共查询到20条相似文献,搜索用时 31 毫秒
1.
Dr. Anna Kwiatkowska Frédéric Couture Dr. Christine Levesque Kévin Ly Sophie Beauchemin Roxane Desjardins Prof. Witold Neugebauer Prof. Yves L. Dory Prof. Robert Day 《ChemMedChem》2016,11(3):289-301
PACE4 plays important roles in prostate cancer cell proliferation. The inhibition of this enzyme has been shown to slow prostate cancer progression and is emerging as a promising therapeutic strategy. In previous work, we developed a highly potent and selective PACE4 inhibitor, the multi‐Leu (ML) peptide, an octapeptide with the sequence Ac‐LLLLRVKR‐NH2. Here, with the objective of developing a useful compound for in vivo administration, we investigate the effect of N‐terminal modifications. The inhibitory activity, toxicity, stability, and cell penetration properties of the resulting analogues were studied and compared to the unmodified inhibitor. Our results show that the incorporation of a polyethylene glycol (PEG) moiety leads to a loss of antiproliferative activity, whereas the attachment of a lipid chain preserves or improves it. However, the lipidated peptides are significantly more toxic when compared with their unmodified counterparts. Therefore, the best results were achieved not by the N‐terminal extension but by the protection of both ends with the d ‐Leu residue and 4‐amidinobenzylamide, which yielded the most stable inhibitor, with an excellent activity and toxicity profile. 相似文献
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Dr. Xianqi Kong Dr. Dragic Vukomanovic Prof. Kanji Nakatsu Prof. Walter A. Szarek 《ChemMedChem》2015,10(8):1435-1441
Devising ways to up‐ or down‐regulate heme oxygenase activity is attracting much interest as a strategy for the treatment of a variety of disorders. With a view of obtaining compounds that exhibit high potency and selectivity as inhibitors of the heme oxygenase‐2 (HO‐2) isozyme (constitutive) relative to the heme oxygenase‐1 (HO‐1) isozyme (inducible), several 1,2‐disubstituted 1H‐benzimidazoles were designed and synthesized. Specifically, analogues were synthesized in which the C2 substituent was the following: (1H‐imidazol‐1‐yl)methyl, (N‐morpholinyl)methyl, cyclopentylmethyl, cyclohexylmethyl, or (norborn‐2‐yl)methyl. Compounds with the cyclic system in the C2 substituent being a carbocyclic ring, especially cyclohexyl or norborn‐2‐yl, and the N1 substituent being a ring‐substituted benzyl group, especially 4‐chlorobenzyl or 4‐bromobenzyl, best exhibited the target criteria of high potency and selectivity toward inhibition of HO‐2. The new candidates should be useful pharmacological tools and may have therapeutic applications. 相似文献
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Francesc Yraola Dr. Antonio Zorzano Prof. Dr. Fernando Albericio Prof. Dr. Miriam Royo Dr. 《ChemMedChem》2009,4(4):495-503
SSAO/VAP‐1 substrates may be valuable for the treatment or prevention of diabetes mellitus, as they show insulin‐mimetic properties. This review highlights the importance of studying the relevant steric and electronic features in the development of new ligands with better SSAO/VAP‐1 recognition, enhanced selectivity over other amine oxidases, and improved metabolic behavior.
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Michael Eisenmann Holger Steuber Matthias Zentgraf Mirko Altenkämper Regina Ortmann Johann Perruchon Gerhard Klebe Martin Schlitzer 《ChemMedChem》2009,4(5):809-819
Virtual screening discovered two prospective hits as potential leads for aldose reductase inhibition. Based on their crystal structures with the enzyme, a systematic optimization has been performed to reveal a first structure–activity relationship. A central thiophen moiety and a terminal nitro group exhibit the best binding properties.
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Ingela Fritzson Bo Svensson Dr. Salam Al‐Karadaghi Prof. Björn Walse Dr. Ulf Wellmar Dr. Ulf J. Nilsson Prof. Dorthe da Graça Thrige Dr. Stig Jönsson Dr. 《ChemMedChem》2010,5(4):608-617
A strategy that combines virtual screening and structure‐guided selection of fragments was used to identify three unexplored classes of human DHODH inhibitor compounds: 4‐hydroxycoumarins, fenamic acids, and N‐(alkylcarbonyl)anthranilic acids. Structure‐guided selection of fragments targeting the inner subsite of the DHODH ubiquinone binding site made these findings possible with screening of fewer than 300 fragments in a DHODH assay. Fragments from the three inhibitor classes identified were subsequently chemically expanded to target an additional subsite of hydrophobic character. All three classes were found to exhibit distinct structure–activity relationships upon expansion. The novel N‐(alkylcarbonyl)anthranilic acid class shows the most promising potency against human DHODH, with IC50 values in the low nanomolar range. The structure of human DHODH in complex with an inhibitor of this class is presented. 相似文献
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Switching Futile para‐Quinone to Efficient Reactive Oxygen Species Generator: Ubiquitin‐Specific Protease‐2 Inhibition,Electrocatalysis, and Quantification 下载免费PDF全文
Dr. Pushparathinam Gopinath Dr. Atif Mahammed Tal Eilon‐Shaffer Mickal Nawatha Shimrit Ohayon Prof. Doron Shabat Prof. Zeev Gross Prof. Ashraf Brik 《Chembiochem : a European journal of chemical biology》2017,18(17):1683-1687
Understanding the correlation between structural features of small‐molecule drugs and their mode of action is a fascinating topic and crucial for the drug‐discovery process. However, in many cases, knowledge of the exact parameters that dictate the mode of action is still lacking. Following a large screening for ubiquitin specific protease 2 (USP2) inhibition, an effective para‐quinone‐based inhibitor with an unclear mode of action was identified. To gain a deeper understanding of the mechanism of inhibition, a set of para‐quinones were prepared and studied for USP2 inhibition, electrocatalysis, and reactive oxygen species (ROS) quantification. The excellent correlation obtained from the above‐mentioned studies disclosed a distinct pattern of “N?C=O?N” in the bicyclic para‐quinones to be a crucial factor for ROS generation, and demonstrated that minor changes in such a skeleton drastically altered the ROS‐generating ability. The knowledge acquired herein would serve as an important guideline for future medicinal chemistry optimization of related structures to select the preferred mode of action. 相似文献
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Mei‐Jung Lai Ching‐Chuan Kuo Dr. Teng‐Kuang Yeh Dr. Hsing‐Pang Hsieh Dr. Li‐Tzong Chen Dr. Wen‐Yu Pan Kuang‐Yang Hsu Dr. Jang‐Yang Chang Dr. Jing‐Ping Liou Dr. 《ChemMedChem》2009,4(4):588-593
Combretastatin A‐4 derivatives : A series of combretastatin A‐4‐derived 1‐benzyl‐4,5,6‐trimethoxyindoles was designed and prepared as a novel class of potent antimitotic agents acting through the colchicine binding site on the microtubule.
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Federica Vacondio Dr. Claudia Silva Prof. Alessio Lodola Dr. Alessandro Fioni Dr. Silvia Rivara Prof. Andrea Duranti Dr. Andrea Tontini Dr. Silvano Sanchini Dr. Jason R. Clapper Dr. Daniele Piomelli Prof. Marco Mor Prof. Giorgio Tarzia Prof. 《ChemMedChem》2009,4(9):1495-1504
Cyclohexylcarbamic acid aryl esters are a class of fatty acid amide hydrolase (FAAH) inhibitors, which includes the reference compound URB597. The reactivity of their carbamate fragment is involved in pharmacological activity and may affect their pharmacokinetic and toxicological properties. We conducted in vitro stability experiments in chemical and biological environments to investigate the structure–stability relationships in this class of compounds. The results show that electrophilicity of the carbamate influences chemical stability, as suggested by the relation between the rate constant of alkaline hydrolysis (log kpH9) and the energy of the lowest unoccupied molecular orbital (LUMO). Introduction of small electron‐donor substituents at conjugated positions of the O‐aryl moiety increased the overall hydrolytic stability of the carbamate group without affecting FAAH inhibitory potency, whereas peripheral non‐conjugated hydrophilic groups, which favor FAAH recognition, helped decrease oxidative metabolism in the liver. 相似文献
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Cover Picture: Switching Futile para‐Quinone to Efficient Reactive Oxygen Species Generator: Ubiquitin‐Specific Protease‐2 Inhibition,Electrocatalysis, and Quantification (ChemBioChem 17/2017) 下载免费PDF全文
Dr. Pushparathinam Gopinath Dr. Atif Mahammed Tal Eilon‐Shaffer Mickal Nawatha Shimrit Ohayon Prof. Doron Shabat Prof. Zeev Gross Prof. Ashraf Brik 《Chembiochem : a European journal of chemical biology》2017,18(17):1669-1669
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Kin‐Fai Chan Dr. Yunzhe Zhao Dr. Toby W. S. Chow Clare S. W. Yan Dik Lung Ma Dr. Brendan A. Burkett Dr. Iris L. K. Wong Dr. Larry M. C. Chow Prof. Tak Hang Chan Prof. 《ChemMedChem》2009,4(4):594-614
Bivalent modulators of P‐glycoprotein : A small library of flavonoid homodimers and heterodimers was synthesized, and their in vitro activity in reversing paclitaxel resistance was evaluated along with structure–activity relationships. SAR trends indicate that flavonoid dimers with nonpolar, hydrophobic, less bulky substituents generally show more potent reversing activity. This will help guide future efforts in the search for more potent compounds.
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Synthesis,Structure–Activity,and Structure–Stability Relationships of 2‐Substituted‐N‐(4‐oxo‐3‐oxetanyl) N‐Acylethanolamine Acid Amidase (NAAA) Inhibitors 下载免费PDF全文
Romina Vitale Dr. Giuliana Ottonello Rita Petracca Sine Mandrup Bertozzi Dr. Stefano Ponzano Dr. Andrea Armirotti Dr. Anna Berteotti Dr. Mauro Dionisi Prof. Andrea Cavalli Prof. Daniele Piomelli Dr. Tiziano Bandiera Dr. Fabio Bertozzi 《ChemMedChem》2014,9(2):323-336
N‐Acylethanolamine acid amidase (NAAA) is a cysteine amidase that preferentially hydrolyzes saturated or monounsaturated fatty acid ethanolamides (FAEs), such as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), which are endogenous agonists of nuclear peroxisome proliferator‐activated receptor‐α (PPAR‐α). Compounds that feature an α‐amino‐β‐lactone ring have been identified as potent and selective NAAA inhibitors and have been shown to exert marked anti‐inflammatory effects that are mediated through FAE‐dependent activation of PPAR‐α. We synthesized and tested a series of racemic, diastereomerically pure β‐substituted α‐amino‐β‐lactones, as either carbamate or amide derivatives, investigating the structure–activity and structure–stability relationships (SAR and SSR) following changes in β‐substituent size, relative stereochemistry at the α‐ and β‐positions, and α‐amino functionality. Substituted carbamate derivatives emerged as more active and stable than amide analogues, with the cis configuration being generally preferred for stability. Increased steric bulk at the β‐position negatively affected NAAA inhibitory potency, while improving both chemical and plasma stability. 相似文献
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Isao Miyazaki Siro Simizu Dr. Keisuke Ishida Dr. Hiroyuki Osada Prof. 《Chembiochem : a European journal of chemical biology》2009,10(5):838-843
Covalent bonds not required : We describe a novel approach in which the concepts of fragment‐based ligand discovery are combined with chemical array techniques to yield bivalent inhibitors. A pair of fragments is mixed and covalently attached to a glass slide by photolinking immobilization. The method does not require the compounds to have specific functional groups, and tedious steps for protein purification are avoided. Thus, the on‐chip fragment‐based approach is relatively simple and efficient for obtaining high‐affinity ligands.
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Insight into the Functional and Structural Properties of 3‐Arylcoumarin as an Interesting Scaffold in Monoamine Oxidase B Inhibition 下载免费PDF全文
Dr. Maria João Matos Dr. Santiago Vilar Dr. Verónica García‐Morales Dr. Nicholas P. Tatonetti Prof. Eugenio Uriarte Prof. Lourdes Santana Prof. Dolores Viña 《ChemMedChem》2014,9(7):1488-1500
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Anti‐Dengue‐Virus Activity and Structure–Activity Relationship Studies of Lycorine Derivatives 下载免费PDF全文
Peng Wang Lin‐Feng Li Dr. Qing‐Yin Wang Dr. Lu‐Qing Shang Dr. Pei‐Yong Shi Prof. Dr. Zheng Yin 《ChemMedChem》2014,9(7):1522-1533
Dengue is a systemic viral infection that is transmitted to humans by Aedes mosquitoes. No vaccines or specific therapeutics are currently available for dengue. Lycorine, which is a natural plant alkaloid, has been shown to possess antiviral activities against flaviviruses. In this study, a series of novel lycorine derivatives were synthesized and assayed for their inhibition of dengue virus (DENV) in cell cultures. Among the lycorine analogues, 1‐acetyllycorine exhibited the most potent anti‐DENV activity (EC50=0.4 μM ) with a reduced cytotoxicity (CC50>300 μM ), which resulted in a selectivity index (CC50/EC50) of more than 750. The ketones 1‐acetyl‐2‐oxolycorine (EC50=1.8 μM ) and 2‐oxolycorine (EC50=0.5 μM ) also exhibited excellent antiviral activities with low cytotoxicity. Structure–activity relationships for the lycorine derivatives against DENV are discussed. A three‐dimensional quantitative structure–activity relationship model was established by using a comparative molecular‐field analysis protocol in order to rationalize the experimental results. Further modifications of the hydroxy group at the C1 position with retention of a ketone at the C2 position could potentially lead to inhibitors with improved overall properties. 相似文献
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Linglin Bian Shining Cao Lihong Cheng Dr. Atsuo Nakazaki Prof. Toshio Nishikawa Prof. Jianhua Qi 《ChemMedChem》2018,13(18):1972-1977
(3S,4R)‐23,28‐Dihydroxyolean‐12‐en‐3‐yl (2E)‐3‐(3,4‐dihydroxyphenyl)acrylate ( 1 a ), which possesses significant neuritogenic activity, was isolated from the traditional Chinese medicine (TCM) plant, Desmodium sambuense. To confirm the structure and to assess biological activity, we semi‐synthesized 1 a from commercially available oleanolic acid. A series of novel 1 a derivatives was then designed and synthesized for a structure–activity relationship (SAR) study. All synthetic derivatives were characterized by analysis of spectral data, and their neuritogenic activities were evaluated in assays with PC12 cells. The SAR results indicate that the number and position of the hydroxy groups on the phenyl ring and the triterpene moiety, as well as the length of the (saturated or unsaturated) alkyl chain that links the phenyl ring with the triterpene critically influence neuritogenic activity. Among all the tested compounds, 1 e [(3S,4R)‐23,28‐dihydroxyolean‐12‐en‐3‐yl (2E)‐3‐(3,4,5‐trihydroxyphenyl)acrylate] was found to be the most potent, inducing significant neurite outgrowth at 1 μm . 相似文献
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Development of Potent Pyrazolopyrimidinone‐Based WEE1 Inhibitors with Limited Single‐Agent Cytotoxicity for Cancer Therapy 下载免费PDF全文
Dr. Christopher J. Matheson Kimberly A. Casalvieri Dr. Donald S. Backos Dr. Philip Reigan 《ChemMedChem》2018,13(16):1681-1694
WEE1 kinase regulates the G2/M cell‐cycle checkpoint, a critical mechanism for DNA repair in cancer cells that can confer resistance to DNA‐damaging agents. We previously reported a series of pyrazolopyrimidinones based on AZD1775, a known WEE1 inhibitor, as an initial investigation into the structural requirements for WEE1 inhibition. Our lead inhibitor demonstrated WEE1 inhibition in the same nanomolar range as AZD1775, and potentiated the effects of cisplatin in medulloblastoma cells, but had reduced single‐agent cytotoxicity. These results prompted the development of a more comprehensive series of WEE1 inhibitors. Herein we report a series of pyrazolopyrimidinones and identify a more potent WEE1 inhibitor than AZD1775 and additional compounds that demonstrate that WEE1 inhibition can be achieved with reduced single‐agent cytotoxicity. These studies support that WEE1 inhibition can be uncoupled from the potent cytotoxic effects observed with AZD1775, and this may have important ramifications in the clinical setting where WEE1 inhibitors are used as chemosensitizers for DNA‐targeted chemotherapy. 相似文献
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Structure‐Based Design of Microsomal Prostaglandin E2 Synthase‐1 (mPGES‐1) Inhibitors using a Virtual Fragment Growing Optimization Scheme 下载免费PDF全文
Dr. Gianluigi Lauro Prof. Paolo Tortorella Dr. Alessia Bertamino Dr. Carmine Ostacolo Dr. Andreas Koeberle Katrin Fischer Prof. Ines Bruno Dr. Stefania Terracciano Dr. Isabel Maria Gomez‐Monterrey Dr. Marilena Tauro Prof. Fulvio Loiodice Prof. Ettore Novellino Prof. Raffaele Riccio Prof. Oliver Werz Prof. Pietro Campiglia Prof. Giuseppe Bifulco 《ChemMedChem》2016,11(6):612-619
A small library of 2,3‐dihydroxybenzamide‐ and N‐(2,3‐dihydroxyphenyl)‐4‐sulfonamide‐based microsomal prostaglandin E2 synthase‐1 (mPGES‐1) inhibitors was identified following a step‐by‐step optimization of small aromatic fragments selected to interact in focused regions in the active site of mPGES‐1. During the virtual optimization process, the 2,3‐dihydroxybenzamide moiety was first selected as a backbone of the proposed new chemical entities; the identified compounds were then synthesized and biologically evaluated, identifying derivatives with very promising inhibitory activities in the micromolar range. Subsequent structure‐guided replacement of the 2,3‐dihydroxybenzamide by the N‐(2,3‐dihydroxyphenyl)sulfonamide moiety led to the identification of N‐(2,3‐dihydroxyphenyl)‐4‐biphenylsulfonamide ( 6 ), the most potent small molecule of the series (IC50=0.53±0.04 μm ). The simple synthetic procedure and the possibility of enhancing the potency of this class of inhibitors through additional structural modifications pave the way for further development of new molecules with mPGES‐1‐inhibitory activity, with potential application as anti‐inflammatory and anticancer agents. 相似文献
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Xiao‐Qing Feng Yong‐Hong Liang Zhao‐Sen Zeng Fen‐Er Chen Prof. Dr. Jan Balzarini Prof. Dr. Christophe Pannecouque Prof. Dr. Erik De Clercq Prof. Dr. 《ChemMedChem》2009,4(2):219-224
A novel series of diarylpyrimidine analogues (DAPYs) featuring a naphthyl moiety at the C4 position were designed, with all compounds exhibiting strong activity against wild‐type HIV‐1.