共查询到20条相似文献,搜索用时 15 毫秒
1.
Fluorophore‐Labeled Cyclooxygenase‐2 Inhibitors for the Imaging of Cyclooxygenase‐2 Overexpression in Cancer: Synthesis and Biological Studies 下载免费PDF全文
Dr. Atul Bhardwaj Dr. Jatinder Kaur Dr. Frank Wuest Dr. Edward E. Knaus 《ChemMedChem》2014,9(1):109-116
A group of cyclooxygenase‐2 (COX‐2)‐specific fluorescent cancer biomarkers were synthesized by linking the anti‐inflammatory drugs ibuprofen, (S)‐naproxen, and celecoxib to the 7‐nitrobenzofurazan (NBD) fluorophore. In vitro COX‐1/COX‐2 inhibition studies indicated that all of these fluorescent conjugates are COX‐2 inhibitors (IC50 range: 0.19–23.0 μM ) with an appreciable COX‐2 selectivity index (SI≥4.3–444). In this study the celecoxib–NBD conjugate N‐(2‐((7‐nitrobenzo[c][1,2,5]oxadiazol‐4‐yl)amino)ethyl)‐4‐(5‐(p‐tolyl)‐3‐(trifluoromethyl)‐1H‐pyrazol‐1‐yl)benzenesulfonamide ( 14 ), which displayed the highest COX‐2 inhibitory potency and selectivity (COX‐2 IC50=0.19 μM ; SI=443.6), was identified as an impending COX‐2‐specific biomarker for the fluorescence imaging of cancer using a COX‐2‐expressing human colon cancer cell line (HCA‐7). 相似文献
2.
3.
Catalytic Mechanism of the Hotdog‐Fold Thioesterase PA1618 Revealed by X‐ray Structure Determination of a Substrate‐Bound Oxygen Ester Analogue Complex 下载免费PDF全文
Dr. John A. Latham Dr. Tianyang Ji Kaila Matthews Dr. Patrick S. Mariano Dr. Karen N. Allen Dr. Debra Dunaway‐Mariano 《Chembiochem : a European journal of chemical biology》2017,18(19):1935-1943
Thioesterase activity accounts for the majority of the activities in the hotdog‐fold superfamily. The structures and mechanisms of catalysis for many hotdog enzymes have been elucidated by X‐ray crystallography and kinetics to probe the specific substrate usage and cellular functions. However, structures of hotdog thioesterases in complexes with substrate analogues reported to date utilize ligands that either represent truncations of the substrate or include additional atoms to prevent hydrolysis. Here we present the synthesis of an isosteric and isoelectronic substrate analogue—benzoyl‐OdCoA—and the X‐ray crystal structure of a complex of the analogue with Pseudomonas aeruginosa hotdog thioesterase PA1618 (at 1.72 Å resolution). The complex is compared with that of the “imperfect” substrate analogue phenacyl‐CoA, refined to a resolution of 1.62 Å. Kinetic and structural results are consistent with Glu64 as the catalytic residue and with the involvement of Gln49 in stabilization of the transition state. Structural comparison of the two ligand‐bound structures revealed a crucial ordered water molecule coordinated in the active site of the benzoyl‐OdCoA structure but not present in the phenacyl‐CoA‐bound structure. This suggests a general base mechanism of catalysis in which Glu64 activates the coordinated water nucleophile. Together, our findings reveal the importance of a closely similar substrate analogue to determine the true substrate binding and catalytic mechanism. 相似文献
4.
Dr. Cecilia Pozzi Dr. Flavio Di Pisa Dr. Filomena De Luca Dr. Manuela Benvenuti Prof. Jean Denis Docquier Prof. Stefano Mangani 《ChemMedChem》2018,13(14):1437-1446
β‐Lactamases (BLs) are important antibiotic‐resistance determinants that significantly compromise the efficacy of valuable β‐lactam antibacterial drugs. Thus, combinations with BL inhibitor were developed. Avibactam is the first non‐β‐lactam BL inhibitor introduced into clinical practice. Ceftazidime–avibactam represents one of the few last‐resort antibiotics available for the treatment of infections caused by near‐pandrug‐resistant bacteria. TRU‐1 is a chromosomally encoded AmpC‐type BL of Aeromonas enteropelogenes, related to the FOX‐type BLs and constitutes a good model for class C BLs. TRU‐1 crystals provided ultrahigh‐resolution diffraction data for the native enzyme and for its complex with avibactam. A comparison of the native and avibactam‐bound structures revealed new details in the conformations of residues relevant for substrate and/or inhibitor binding. Furthermore, a comparison of the TRU‐1 and Pseudomonas aeruginosa AmpC avibactam‐bound structures revealed two inhibitor conformations that were likely to correspond to two different states occurring during inhibitor carbamylation/recyclization. 相似文献
5.
Yanira Méndez Karell Pérez‐Labrada Jorge González‐Bacerio Gilberto Valdés María Á. de los Chávez Joel Osuna Jean‐Louis Charli Isel Pascual Daniel G. Rivera 《ChemMedChem》2014,9(10):2351-2359
The development of selective inhibitors of microbial metallo‐aminopeptidases is an important goal in the pursuit of antimicrobials for therapeutic applications. Herein, we disclose a combinatorial approach relying on two Ugi reactions for the generation of peptidomimetics inspired by natural metallo‐aminopeptidase inhibitors. The library was screened for inhibitory activity against the neutral metallo‐aminopeptidase of Escherichia coli (ePepN) and the porcine kidney cortex metallo‐aminopeptidase (pAPN), which was used as a model of the M1‐aminopeptidases of mammals. Six compounds showed typical dose–response inhibition profiles toward recombinant ePepN, with two of them being very potent and highly selective for ePepN over pAPN. Another compound showed moderate ePepN inhibition but total selectivity for this bacterial enzyme over its mammalian orthologue at concentrations of physiological relevance. This strategy proved to be useful for the identification of lead compounds for further optimization and development. 相似文献
6.
Athanasios Papakyriakou Dr. Maria E. Katsarou Dr. Maria Belimezi Dr. Michael Karpusas Dr. Dionisios Vourloumis Dr. 《ChemMedChem》2010,5(1):118-129
Substantial evidence over the last decades has implicated uncontrolled angiogenesis with various pathological states, including cancer. Vascular endothelial growth factor (VEGF) plays a critical role in its regulation. Because the tyrosine kinase VEGF receptor‐2 (VEGFR‐2) is the major mediator of the mitogenic, angiogenic, and permeability‐enhancing effects of VEGF, it has become one of the most profound anti‐angiogenesis targets. Inspired by the anthranilamide class of VEGFR‐2 inhibitors, we performed a computational analysis of some potent representative members, using docking and molecular dynamics calculations. Based on the observations drawn from introducing the effect of the receptor's flexibility in implicit aqueous environment, we designed, synthesized, and characterized several new analogues of related scaffolds with modifications in their steric and electronic characteristics. In vitro evaluation of these compounds revealed several novel VEGFR‐2 inhibitors that are less cytotoxic and more potent than the parent compounds. 相似文献
7.
4‐Biphenylalanine‐ and 3‐Phenyltyrosine‐Derived Hydroxamic Acids as Inhibitors of the JumonjiC‐Domain‐Containing Histone Demethylase KDM4A 下载免费PDF全文
Dr. Ludovica Morera Dr. Martin Roatsch Michael C. D. Fürst Dr. Inga Hoffmann Dr. Johanna Senger Mirjam Hau Dr. Henriette Franz Prof. Dr. Roland Schüle Prof. Dr. Markus R. Heinrich Prof. Dr. Manfred Jung 《ChemMedChem》2016,11(18):2063-2083
Overexpression of the histone lysine demethylase KDM4A, which regulates H3K9 and H3K36 methylation states, has been related to the pathology of several human cancers. We found that a previously reported hydroxamate‐based histone deacetylase (HDAC) inhibitor (SW55) was also able to weakly inhibit this demethylase with an IC50 value of 25.4 μm . Herein we report the synthesis and biochemical evaluations, with two orthogonal in vitro assays, of a series of derivatives of this lead structure. With extensive chemical modifications on the lead structure, also by exploiting the versatility of the radical arylation with aryldiazonium salts, we were able to increase the potency of the derivatives against KDM4A to the low‐micromolar range and, more importantly, to obtain demethylase selectivity with respect to HDACs. Cell‐permeable derivatives clearly showed a demethylase‐inhibition‐dependent antiproliferative effect against HL‐60 human promyelocytic leukemia cells. 相似文献
8.
9.
Dr. Danielle L. Aubele Dr. Roy K. Hom Dr. Marc Adler Dr. Robert A. Galemmo Jr. Dr. Simeon Bowers Dr. Anh P. Truong Dr. Hu Pan Dr. Paul Beroza Dr. R. Jeffrey Neitz Dr. Nanhua Yao May Lin Dr. George Tonn Heather Zhang Dr. Michael P. Bova Dr. Zhao Ren Danny Tam Lany Ruslim Dr. Jeanne Baker Linnea Diep Dr. Kent Fitzgerald Jennifer Hoffman Ruth Motter Donald Fauss Pearl Tanaka Dr. Michael Dappen Dr. Jacek Jagodzinski Wayman Chan Dr. Andrei W. Konradi Dr. Lee Latimer Dr. Yong L. Zhu Dr. Hing L. Sham Dr. John P. Anderson Dr. Marcelle Bergeron Dr. Dean R. Artis 《ChemMedChem》2013,8(8):1295-1313
Polo‐like kinase‐2 (Plk‐2) has been implicated as the dominant kinase involved in the phosphorylation of α‐synuclein in Lewy bodies, which are one of the hallmarks of Parkinson’s disease neuropathology. Potent, selective, brain‐penetrant inhibitors of Plk‐2 were obtained from a structure‐guided drug discovery approach driven by the first reported Plk‐2–inhibitor complexes. The best of these compounds showed excellent isoform and kinome‐wide selectivity, with physicochemical properties sufficient to interrogate the role of Plk‐2 inhibition in vivo. One such compound significantly decreased phosphorylation of α‐synuclein in rat brain upon oral administration and represents a useful probe for future studies of this therapeutic avenue toward the potential treatment of Parkinson’s disease. 相似文献
10.
Stephen Patterson Dr. Deuan C. Jones Dr. Emma J. Shanks Dr. Julie A. Frearson Prof. Ian H. Gilbert Prof. Paul G. Wyatt Prof. Alan H. Fairlamb Prof. 《ChemMedChem》2009,4(8):1341-1353
Thirty two analogues of phencyclidine were synthesised and tested as inhibitors of trypanothione reductase (TryR), a potential drug target in trypanosome and leishmania parasites. The lead compound BTCP ( 1 , 1‐(1‐benzo[b]thiophen‐2‐yl‐cyclohexyl) piperidine) was found to be a competitive inhibitor of the enzyme (Ki=1 μM ) and biologically active against bloodstream T. brucei (EC50=10 μM ), but with poor selectivity against mammalian MRC5 cells (EC50=29 μM ). Analogues with improved enzymatic and biological activity were obtained. The structure–activity relationships of this novel series are discussed. 相似文献
11.
Dr. Yafeng Xue Dr. Paul T. Wan Dr. Per Hillertz Dr. Fritz Schweikart Dr. Yanlong Zhao Lisa Wissler Dr. Niek Dekker 《ChemMedChem》2013,8(11):1846-1854
Tau‐tubulin kinase 1 (TTBK1) is a serine/threonine/tyrosine kinase that putatively phosphorylates residues including S422 in tau protein. Hyperphosphorylation of tau protein is the primary cause of tau pathology and neuronal death associated with Alzheimer’s disease. A library of 12 truncation variants comprising the TTBK1 kinase domain was screened for expression in Escherichia coli and insect cells. One variant (residues 14–313) could be purified, but mass spectrometric analysis revealed extensive phosphorylation of the protein. Co‐expression with lambda phosphatase in E. coli resulted in production of homogeneous, nonphosphorylated TTBK1. Binding of ATP and several compounds to TTBK1 was characterized by surface plasmon resonance. Crystal structures of TTBK1 in the unliganded form and in complex with ATP, and two high‐affinity ATP‐competitive inhibitors, 3‐[(6,7‐dimethoxyquinazolin‐4‐yl)amino]phenol ( 1 ) and methyl 2‐bromo‐5‐(7H‐pyrrolo[2,3‐d]pyrimidin‐4‐ylamino)benzoate ( 2 ), were elucidated. The structure revealed two clear basic patches near the ATP pocket providing an explanation of TTBK1 for phosphorylation‐primed substrates. Interestingly, compound 2 displayed slow binding kinetics to TTBK1, the structure of TTBK1 in complex with this compound revealed a reorganization of the L199–D200 peptide backbone conformation together with altered hydrogen bonding with compound 2 . These conformational changes necessary for the binding of compound 2 are likely the basis of the slow kinetics. This first TTBK1 structure can assist the discovery of novel inhibitors for the treatment of Alzheimer’s disease. 相似文献
12.
Dr. Giannamaria Annunziato Dr. Andrea Angeli Dr. Francesca D'Alba Dr. Agostino Bruno Dr. Marco Pieroni Dr. Daniela Vullo Dr. Viviana De Luca Dr. Clemente Capasso Prof. Claudiu T. Supuran Prof. Gabriele Costantino 《ChemMedChem》2016,11(17):1904-1914
In academia, compound recycling represents an alternative drug discovery strategy to identify new pharmaceutical targets from a library of chemical compounds available in house. Herein we report the application of a rational target‐based drug‐repurposing approach to find diverse applications for our in‐house collection of compounds. The carbonic anhydrase (CA, EC 4.2.1.1) metalloenzyme superfamily was identified as a potential target of our compounds. The combination of a thoroughly validated docking screening protocol, together with in vitro assays against various CA families and isoforms, allowed us to identify two unprecedented chemotypes as CA inhibitors. The identified compounds have the capacity to preferentially bind pathogenic (bacterial/protozoan) CAs over human isoforms and represent excellent hits for further optimization in hit‐to‐lead campaigns. 相似文献
13.
Dr. Sylvain Clède Noemi Cowan Dr. François Lambert Dr. Hélène C. Bertrand Dr. Riccardo Rubbiani Dr. Malay Patra Jeannine Hess Dr. Christophe Sandt Dr. Nicolas Trcera Prof. Dr. Gilles Gasser Prof. Dr. Jennifer Keiser Prof. Dr. Clotilde Policar 《Chembiochem : a European journal of chemical biology》2016,17(11):1004-1007
An organometallic derivative of praziquantel was studied directly in worms by using inductively coupled plasma‐mass spectrometry (ICP‐MS) for quantification and synchrotron‐based imaging. X‐ray fluorescence (XRF) and IR absorption spectromicroscopy were used for the first time in combination to directly locate this organometallic drug candidate in schistosomes. The detection of both CO (IR) and Cr (XRF) signatures proved that the Cr(CO)3 core remained intact in the worms. Images showed a preferential accumulation at the worm's tegument, consistent with a possible targeting of the calcium channel but not excluding other biological targets inside the worm. 相似文献
14.
Synthesis and Structure–Activity Relationship Studies of 2‐(1,3,4‐Oxadiazole‐2(3H)‐thione)‐3‐amino‐5‐arylthieno[2,3‐b]pyridines as Inhibitors of DRAK2 下载免费PDF全文
Dr. Piotr Leonczak Dr. Ling‐Jie Gao Dr. Anna Teresa Ramadori Prof. Eveline Lescrinier Prof. Jef Rozenski Dr. Steven De Jonghe Prof. Piet Herdewijn 《ChemMedChem》2014,9(11):2587-2601
In recent years, DAPK‐related apoptosis‐inducing protein kinase 2 (DRAK2) has emerged as a promising target for the treatment of a variety of autoimmune diseases and for the prevention of graft rejection after organ transplantation. However, medicinal chemistry optimization campaigns for the discovery of novel small‐molecule inhibitors of DRAK2 have not yet been published. Screening of a proprietary compound library led to the discovery of a benzothiophene analogue that displays an affinity constant (Kd) value of 0.25 μM . Variation of the core scaffold and of the substitution pattern afforded a series of 5‐arylthieno[2,3‐b]pyridines with strong binding affinity (Kd=0.008 μM for the most potent representative). These compounds also show promising activity in a functional biochemical DRAK2 enzyme assay, with an IC50 value of 0.029 μM for the most potent congener. Selectivity profiling of the most potent compounds revealed that they lack selectivity within the DAPK family of kinases. However, one of the less potent analogues is a selective ligand for DRAK2 and can be used as starting point for the synthesis of selective and potent DRAK2 inhibitors. 相似文献
15.
Prof. Dr. Massimo Bertinaria Dr. Mohammed Abrar Abdul Gaffar Shaikh Dr. Carola Buccellati Prof. Dr. Clara Cena Dr. Barbara Rolando Dr. Loretta Lazzarato Prof. Roberta Fruttero Prof. Alberto Gasco Dr. Malvina Hoxha Dr. Valérie Capra Prof. Dr. Angelo Sala Prof. Dr. G. Enrico Rovati 《ChemMedChem》2012,7(12):2054-2054
16.
Dr. Paola Baiocco Dr. Giovanna Poce Dr. Salvatore Alfonso Dr. Martina Cocozza Dr. Giulio Cesare Porretta Dr. Gianni Colotti Dr. Mariangela Biava Dr. Francesca Moraca Dr. Maurizio Botta Dr. Vanessa Yardley Dr. Annarita Fiorillo Dr. Antonella Lantella Dr. Francesco Malatesta Dr. Andrea Ilari 《ChemMedChem》2013,8(7):1175-1183
Herein we report a study aimed at discovering a new class of compounds that are able to inhibit Leishmania donovani cell growth. Evaluation of an in‐house library of compounds in a whole‐cell screening assay highlighted 4‐((1‐(4‐ethylphenyl)‐2‐methyl‐5‐(4‐(methylthio)phenyl)‐1H‐pyrrol‐3‐yl)methyl)thiomorpholine (compound 1 ) as the most active. Enzymatic assays on Leishmania infantum trypanothione reductase (LiTR, belonging to the Leishmania donovani complex) shed light on both the interaction with, and the nature of inhibition by, compound 1 . A molecular modeling approach based on docking studies and on the estimation of the binding free energy aided our rationalization of the biological data. Moreover, X‐ray crystal structure determination of LiTR in complex with compound 1 confirmed all our results: compound 1 binds to the T(SH)2 binding site, lined by hydrophobic residues such as Trp21 and Met113, as well as residues Glu18 and Tyr110. Analysis of the structure of LiTR in complex with trypanothione shows that Glu18 and Tyr110 are also involved in substrate binding, according to a competitive inhibition mechanism. 相似文献
17.
Dr. Jozef Stec Alina Fomovska Gustavo A. Afanador Prof. Dr. Stephen P. Muench Dr. Ying Zhou Bo‐Shiun Lai Prof. Dr. Kamal El Bissati Dr. Mark R. Hickman Patty J. Lee Susan E. Leed Jennifer M. Auschwitz Dr. Caroline Sommervile Dr. Stuart Woods Prof. Dr. Craig W. Roberts Prof. Dr. David Rice Dr. Sean T. Prigge Dr. Rima McLeod Prof. Dr. Alan P. Kozikowski 《ChemMedChem》2013,8(7):1138-1160
Through our focused effort to discover new and effective agents against toxoplasmosis, a structure‐based drug design approach was used to develop a series of potent inhibitors of the enoyl‐acyl carrier protein (ACP) reductase (ENR) enzyme in Toxoplasma gondii (TgENR). Modifications to positions 5 and 4′ of the well‐known ENR inhibitor triclosan afforded a series of 29 new analogues. Among the resulting compounds, many showed high potency and improved physicochemical properties in comparison with the lead. The most potent compounds 16 a and 16 c have IC50 values of 250 nM against Toxoplasma gondii tachyzoites without apparent toxicity to the host cells. Their IC50 values against recombinant TgENR were found to be 43 and 26 nM , respectively. Additionally, 11 other analogues in this series had IC50 values ranging from 17 to 130 nM in the enzyme‐based assay. With respect to their excellent in vitro activity as well as improved drug‐like properties, the lead compounds 16 a and 16 c are deemed to be excellent starting points for the development of new medicines to effectively treat Toxoplasma gondii infections. 相似文献
18.