.,Baell, Jonathan B.
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p. 679 - 693
(2020/11/30)
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- Nucleus-independent chemical shift (NICS) as a criterion for the design of new antifungal benzofuranones
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The assertion made by Wu et al. that aromaticity may have considerable implications for molecular design motivated us to use nucleus-independent chemical shifts (NICS) as an aromaticity criterion to evaluate the antifungal activity of two series of indol-4-ones. A linear regression analysis of NICS and antifungal activity showed that both tested variables were significantly related (p –1 for Candida glabrata, Candida krusei and Candida guilliermondii with compounds 15-32, 15-15 and 15-1. The MIC for filamentous fungi was 1.95 μg·mL–1 for Aspergillus niger for compounds 15-1, 15-33 and 15-34. The results obtained support the use of NICS in the molecular design of compounds with antifungal activity.
- González-Chávez, Marco Martín,González-Chávez, Rodolfo,Méndez, Francisco,Martínez, Roberto,Ni?o-Moreno, Perla Del Carmen,Ojeda-Fuentes, Luis Enrique,Richaud, Arlette,Zerme?o-Macías, María de los ángeles
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- Pyridine-substituted thiazolylphenol derivatives: Synthesis, modeling studies, aromatase inhibition, and antiproliferative activity evaluation
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Drugs used in breast cancer treatments target the suppression of estrogen biosynthesis. During this suppression, the main goal is to inhibit the aromatase enzyme that is responsible for the cyclization and structuring of estrogens either with steroid or non-steroidal-type inhibitors. Non-steroidal derivatives generally have a planar aromatic structure attached to the triazole ring system in their structures, which inhibits hydroxylation reactions during aromatization by coordinating the heme group. Bioisosteric replacement of the triazole ring system and development of aromatic/cyclic structures of the side chain can increase the selectivity for aromatase enzyme inhibition. In this study, pyridine-substituted thiazolylphenol derivatives, which are non-steroidal triazole bioisosteres, were synthesized using the Hantzsch method, and physical analysis and structural determination studies were performed. The IC50 values of the compounds were determined by a fluorescence-based aromatase inhibition assay. Then, their antiproliferative activities on the MCF7 and HEK 293 cell lines were evaluated with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Furthermore, the crystal structure of human placental aromatase was subjected to a series of docking experiments to identify the possible interactions between the most active structure and the active site. Lastly, an in silico technique was performed to analyze and predict the drug-likeness, molecular and ADME properties of the synthesized molecules.
- Ertas, Merve,Sahin, Zafer,Berk, Barkin,Yurttas, Leyla,Biltekin, Sevde N.,Demirayak, Seref
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- Studies on non-steroidal inhibitors of aromatase enzyme; 4-(aryl/heteroaryl)-2-(pyrimidin-2-yl)thiazole derivatives
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Steroidal and non-steroidal aromatase inhibitors target the suppression of estrogen biosynthesis in the treatment of breast cancer. Researchers have increasingly focused on developing non-steroidal derivatives for their potential clinical use avoiding steroidal side-effects. Non-steroidal derivatives generally have planar aromatic structures attached to the azole ring system. One part of this ring system comprises functional groups that inhibit aromatization through the coordination of the haem group of the aromatase enzyme. Replacement of the triazole ring system and development of aromatic/cyclic structures of the side chain can increase selectivity over aromatase enzyme inhibition. In this study, 4-(aryl/heteroaryl)-2-(pyrimidin-2-yl)thiazole derivatives were synthesized and physical analyses and structural determination studies were performed. The IC50 values were determined by a fluorescence-based aromatase inhibition assay and compound 1 (4-(2-hydroxyphenyl)-2-(pyrimidine-2-yl)thiazole) were found potent inhibitor of enzyme (IC50:0.42 nM). Then, their antiproliferative activity over MCF-7 and HEK-293 cell lines was evaluated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Compounds 1, 7, 8, 13, 15, 18, 21 were active against MCF-7 breast cancer cells. Lastly, a series of docking experiments were undertaken to analyze the crystal structure of human placental aromatase and identify the possible interactions between the most active structure and the active site.
- Sahin, Zafer,Ertas, Merve,Berk, Bark?n,Biltekin, Sevde Nur,Yurttas, Leyla,Demirayak, Seref
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p. 1986 - 1995
(2018/03/12)
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- Synthesis and biological evaluation of novel SIPI-7623 derivatives as farnesoid X receptor (FXR) antagonists
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Most of reported steroidal FXR antagonists are restricted due to low potency. We described the design and synthesis of novel nonsteroidal scaffold SIPI-7623 derivatives as FXR antagonists. The most potent compound A-11 (IC50 = 7.8 ± 1.1 μM) showed better activity compared to SIPI-7623 (IC50 = 40.8 ± 1.7 μM) and guggulsterone (IC50 = 45.9 ± 1.1 μM). Docking of A-11 in FXR’s ligand-binding domain was also studied.
- Nian, Si-Yun,Wang, Guo-Ping,Jiang, Zheng-Li,Xiao, Ying,Huang, Mo-Han,Zhou, Yi-Huan,Tan, Xiang-Duan
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- Efficient synthesis of (R)-phenylephrine using a polymer-supported Corey-Bakshi-Shibata catalyst
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An efficient and mild synthetic route to (R)-phenylephrine hydrochloride using Corey-Bakshi-Shibata (CBS) catalyst was reported. In order to avoid a lengthy recovery process of the catalyst from homogeneous reaction, a polymer-supported CBS catalyst was prepared, and a preliminary attempt was made to achieve a continuous reduction on a laboratory scale, which contributes to synthesis of (R)-phenylephrine in a cost-effective way.
- Dai, Shuangxiong,Li, Guohua,Zhang, Wenbo,Zhang, Cuiyan,Song, Xiaoling,Huang, Di
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p. 740 - 743
(2017/05/16)
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- Citric Acid-catalyzed Synthesis of 2,4-Disubstituted Thiazoles from Ketones via C–Br, C–S, and C–N Bond Formations in One Pot: A Green Approach
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An improved and greener protocol has been developed for the synthesis of 2,4-disubstituted thiazoles via C–Br, C–S, and, C–N bond formations in a single step from readily available ketones, N-bromosuccinimide (NBS), and thiourea catalyzed by citric acid in a mixture of ethanol and water (3:1) under reflux conditions. This method has the advantages of freedom from the isolation of lachrymatory α-bromoketones, ease of carrying out, cleaner reaction profile, broad substrate scope, freedom from chromatographic purification, and suitability for large-scale synthesis.
- Gundala, Trivikram Reddy,Godugu, Kumar,Nallagondu, Chinna Gangi Reddy
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p. 1408 - 1416
(2017/10/23)
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- Highly Efficient Synthesis of α-Halomethylketones via Ce(SO4)2/Acid Co-Catalyzed Hydration of Alkynes
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A general atom-economical approach for the synthesis of α-halomethyl ketones is demonstrated through Ce(SO4)2/acid co-catalyzed hydration of a wide range of haloalkynes. The reactions are conducted under convenient conditions and provide products with excellent regioselectivity in good to excellent yields, with broad substrate scope. This protocol is an alternative to conventional α-halogenation of ketones.
- Zou, Huaxu,Jiang, Jun,Yi, Niannian,Fu, Wenqiang,Deng, Wei,Xiang, Jiannan
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supporting information
p. 1251 - 1254
(2016/12/27)
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- In(OTf)3/acid co-catalyzed hydration of 1-haloalkynes to α-halomethyl ketones
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A novel and efficient In(OTf)3and HOAc cooperatively catalyzed hydration of 1-haloalkynes is described. This method provides ready access to α-chloromethyl ketones, α-bromomethyl ketones and α-iodomethyl ketones in moderate to high yields from simple, inexpensive starting materials. A broad substrate scope is achieved, and the reaction is compatible with various functional groups, including alkoxy, trifluoromethyl, halide, hydroxyl, cyclohexyl, and heterocyclic groups.
- Zeng, Ming,Huang, Rui-Xue,Li, Wen-Yi,Liu, Xiao-Wen,He, Fu-Ling,Zhang, Yi-Yuan,Xiao, Fang
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p. 3818 - 3822
(2016/07/06)
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- Synthesis and structure-activity relationship of aminoarylthiazole derivatives as correctors of the chloride transport defect in cystic fibrosis
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Abstract The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel present in the membrane of epithelial cells. Mutations affecting the CFTR gene cause cystic fibrosis (CF), a multi-organ severe disease. The most common CF mutation, F508del, impairs the processing and activity (gating) of CFTR protein. Other mutations, like G551D, only cause a gating defect. Processing and gating defects can be targeted by small molecules called generically correctors and potentiators, respectively. Aminoarylthiazoles (AATs) represent an interesting class of compounds that includes molecules with dual activity, as correctors and potentiators. With the aim to improve the activity profile of AATs, we have now designed and synthesized a library of novel compounds in order to establish an initial SAR that may provide indications about the chemical groups that are beneficial or detrimental for rescue activity. The new compounds were tested as correctors and potentiators in CFBE41o-expressing F508del-CFTR using a functional assay. A dual active compound, AAT-4a, characterized by improved efficacy and marked synergy when combined with the corrector VX-809 has been identified. Moreover, by computational methods, a possible binding site for AATs in nucleotide binding domain NBD1 has been detected. These results will direct the synthesis of new analogues with possibly improved activity.
- Pesce, Emanuela,Bellotti, Marta,Liessi, Nara,Guariento, Sara,Damonte, Gianluca,Cichero, Elena,Galatini, Andrea,Salis, Annalisa,Gianotti, Ambra,Pedemonte, Nicoletta,Zegarra-Moran, Olga,Fossa, Paola,Galietta, Luis J.V.,Millo, Enrico
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supporting information
p. 14 - 35
(2015/06/08)
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- Synthesis and in-vitro evaluation of 2-amino-4-arylthiazole as inhibitor of 3D polymerase against foot-and-mouth disease (FMD)
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Foot-and-mouth disease (FMD) is a highly contagious vesicular disease of livestock caused by a highly variable RNA virus, foot-and-mouth disease virus (FMDV). One of the targets to suppress expansion of and to control FMD is 3D polymerase (FMDV 3Dpol). In this study, 2-amino-4-arylthiazole derivatives were synthesized and evaluated for their inhibitory activity against FMDV 3Dpol. Among them, compound 20i exhibited the most potent functional inhibition (IC50 = 0.39μM) of FMDV 3D polymerase and compound 24a (EC50=13.09 μM) showed more potent antiviral activity than ribavirin (EC50=1367 μM) and T1105 (EC50=347 μM) with IBRS-2 cells infected by the FMDV O/SKR/2010 strain.
- Jeong, Kwi-Wan,Lee, Jung-Hun,Park, Sun-Mi,Choi, Joo-Hyung,Jeong, Dae-Youn,Choi, Dong-Hwa,Nam, Yeonju,Park, Jong-Hyeon,Lee, Kwang-Nyeong,Kim, Su-Mi,Ku, Jin-Mo
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p. 387 - 397
(2015/09/01)
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- Inhibition of protein kinase C-driven nuclear factor-κB activation: Synthesis, structure-activity relationship, and pharmacological profiling of pathway specific benzimidazole probe molecules
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A unique series of biologically active chemical probes that selectively inhibit NF-κB activation induced by protein kinase C (PKC) pathway activators have been identified through a cell-based phenotypic reporter gene assay. These 2-aminobenzimidazoles represent initial chemical tools to be used in gaining further understanding on the cellular mechanisms driven by B and T cell antigen receptors. Starting from the founding member of this chemical series 1a (notated in PubChem as CID-2858522), we report the chemical synthesis, SAR studies, and pharmacological profiling of this pathway-selective inhibitor of NF-κB activation.
- Peddibhotla, Satyamaheshwar,Shi, Ranxin,Khan, Pasha,Smith, Layton H.,Mangravita-Novo, Arianna,Vicchiarelli, Michael,Su, Ying,Okolotowicz, Karl J.,Cashman, John R.,Reed, John C.,Roth, Gregory P.
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supporting information; experimental part
p. 4793 - 4797
(2010/10/19)
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- Ultrasounds-assisted synthesis of highly functionalized acetophenone derivatives in heterogeneous catalysis
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A fast, general, environmentally friendly, and facile method for preparation of highly functionalized acetophenone derivatives under ultrasound irradiation in heterogeneous catalysis is presented. The ultrasound enhanced a remarkable rate of acceleration for bromination, the reaction time decrease significantly, reaction conditions are milder, the consumed energy decreases considerably and the amount of used solvents was reduced. Consequently, the ultrasounds-assisted bromination reaction could be considered ecofriendly. In the most cases under ultrasound irradiation the yields are higher, in some cases substantially. A comparative study, ultrasounds-conventional conditions was done.
- Zbancioc, Gheorghita N.,Zbancioc, Ana Maria V.,Mantu, Dorina,Miron, Anca,Tanase, Catalin,Mangalagiu, Ionel I.
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experimental part
p. 983 - 987
(2012/01/13)
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- NOVEL COMPOUND HAVING AFFINITY FOR AMYLOID
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The present invention provides a compound which has affinity with amyloid, shows sufficiently rapid clearance from normal tissues and is suppressed in toxicity such as mutagencity. Provided is a compound represented by the following formula (1) or a salt thereof: wherein A1, A2, A3 and A4 independently represents a carbon or nitrogen; R1 is a halogen substituent; R2 is a halogen substituent; and m is an integer of 0 to 2, provided that at least one of R1 and R2 is a radioactive halogen substituent, at least one of A1, A2, A3 and A4 represents a carbon, and R1 binds to a carbon represented by A1, A2, A3 or A4 as well as a low-toxic diagnostic agent comprising a compound represented by the preceding formula or a salt thereof.
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Page/Page column 36
(2009/02/10)
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- PROCESS FOR THE PREPARATION OF OPTICALLY ACTIVE 2-AMINO-1-PHENYLETHANOLS
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Optically active 2-amino-l-phenylethanols of formula (I) or its mirror image, wherein R1 is hydrogen, C1-6alkyl or aryl-substituted C1-6alkyl and R2 through R6 are independently hydrogen, hydroxy or C1-6alkoxy, or salts thereof are prepared by asymmetric hydrogenation of the corresponding 2-aminoacetophenones in the presence of a ruthenium complex catalyst comprising a chiral phosphine ligand.
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Page/Page column 9
(2008/12/06)
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- PROCESS FOR THE PREPARATION OF OPTICALLY ACTIVE 2-AMINO-1-PHENYLETHANOLS
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Optically active 2-amino-l-phenylethanols of formula (I) or its mirror image, wherein R1 is C1-6 alkyl or aryl-substituted C1-6 alkyl and R2 through R6 are independently hydrogen, hydroxy or C1-6 alkoxy, or salts thereof are prepared by asymmetric hydrogenation of the corresponding 2-aminoaceto-phenones in the presence of a rhodium complex catalyst comprising a chiral diphosphine ligand, wherein each phosphorus atom is part of a heterocyclic ring system which contains at least one chiral carbon atom directly bound to the phosphorus atom.
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Page/Page column 11
(2008/12/08)
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- Diaminothiazoles
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Novel diaminothiazoles of formula (I): [image] are discussed. These compounds selectively inhibit the activity of Cdk4 and are thus useful in the treatment or control of cancer, in particular, the treatment or control of solid tumors. This invention also provides pharmaceutical compositions containing such compounds and methods of treating or controlling cancer, most particularly, the treatment or control of breast, lung, colon, and prostate tumors.
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Page/Page column 55
(2008/06/13)
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- Montmorillonite K10 - AlCl3 catalyzed enolization: A bifunctional system for selective bromination of hydroxyacetophenones
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A heterogeneous system consisting of montmorillonite K-10 and AlCl3 (catalytic amount) in ethyl acetate serves as an effective catalyst for the enolization of hydroxyacetophenones thereby facilitating selective bromination of side chain using molecular bromine.
- Uchil, Vinod Rama,Joshi, Vidya
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p. 408 - 411
(2007/10/03)
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- Compounds and compositons for treating C1s-mediated diseases and conditions
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Disclosed is a method for treating the symptoms of an acute or chronic disorder mediated by the classical pathway of the complement cascade, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula I or a solvate, hydrate or pharmaceutically acceptable salt thereof; wherein R1, R2, R3, R4, X, Y and Z are defined in the specification.
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- Diaminothiazoles having antiproliferative activity
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Disclosed are novel diaminothiazoles that are selective inhibitors of Cdk4. These compounds and their pharmaceutically acceptable salts and esters are anti-proliferative agents useful in the treatment or control of solid tumors, in particular breast, colon, lung and prostate tumors. Also disclosed are pharmaceutical compositions containing these compounds as well as intermediates useful in the preparation of the compounds.
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- Heteroaryl amidines, methylamidines and guanidines, preparation thereof, and use thereof as protease inhibitors
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The present invention is directed to compounds of Formula I: wherein X is O, S or NR7and R1-R7, Y and Z are set forth in the specification, as well as hydrates, solvates or pharmaceutically acceptable salts thereof. Also described are methods for preparing the compounds of Formula I. The novel compounds of the present invention are potent inhibitors of proteases, especially trypsin-like serine proteases, such as chymotrypsin, trypsin, plasmin and urokinase. Certain of the compounds exhibit direct, selective inhibition of urokinase, or are intermediates useful for forming compounds having such activity.
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- Discovery and structure-activity relationship of the first non-pep tide competitive human glucagon receptor antagonists
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The first non-peptide competitive human glucagon receptor antagonist, 2-(benzimidazol-2ylthio)-l-(3,4-dihydroxyphenyl)-l-ethanone, NNC 92-1687 (2), is described. This antagonist has a binding affinity of 20 μM (ICso) and a functional Ki = 9.1 μM at the human glucagon receptor. A structure-activity relationship (SAR) was obtained on this compound, and the results show that only the benzimidazole part can be changed without complete loss of affinity. Analogues with tert-butyl or benzyloxy groups in the 5-position of the benzimidazole moiety were found to be equipotent or slightly more potent, all displaying binding affinities around 5-20 μM. Most of the changes to the catechol and the linker gave compounds without any affinity toward the human glucagon receptor. The 3-hydroxy group could, however, in the presence of a 4-hydroxy group be changed to a methoxy or a chloro group while retaining affinity.
- Madsen, Peter,Knudsen, Lotte B.,Wiberg, Finn C.,Carr, Richard D.
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p. 5150 - 5157
(2007/10/03)
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