ABSTRACT
Using a high-throughput, cell-based HCV luciferase reporter assay to screen a diverse small-molecule compound collection (â¼ 300,000 compounds), we identified a benzofuran compound class of HCV inhibitors. The optimization of the benzofuran scaffold led to the identification of several exemplars with potent inhibition (EC50 < 100 nM) of HCV, low cytotoxicity (CC50 > 25 µM), and excellent selectivity (selective index = CC50/EC50, > 371-fold). The structure-activity studies culminated in the design and synthesis of a 45-compound library to comprehensively explore the anti-HCV activity. The identification, design, synthesis, and biological characterization for this benzofuran series is discussed.
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Benzofurans/chemical synthesis , Benzofurans/pharmacology , Hepacivirus/drug effects , Antiviral Agents/toxicity , Benzofurans/toxicity , Cell Line , Drug Discovery , Hepatitis C/drug therapy , Hepatitis C/virology , High-Throughput Screening Assays , Humans , Small Molecule Libraries , Structure-Activity Relationship , Virus Replication/drug effectsABSTRACT
We herein report on the pharmacophore determination of the ERK docking domain inhibitor (Z)-3-(2-aminoethyl)-5-(4-ethoxybenzylidene)thiazolidine-2,4-dione, which has led to the discovery of compounds with greater selectivities for inhibiting the proliferation of melanoma cells containing active ERK signaling.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Proliferation/drug effects , Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors , Melanoma/drug therapy , Thiazolidinediones/chemistry , Thiazolidinediones/pharmacology , Cell Line, Tumor , Extracellular Signal-Regulated MAP Kinases/metabolism , HeLa Cells , Humans , MAP Kinase Signaling System/drug effects , Melanoma/enzymology , Structure-Activity RelationshipSubject(s)
Antineoplastic Agents/pharmacology , Enzyme Inhibitors/pharmacology , Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors , Small Molecule Libraries/pharmacology , raf Kinases/antagonists & inhibitors , Animals , Antineoplastic Agents/metabolism , Cell Line, Tumor , Enzyme Inhibitors/metabolism , Extracellular Signal-Regulated MAP Kinases/metabolism , Humans , MAP Kinase Signaling System/drug effects , Mice , Neoplasms/drug therapy , Protein Binding/drug effects , Quantitative Structure-Activity Relationship , Signal Transduction/drug effects , Small Molecule Libraries/metabolism , raf Kinases/metabolismABSTRACT
A number of functionally substituted 9-fluorenylidenes and 9,10-phenanthrenes have been synthesized from substituted o-halostyrenes and o-halo allylic benzenes respectively in good yields by the palladium-catalyzed annulation of arynes. The methodology tolerates a variety of functional groups, including cyano, ester, aldehyde, and ketone groups, occurs under relatively mild reaction conditions, and involves the generation of two new carbon-carbon bonds, thus providing these important carbocyclic ring systems in a single synthetic step.
Subject(s)
Fluorenes/chemical synthesis , Phenanthrenes/chemical synthesis , Allyl Compounds , Benzene , Catalysis , Methods , Palladium , StyrenesABSTRACT
3-Iodoindoles have been synthesized by the iodocyclization of N,N-dialkyl-o-(1-alkynyl)anilines, obtained by the Pd/Cu catalyzed coupling of terminal acetylenes with N,N-dialkyl-o-iodoanilines. These 3-iodoindoles undergo palladium-catalyzed Sonogashira and Suzuki coupling reactions to yield 1,2,3-trisubstituted indoles. These reactions have been applied to parallel library synthesis utilizing commercially available terminal acetylenes and boronic acids. The aforementioned chemistry has also been carried out on a chlorinated Wang resin as a solid support, affording 1,2,3,5-tetrasubstituted indoles after cleavage from the support. A diverse 42-member library of highly substituted indoles has been synthesized.
Subject(s)
Combinatorial Chemistry Techniques , Indoles/chemical synthesis , Palladium/chemistry , Catalysis , Chromatography, High Pressure Liquid , Indoles/chemistry , Magnetic Resonance Spectroscopy , Mass Spectrometry , Molecular Sequence Data , SolutionsABSTRACT
The palladium-catalyzed annulation of arynes by substituted o-halostyrenes produces substituted 9-fluorenylidenes in good yields. This methodology provides this important carbocyclic ring system in a single step, which involves the generation of two new carbon-carbon bonds, occurs under relatively mild reaction conditions, and tolerates a variety of functional groups, including cyano, ester, aldehyde, and ketone groups.
Subject(s)
Fluorenes/chemical synthesis , Palladium/chemistry , Catalysis , Combinatorial Chemistry Techniques , Cyclization , Fluorenes/chemistry , Molecular Structure , Styrenes/chemistryABSTRACT
The palladium-catalyzed aminocarbonylation of o-halobenzoates produces 2-substituted isoindole-1,3-diones in good yields. This methodology provides a good one-step approach to this important class of heterocycles and tolerates a variety of functional groups, including methoxy, alcohol, ketone, and nitro groups.
Subject(s)
Amines/chemistry , Bromobenzoates/chemistry , Chlorobenzoates/chemistry , Iodobenzoates/chemistry , Isoindoles/chemical synthesis , Palladium/chemistry , Catalysis , Cyclization , Isoindoles/chemistry , Molecular Structure , StereoisomerismABSTRACT
The electrophilic cyclization of substituted propargylic aryl ethers by I2, ICl, and PhSeBr produces 3,4-disubstituted 2H-benzopyrans in excellent yields. This methodology results in vinylic halides or selenides under mild reaction conditions and tolerates a variety of functional groups, including methoxy, alcohol, aldehyde, and nitro groups.
Subject(s)
Benzopyrans/chemistry , Benzopyrans/chemical synthesis , Carbon/chemistry , Cyclization , Electrochemistry , Molecular StructureABSTRACT
2,3-Disubstituted benzo[b]selenophenes have been prepared by the electrophilic cyclization of various 1-(1-alkynyl)-2-(methylseleno)arenes by Br2, NBS, I2, ICl, PhSeCl, PhSeBr, and Hg(OAc)2. This method tolerates a wide variety of functional groups, including alcohol, ester, nitrile, nitro, and silyl groups, and proceeds under exceptionally mild reaction conditions.
