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1.
GluN2B‐Selective N‐Methyl‐d‐aspartate (NMDA) Receptor Antagonists Derived from 3‐Benzazepines: Synthesis and Pharmacological Evaluation of Benzo[7]annulen‐7‐amines 下载免费PDF全文
Dr. Andre Benner Alessandro Bonifazi Chikako Shirataki Louisa Temme Dr. Dirk Schepmann Prof. Wilma Quaglia Prof. Osami Shoji Prof. Yoshihito Watanabe Dr. Constantin Daniliuc Prof. Dr. Bernhard Wünsch 《ChemMedChem》2014,9(4):741-751
Given their high neuroprotective potential, ligands that block GluN2B‐containing N‐methyl‐D ‐aspartate (NMDA) receptors by interacting with the ifenprodil binding site located on the GluN2B subunit are of great interest for the treatment of various neuronal disorders. In this study, a novel class of GluN2B‐selective NMDA receptor antagonists with the benzo[7]annulene scaffold was prepared and pharmacologically evaluated. The key intermediate, N‐(2‐methoxy‐5‐oxo‐6,7,8,9‐tetrahydro‐5H‐benzo[7]annulen‐7‐yl)acetamide ( 11 ), was obtained by cyclization of 3‐acetamido‐5‐(3‐methoxyphenyl)pentanoic acid ( 10 b ). The final reaction steps comprise hydrolysis of the amide, reduction of the ketone, and reductive alkylation, leading to cis‐ and trans‐configured 7‐(ω‐phenylalkylamino)benzo[7]annulen‐5‐ols. High GluN2B affinity was observed with cis‐configured γ‐amino alcohols substituted with a 3‐phenylpropyl moiety at the amino group. Removal of the benzylic hydroxy moiety led to the most potent GluN2B antagonists of this series: 2‐methoxy‐N‐(3‐phenylpropyl)‐6,7,8,9‐tetrahydro‐5H‐benzo[7]annulen‐7‐amine ( 20 a , Ki=10 nM ) and 2‐methoxy‐N‐methyl‐N‐(3‐phenylpropyl)‐6,7,8,9‐tetrahydro‐5H‐benzo[7]annulen‐7‐amine ( 23 a , Ki=7.9 nM ). The selectivity over related receptors (phencyclidine binding site of the NMDA receptor, σ1 and σ2 receptors) was recorded. In a functional assay measuring the cytoprotective activity of the benzo[7]annulenamines, all tested compounds showed potent NMDA receptor antagonistic activity. Cytotoxicity induced via GluN2A subunit‐containing NMDA receptors was not inhibited by the new ligands. 相似文献
2.
Synthesis and Pharmacological Evaluation of Enantiomerically Pure GluN2B Selective NMDA Receptor Antagonists 下载免费PDF全文
Frederik Börgel Dr. Marina Szermerski Julian A. Schreiber Dr. Louisa Temme Dr. Nathalie Strutz‐Seebohm Kirstin Lehmkuhl Dr. Dirk Schepmann Prof. Dr. Simon M. Ametamey Prof. Dr. Guiscard Seebohm Prof. Dr. Thomas J. Schmidt Prof. Dr. Bernhard Wünsch 《ChemMedChem》2018,13(15):1580-1587
To determine the eutomers of potent GluN2B‐selective N‐methyl‐d ‐aspartate (NMDA) receptor antagonists with a 3‐benzazepine scaffold, 7‐benzyloxy‐3‐(4‐phenylbutyl)‐2,3,4,5‐tetrahydro‐1H‐3‐benzazepin‐1‐ols (S)‐ 2 and (R)‐ 2 were separated by chiral HPLC. Hydrogenolysis and subsequent methylation of the enantiomerically pure benzyl ethers of (S)‐ 2 and (R)‐ 2 provided the enantiomeric phenols (S)‐ 3 and (R)‐ 3 [3‐(4‐phenylbutyl)‐2,3,4,5‐tetrahydro‐1H‐3‐benzazepine‐1,7‐diol] and methyl ethers (S)‐ 4 and (R)‐ 4 . All enantiomers were obtained with high enantiomeric purity (≥99.7 % ee). The absolute configurations were determined by CD spectroscopy. R‐configured enantiomers turned out to be the eutomers in receptor binding studies and two‐electrode voltage clamp experiments. The most promising ligand of this compound series is the R‐configured phenol (R)‐ 3 , displaying high GluN2B affinity (Ki=30 nm ), high inhibition of ion flux (IC50=61 nm ), and high cytoprotective activity (IC50=93 nm ). Whereas the eudismic ratio in the receptor binding assay is 25, the eudismic ratio in the electrophysiological experiment is 3. 相似文献
3.
Synthesis, σ Receptor Affinity,and Pharmacological Evaluation of 5‐Phenylsulfanyl‐ and 5‐Benzyl‐Substituted Tetrahydro‐2‐benzazepines 下载免费PDF全文
Dr. Peer Hasebein Bastian Frehland Dr. Dirk Schepmann Prof. Dr. Bernhard Wünsch 《ChemMedChem》2014,9(8):1697-1703
In accordance with a novel strategy for generating the 2‐benzazepine scaffold by connecting C6–C1 and C3–N building blocks, a set of 5‐phenylsulfanyl‐ and 5‐benzyl‐substituted tetrahydro‐2‐benzazepines was synthesized and pharmacologically evaluated. Key steps of the synthesis were the Heck reaction, the Stetter reaction, a reductive cyclization, and the introduction of diverse N substituents at the end of the synthesis. High σ1 affinity was achieved for 2‐benzazepines with linear or branched alk(en)yl residues containing at least an n‐butyl substructure. The butyl‐ and 4‐fluorobenzyl‐substituted derivatives, (±)‐5‐benzyl‐2‐butyl‐2,3,4,5‐tetrahydro‐1H‐2‐benzazepine ( 19 b ) and (±)‐5‐benzyl‐2‐(4‐fluorobenzyl)‐2,3,4,5‐tetrahydro‐1H‐2‐benzazepine ( 19 m ), show high selectivity over more than 50 other relevant targets, including the σ2 subtype and various binding sites of the N‐methyl‐D ‐aspartate (NMDA) receptor. In the Irwin screen, 19 b and 19 m showed clean profiles without inducing considerable side effects. Compounds 19 b and 19 m did not reveal significant analgesic and cognition‐enhancing activity. Compound 19 m did not have any antidepressant‐like effects in mice. 相似文献
4.
Mangaleswaran Sivaprakasam Dr. Kasper B. Hansen Dr. Olivier David Dr. Birgitte Nielsen Stephen F. Traynelis Prof. Rasmus P. Clausen Prof. François Couty Prof. Lennart Bunch Prof. 《ChemMedChem》2009,4(1):110-117
The four stereoisomers of azetidine‐2,3‐dicaroxylic acid (L ‐trans‐ADC, L ‐cis‐ADC, D ‐trans‐ADC, and D ‐cis‐ADC) were synthesized in a stereocontrolled fashion following two distinct strategies: one providing the two cis‐ADC enantiomers and one giving access to the two trans‐ADC enantiomers. The four azetidinic amino acids were characterized in a radioligand binding assay ([3H]CGP39653) at native NMDA receptors: L ‐trans‐ADC showed the highest affinity (Ki=10 μM ) followed by the D ‐cis‐ADC stereoisomer (21 μM ). In contrast, the two analogues L ‐cis‐ADC and D ‐trans‐ADC were low‐affinity ligands (>100 and 90 μM , respectively). Electrophysiological characterization of the ADC compounds at the four NMDA receptor subtypes NR1/NR2A, NR1/NR2B, NR1/NR2C, and NR1/NR2D expressed in Xenopus oocytes showed that L ‐trans‐ADC displayed the highest agonist potency at NR1/NR2D (EC50=50 μM ), which was 9.4‐, 3.4‐, and 1.9‐fold higher than the respective potencies at NR1/NR2A–C. D ‐cis‐ADC was shown to be a partial agonist at NR1/NR2C and NR1/NR2D with medium‐range micromolar potencies (EC50=720 and 230 μM , respectively). A subsequent in silico ligand–protein docking study suggested an unusual binding mode for these amino acids in the agonist binding site. 相似文献
5.
Evaluation of (4‐Arylpiperidin‐1‐yl)cyclopentanecarboxamides As High‐Affinity and Long‐Residence‐Time Antagonists for the CCR2 Receptor 下载免费PDF全文
Dr. Maris Vilums Dr. Annelien J. M. Zweemer Arian Dilanchian Jacobus P. D. van Veldhoven Henk de Vries Dr. Johannes Brussee Dr. John Saunders Dr. Dean Stamos Dr. Laura H. Heitman Prof. Adriaan P. IJzerman 《ChemMedChem》2015,10(7):1249-1258
Animal models suggest that the chemokine ligand 2/CC‐chemokine receptor 2 (CCL2/CCR2) axis plays an important role in the development of inflammatory diseases. However, CCR2 antagonists have failed in clinical trials because of a lack of efficacy. We previously described a new approach for the design of CCR2 antagonists by the use of structure–kinetics relationships (SKRs). Herein we report new findings on the structure–affinity relationships (SARs) and SKRs of the reference compound MK‐0483, its diastereomers, and its structural analogues as CCR2 antagonists. The SARs of the 4‐arylpiperidine group suggest that lipophilic hydrogen‐bond‐accepting substituents at the 3‐position are favorable. However, the SKRs suggest that a lipophilic group with a certain size is desired [e.g., 3‐Br: Ki=2.8 nM , residence time (tres)=243 min; 3‐iPr: Ki=3.6 nM , tres=266 min]. Alternatively, additional substituents and further optimization of the molecule, while keeping a carboxylic acid at the 3‐position, can also prolong tres; this was most prominently observed in MK‐0483 (Ki=1.2 nM , tres=724 min) and a close analogue (Ki=7.8 nM ) with a short residence time. 相似文献
6.
Emma Langella Dr. Sébastien Pierre Dr. Wadih Ghattas Dr. Michel Giorgi Dr. Marius Réglier Dr. Michele Saviano Dr. Luciana Esposito Dr. Renaud Hardré Dr. 《ChemMedChem》2010,5(9):1568-1576
Specific inhibition of the copper‐containing peptidylglycine α‐hydroxylating monooxygenase (PHM), which catalyzes the post‐translational modification of peptides involved in carcinogenesis and tumor progression, constitutes a new approach for combating cancer. We carried out a structure–activity study of new compounds derived from a well‐known PHM substrate analogue, the olefinic compound 4‐phenyl‐3‐butenoic acid (PBA). We designed, synthesized, and tested various PBA derivatives both in vitro and in silico. We show that it is possible to increase PBA affinity for PHM by appropriate functionalization of its aromatic nucleus. Compound 2 d , for example, bears a meta‐benzyloxy substituent, and exhibits better inhibition features (Ki=3.9 μM , kinact/Ki=427 M ?1 s?1) than the parent PBA (Ki=19 μM , kinact/Ki=82 M ?1 s?1). Docking calculations also suggest two different binding modes for PBA derivatives; these results will aid in the development of further PHM inhibitors with improved features. 相似文献
7.
Yu‐Nong Lin Daniel Stein Sheng‐Wei Lin Sue‐Ming Chang Ting‐Chien Lin Yu‐Ruei Chuang Jacquelyn Gervay‐Hague Hisashi Narimatsu Chun‐Hung Lin 《Advanced Synthesis \u0026amp; Catalysis》2012,354(9):1750-1758
Fucosyltransferases (FucTs) usually catalyze the final step of glycosylation and are critical to many biological processes. High levels of specific FucT activities are often associated with various cancers. Here we report the development of a chemoenzymatic method for synthesizing a library of guanosine diphosphate β‐L ‐fucose (GDP‐Fuc) derivatives, followed by in situ screening for inhibitory activity against bacterial and human α‐1,3‐FucTs. Several compounds incorporating appropriate hydrophobic moieties were identified from the initial screening. These were individually synthesized, purified and characterized in detail for their inhibition kinetics. Compound 5 had a Ki of 29 nM for human FucT‐VI, and is 269 and 11 times more selective than for Helicobacter pylori FucT (Ki=7.8 μM) and for human FucT‐V (Ki=0.31 μM). 相似文献
8.
Diaryl‐Substituted Azolylthioacetamides: Inhibitor Discovery of New Delhi Metallo‐β‐Lactamase‐1 (NDM‐1) 下载免费PDF全文
Yi‐Lin Zhang Prof. Ke‐Wu Yang Ya‐Jun Zhou Alecander E. LaCuran Prof. Peter Oelschlaeger Prof. Michael W. Crowder 《ChemMedChem》2014,9(11):2445-2448
The emergence and spread of antibiotic‐resistant pathogens is a global public health problem. Metallo‐β‐lactamases (MβLs) such as New Delhi MβL‐1 (NDM‐1) are principle contributors to the emergence of resistance because of their ability to hydrolyze almost all known β‐lactam antibiotics including penicillins, cephalosporins, and carbapenems. A clinical inhibitor of MBLs has not yet been found. In this study we developed eighteen new diaryl‐substituted azolylthioacetamides and found all of them to be inhibitors of the MβL L1 from Stenotrophomonas maltophilia (Ki<2 μM ), thirteen to be mixed inhibitors of NDM‐1 (Ki<7 μM ), and four to be broad‐spectrum inhibitors of all four tested MβLs CcrA from Bacteroides fragilis, NDM‐1 and ImiS from Aeromonas veronii, and L1 (Ki<52 μM ), which are representative of the B1a, B1b, B2, and B3 subclasses, respectively. Docking studies revealed that the azolylthioacetamides, which have the broadest inhibitory activity, coordinate to the ZnII ion(s) preferentially via the triazole moiety, while other moieties interact mostly with the conserved active site residues Lys224 (CcrA, NDM‐1, and ImiS) or Ser221 (L1). 相似文献
9.
8‐Benzyltetrahydropyrazino[2,1‐f]purinediones: Water‐Soluble Tricyclic Xanthine Derivatives as Multitarget Drugs for Neurodegenerative Diseases 下载免费PDF全文
Dr. Andreas Brunschweiger Dr. Pierre Koch Dr. Miriam Schlenk Dr. Felipe Pineda Dr. Petra Küppers Dr. Sonja Hinz Dr. Meryem Köse Dr. Stefan Ullrich Dr. Jörg Hockemeyer Prof. Dr. Michael Wiese Dr. Jag Heer Prof. Dr. Christa E. Müller 《ChemMedChem》2014,9(8):1704-1724
8‐Benzyl‐substituted tetrahydropyrazino[2,1‐f]purinediones were designed as tricyclic xanthine derivatives containing a basic nitrogen atom in the tetrahydropyrazine ring to improve water solubility. A library of 69 derivatives was prepared and evaluated in radioligand binding studies at adenosine receptor (AR) subtypes and for their ability to inhibit monoamine oxidases (MAO). Potent dual‐target‐directed A1/A2A adenosine receptor antagonists were identified. Several compounds showed triple‐target inhibition; one of the best compounds was 8‐(2,4‐dichloro‐5‐fluorobenzyl)‐1,3‐dimethyl‐6,7,8,9‐tetrahydropyrazino[2,1‐f]purine‐2,4(1H,3H)‐dione ( 72 ) (human AR: Ki A1 217 nM , A2A 233 nM ; IC50 MAO‐B: 508 nM ). Dichlorinated compound 36 [8‐(3,4‐dichlorobenzyl)‐1,3‐dimethyl‐6,7,8,9‐tetrahydropyrazino[2,1‐f]purine‐2,4(1H,3H)‐dione] was found to be the best triple‐target drug in rat (Ki A1 351 nM , A2A 322 nm; IC50 MAO‐B: 260 nM ), and may serve as a useful tool for preclinical proof‐of‐principle studies. Compounds that act at multiple targets relevant for symptomatic as well as disease‐modifying treatment of neurodegenerative diseases are expected to show advantages over single‐target therapeutics. 相似文献
10.
Dr. Giulio Ferino Prof. Enzo Cadoni Dr. Maria João Matos Dr. Elias Quezada Prof. Eugenio Uriarte Prof. Lourdes Santana Dr. Santiago Vilar Dr. Nicholas P. Tatonetti Matilde Yáñez Dolores Viña Dr. Carmen Picciau Dr. Silvia Serra Prof. Giovanna Delogu 《ChemMedChem》2013,8(6):956-966
Monoamine oxidase (MAO) is an important drug target for the treatment of neurological disorders. Several 3‐arylcoumarin derivatives were previously described as interesting selective MAO‐B inhibitors. Preserving the trans‐stilbene structure, a series of 2‐arylbenzofuran and corresponding 3‐arylcoumarin derivatives were synthesized and evaluated as inhibitors of both MAO isoforms, MAO‐A and MAO‐B. In general, both types of derivatives were found to be selective MAO‐B inhibitors, with IC50 values in the nano‐ to micromolar range. 5‐Nitro‐2‐(4‐methoxyphenyl)benzofuran ( 8 ) is the most active compound of the benzofuran series, presenting MAO‐B selectivity and reversible inhibition (IC50=140 nM ). 3‐(4′‐Methoxyphenyl)‐6‐nitrocoumarin ( 15 ), with the same substitution pattern as that of compound 8 , was found to be the most active MAO‐B inhibitor of the coumarin series (IC50=3 nM ). However, 3‐phenylcoumarin 14 showed activity in the same range (IC50=6 nM ), is reversible, and also severalfold more selective than compound 15 . Docking experiments for the most active compounds into the MAO‐B and MAO‐A binding pockets highlighted different interactions between the derivative classes (2‐arylbenzofurans and 3‐arylcoumarins), and provided new information about the enzyme–inhibitor interaction and the potential therapeutic application of these scaffolds. 相似文献
11.
Development of 3‐Phenyl‐N‐(2‐(3‐phenylureido)ethyl)‐thiophene‐2‐sulfonamide Compounds as Inhibitors of Antiapoptotic Bcl‐2 Family Proteins 下载免费PDF全文
Dr. Chengwen Yang Sha Chen Mi Zhou Dr. Yan Li Yangfeng Li Zhengxi Zhang Dr. Zhen Liu Dr. Qian Ba Dr. Jingquan Li Prof. Hui Wang Prof. Xiaomei Yan Prof. Dawei Ma Prof. Renxiao Wang 《ChemMedChem》2014,9(7):1436-1452
Antiapoptotic Bcl‐2 family proteins, such as Bcl‐xL, Bcl‐2, and Mcl‐1, are often overexpressed in tumor cells, which contributes to tumor cell resistance to chemotherapies and radiotherapies. Inhibitors of these proteins thus have potential applications in cancer treatment. We discovered, through structure‐based virtual screening, a lead compound with micromolar binding affinity to Mcl‐1 (inhibition constant (Ki)=3 μM ). It contains a phenyltetrazole and a hydrazinecarbothioamide moiety, and it represents a structural scaffold not observed among known Bcl‐2 inhibitors. This work presents the structural optimization of this lead compound. By following the scaffold‐hopping strategy, we have designed and synthesized a total of 82 compounds in three sets. All of the compounds were evaluated in a fluorescence‐polarization binding assay to measure their binding affinities to Bcl‐xL, Bcl‐2, and Mcl‐1. Some of the compounds with a 3‐phenylthiophene‐2‐sulfonamide core moiety showed sub‐micromolar binding affinities to Mcl‐1 (Ki=0.3–0.4 μM ) or Bcl‐2 (Ki≈1 μM ). They also showed obvious cytotoxicity on tumor cells (IC50<10 μM ). Two‐dimensional heteronuclear single quantum coherence NMR spectra of three selected compounds, that is, YCW‐E5, YCW‐E10, and YCW‐E11, indicated that they bind to the BH3‐binding groove on Bcl‐xL in a similar mode to ABT‐737. Several apoptotic assays conducted on HL‐60 cells demonstrated that these compounds are able to induce cell apoptosis through the mitochondrial pathway. We propose that the compounds with the 3‐phenylthiophene‐2‐sulfonamide core moiety are worth further optimization as effective apoptosis inducers with an interesting selectivity towards Mcl‐1 and Bcl‐2. 相似文献
12.
Two‐Face,Two‐Turn α‐Helix Mimetics Based on a Cross‐Acridine Scaffold: Analogues of the Bim BH3 Domain 下载免费PDF全文
Xiangqian Li Ziqian Wang Prof. Yingang Feng Ting Song Pengchen Su Chengbin Chen Gaobo Chai Ying Yang Prof. Zhichao Zhang 《Chembiochem : a European journal of chemical biology》2014,15(9):1280-1285
The design of a cross‐acridine scaffold mimicking the i, i+3, i+5, and i+7 residues distributed over a two‐face, two‐turn α‐helix is described. Docking studies and 2D 1H,15N HSQC NMR spectroscopy provide compelling evidence that compound 3 d accurately reproduces the arrangement of four hotspots in the Bim BH3 peptide to permit binding to the Mcl‐1 and Bcl‐2 proteins (Ki 0.079 and 0.056 μM , respectively). Furthermore, the hotspot mutation could also be mimicked by individual or multiple deletions of side chains on the scaffold. 相似文献
13.
Potent,Metabolically Stable 2‐Alkyl‐8‐(2H‐1,2,3‐triazol‐2‐yl)‐9H‐adenines as Adenosine A2A Receptor Ligands 下载免费PDF全文
Dr. Silvia Pace Dr. Giandomenico Brogin Dr. Maria Antonietta Stasi Dr. Teresa Riccioni Franco Borsini Dr. Francesca Capocasa Dr. Francesco Manera Carlo Tallarico Dr. Pietro Grossi Dr. Federica Vacondio Dr. Michele Bassi Dr. Francesca Bartoccini Dr. Simone Lucarini Dr. Giovanni Piersanti Prof. Giorgio Tarzia Walter Cabri Dr. Patrizia Minetti 《ChemMedChem》2015,10(7):1149-1152
Inhibition of adenosine A2A receptors has been shown to elicit a therapeutic response in preclinical animal models of Parkinson’s disease (PD). We previously identified the triazolo‐9H‐purine, ST1535, as a potent A2AR antagonist. Studies revealed that ST1535 is extensively hydroxylated at the ω‐1 position of the butyl side chain. Here, we describe the synthesis and evaluation of derivatives in which the ω‐1 position has been substituted (F, Me, OH) in order to block metabolism. The stability of the compounds was evaluated in human liver microsomes (HLM), and the affinity for A2AR was determined. Two compounds, (2‐(3,3‐dimethylbutyl)‐9‐methyl‐8‐(2H‐1,2,3‐triazol‐2‐yl)‐9H‐purin‐6‐amine ( 3 b ) and 4‐(6‐amino‐9‐methyl‐8‐(2H‐1,2,3‐triazol‐2‐yl)‐9H‐purin‐2‐yl)‐2‐methylbutan‐2‐ol ( 3 c ), exhibited good affinity against A2AR (Ki=0.4 nM and 2 nM , respectively) and high in vitro metabolic stability (89.5 % and 95.3 % recovery, respectively, after incubation with HLM for two hours). 相似文献
14.
Dr. Soumava Santra Dr. Sanjib Gogoi Dr. Bhaskar Gopishetty Tamara Antonio Dr. Juan Zhen Prof. Dr. Maarten E. A. Reith Prof. Dr. Aloke K. Dutta 《ChemMedChem》2012,7(12):2093-2100
To further explore the basic structural motifs (3S,6S)‐6‐benzhydryl‐N‐benzyltetrahydro‐2H‐pyran‐3‐amine and (2S,4R,5R)‐2‐benzhydryl‐5‐(benzylamino)tetrahydro‐2H‐pyran‐4‐ol, developed by our research group, for monoamine transport inhibition, we designed and synthesized various structurally altered analogues. The new compounds were tested for their affinities for the dopamine transporter (DAT), the serotonin transporter (SERT), and the norepinephrine transporter (NET) in rat brain by measuring their capacity to inhibit the uptake of [3H]DA, [3H]5‐HT, and [3H]NE, respectively. Our results point to novel compounds with a TUI, DNRI, SNRI, or SSRI profile. Among the TUIs, compound 2 g exhibited a balanced potency for all three monoamine transporters (Ki: 60, 79, and 70.3 nM for DAT, SERT, and NET, respectively). In the rat forced swim test, compound 2 g produced a significant decrease in immobility in drug‐treated rats relative to vehicle, indicating a potential antidepressant property. 相似文献
15.
Yinglei Wang Kangzhen Xu Fengqi Zhao Yueping Ji Jianhua Yi Siyu Xu Fulei Gao Bin Chen 《Propellants, Explosives, Pyrotechnics》2013,38(5):644-650
The energetic material, 3‐nitro‐1,5‐bis(4,4′‐dimethyl azide)‐1,2,3‐triazolyl‐3‐azapentane (NDTAP), was firstly synthesized by means of Click Chemistry using 1,5‐diazido‐3‐nitrazapentane as main material. The structure of NDTAP was confirmed by IR, 1H NMR, and 13C NMR spectroscopy; mass spectrometry, and elemental analysis. The crystal structure of NDTAP was determined by X‐ray diffraction. It belongs to monoclinic system, space group C2/c with crystal parameters a=1.7285(8) nm, b=0.6061(3) nm, c=1.6712(8) nm, β=104.846(8)°, V=1.6924(13) nm3, Z=8, μ=0.109 mm−1, F(000)=752, and Dc=1.422 g cm−3. The thermal behavior and non‐isothermal decomposition kinetics of NDTAP were studied with DSC and TG‐DTG methods. The self‐accelerating decomposition temperature and critical temperature of thermal explosion are 195.5 and 208.2 °C, respectively. NDTAP presents good thermal stability and is insensitive. 相似文献
16.
Jun Young Kim Ji Won Lee Young Soo Kim Yuno Lee Dr. Young Bae Ryu Songmi Kim Hyung Won Ryu Marcus J. Curtis‐Long Prof. Dr. Keun Woo Lee Dr. Woo Song Lee Prof. Dr. Ki Hun Park 《Chembiochem : a European journal of chemical biology》2010,11(15):2125-2131
Competitive glycosidase inhibitors are generally sugar mimics that are costly and tedious to obtain because they require challenging and elongated chemical synthesis, which must be stereo‐ and regiocontrolled. Here, we show that readily accessible achiral (E)‐1‐phenyl‐3‐(4‐strylphenyl)ureas are potent competitive α‐glucosidase inhibitors. A systematic synthesis study shows that the 1‐phenyl moiety on the urea is critical for ensuring competitive inhibition, and substituents on both terminal phenyl groups contribute to inhibition potency. The most potent inhibitor, compound 12 (IC50=8.4 μM , Ki=3.2 μM ), manifested a simple slow‐binding inhibition profile for α‐glucosidase with the kinetic parameters k3=0.005256 μM ?1 min?1, k4=0.003024 min?1, and ${K{{{\rm app}\hfill \atop {\rm i}\hfill}}}$ =0.5753 μM . 相似文献
17.
Gialih Lin Gan‐Hong Chen Yan‐Fu Lin Li‐Hsiang Su Pei‐Shin Liao 《European Journal of Lipid Science and Technology》2005,107(2):65-73
4,4'‐Biphenyl‐4‐acylate‐4'‐N‐n‐butylcarbamates ( 1–8 ) are synthesized and characterized as highly potent and selective pseudo‐substrate inhibitors of Pseudomonas species lipase. Thus, the n‐butylcarbamate moieties of the inhibitors bind to the first acyl chain binding site (ACS) of the enzyme. Therefore, the ester moieties of the inhibitors may bind to the second ACS of the enzyme, due to the linear 4,4'‐biphenyl moiety of the inhibitors. –logKi, logk2, and logki values of carbamates 1–8 are multiply linearly correlated with the Taft steric constant (ES) and the Hansch hydrophobicity constant (π), but not with the Taft substituent constant (σ*). For –logKi, logk2, and logki correlations, values of δ are 0.8, 0.34, and 1.0, respectively, and values of ψ are 1.0, 0.4, and 1.3, respectively. Positive δ and ψ values for these correlations indicate that the second ACS of the enzyme prefers to bind to small and hydrophobic ester groups of the inhibitors. Among carbamates 1–8 , carbamate 3 , with a Ki value of 2.5 nM, is the most potent inhibitor. 相似文献
18.
Hanna Radzey Markus Rethmeier Dennis Klimpel Maresa Grundhuber Prof. Dr. Christian P. Sommerhoff Priv.‐Doz. Dr. Norbert Schaschke 《ChemMedChem》2013,8(8):1314-1321
Cathepsin C is a papain‐like cysteine protease with dipeptidyl aminopeptidase activity that is thought to activate various granule‐associated serine proteases. Its exopeptidase activity is structurally explained by the so‐called exclusion domain, which blocks the active‐site cleft beyond the S2 site and, with its Asp 1 residue, provides an anchoring point for the N terminus of peptide and protein substrates. Here, the hydrazide of (2S,3S)‐trans‐epoxysuccinyl‐L ‐leucylamido‐3‐methylbutane (E‐64c) (k2/Ki=140±5 M ?1 s?1) is demonstrated to be a lead structure for the development of irreversible cathepsin C inhibitors. The distal amino group of the hydrazide moiety addresses the acidic Asp 1 residue at the entrance of the S2 pocket by hydrogen bonding while also occupying the flat hydrophobic S1′–S2′ area with its leucine‐isoamylamide moiety. Furthermore, structure–activity relationship studies revealed that functionalization of this distal amino group with alkyl residues can be used to occupy the conserved hydrophobic S2 pocket. In particular, the n‐butyl derivative was identified as the most potent inhibitor of the series (k2/Ki=56 000±1700 M ?1 s?1). 相似文献
19.
6,7‐Dimethoxy‐2‐{2‐[4‐(1H‐1,2,3‐triazol‐1‐yl)phenyl]ethyl}‐1,2,3,4‐tetrahydroisoquinolines as Superior Reversal Agents for P‐Glycoprotein‐Mediated Multidrug Resistance 下载免费PDF全文
Dr. Baomin Liu Qianqian Qiu Tianxiao Zhao Lei Jiao Prof. Yunman Li Prof. Wenlong Huang Prof. Hai Qian 《ChemMedChem》2015,10(2):336-344
P‐glycoprotein (P‐gp)‐mediated multidrug resistance (MDR) is a major obstacle for successful cancer chemotherapy. Based on our previous study, 17 novel compounds with the 6,7‐dimethoxy‐2‐{2‐[4‐(1H‐1,2,3‐triazol‐1‐yl)phenyl]ethyl}‐1,2,3,4‐tetrahydroisoquinoline scaffold were designed and synthesized. Among them, 2‐[(1‐{4‐[2‐(6,7‐dimethoxy‐3,4‐dihydroisoquinolin‐2(1H)‐yl)ethyl]phenyl}‐1H‐1,2,3‐triazol‐4‐yl)methoxy]‐N‐(p‐tolyl)benzamide (compound 7 h ) was identified as a potent modulator of P‐gp‐mediated MDR, with high potency (EC50=127.5±9.1 nM ), low cytotoxicity (TI>784.3), and long duration (>24 h) in reversing doxorubicin (DOX) resistance in K562/A02 cells. Compound 7 h also enhanced the effects of other MDR‐related cytotoxic agents (paclitaxel, vinblastine, and daunorubicin), increased the accumulation of DOX and blocked P‐gp‐mediated rhodamine 123 efflux function in K562/A02 MDR cells. Moreover, 7 h did not have any effect on cytochrome (CYP3A4) activity. These results indicate that 7 h is a relatively safe modulator of P‐gp‐mediated MDR that has good potential for further development. 相似文献
20.
Silvia Franchini Dr. Annalisa Tait Prof. Adolfo Prandi Dr. Claudia Sorbi Dr. Rossella Gallesi Michela Buccioni Dr. Gabriella Marucci Prof. Carla De Stefani Dr. Antonio Cilia Dr. Livio Brasili Prof. 《ChemMedChem》2009,4(2):196-203
A selective 5‐HT 1A receptor agonist : A new series of ligands acting at 5‐HT1A serotonin receptor were identified. Among them (2,2‐diphenyl‐[1,3]oxathiolan‐5‐yl‐methyl)‐(3‐phenyl‐propyl)amine (shown) possesses outstanding activity (pKi=8.72, pD2=7.67, Emax=85) and selectivity (5‐HT1A/α1D>150), and represents a new 5‐HT1A agonist chemotype.