ABSTRACT
A series of benzo[b]furan derivatives having a five-membered heterocyclic substituent at the 2-position were prepared from 2-(1-chloro-2-formylvinyl)benzo[b]furans (2) and 2-(4-alkylcarbamoylbuta-1,3-dienyl)benzo[b]furans. These 2-heterocyclic benzo[b]furans were evaluated for their cysteinyl leukotriene receptor (cysLT1, cysLT2) inhibitory activity. Several compounds showed moderate inhibition of calcium mobilization in HEK 293T-cysLT2 or CHO-cysLT1 cells.
Subject(s)
Benzofurans/chemistry , Benzofurans/pharmacology , Leukotriene Antagonists/chemistry , Leukotriene Antagonists/pharmacology , Receptors, Leukotriene/metabolism , Animals , Benzofurans/chemical synthesis , CHO Cells , Calcium/metabolism , Cricetinae , HEK293 Cells , Humans , Leukotriene Antagonists/chemical synthesisABSTRACT
A reaction of 2-acetyl-3-acylaminobenzo[b]furans (9d-o) with Vilsmeier (VM) reagent afforded a mixture of (E)- and (Z)-{(E)-2-aralkenylbenzo[b]furo[3,2-d][1,3]oxazin-4-ylidene}acetaldehydes (5) with a characteristic exo-formylmethylene group on the oxazine ring. The Z-isomer was more stable than the E-isomer. The Z-isomers ((Z)-5) were reacted with phosphonate reagents under two different conditions to obtain various butadiene derivatives (12) containing benzo[b]furo[3,2-d][1,3]oxazine skeleton. Typical compounds (5 and 12) were evaluated for their anti-osteoclastic bone resorption activity, antagonistic activity for the cysLT1 receptor and growth inhibitory activity for MIA PaCa-2 and MCF-7. Compounds 12f and 12j showed potent anti-osteoclastic bone resorption activity comparable to E(2) (17beta-estradiol).
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Osteoblasts/drug effects , Oxazines/chemical synthesis , Oxazines/pharmacology , Animals , Antineoplastic Agents/chemistry , Bone Resorption , Breast Neoplasms/drug therapy , Cell Line, Tumor , Cell Proliferation/drug effects , Female , Humans , Male , Mice , Molecular Structure , Oxazines/chemistry , Pancreatic Neoplasms/drug therapyABSTRACT
A series of 2-(2-aminothiazol-4-yl)benzo[b]furan and 3-(2-aminothiazol-4-yl)benzo[b]furan derivatives were prepared, and their leukotriene B(4) inhibitory activity and growth inhibitory activity in cancer cell lines were evaluated. Several compounds showed strong inhibition of calcium mobilization in CHO cells overexpressing human BLT(1) and BLT(2) receptors and growth inhibition to human pancreatic cancer cells MIA PaCa-2. 3-(4-Chlorophenyl)-2-[5-formyl-2-[(dimethylamino)methyleneamino]thiazol-4-yl]-5-methoxybenzo[b]furan 8b showed the most potent and selective inhibition for the human BLT(2) receptor, and its IC(50) value was smaller than that of the selected positive control compound, ZK-158252. 3-(4-Chlorophenyl)-2-[2-[(dimethylamino)methyleneamino]-5-(2-hydroxyethyliminomethyl)thiazol-4-yl]-5-methoxybenzo[b]furan 9a displayed growth inhibitory activity towards MIA PaCa-2.
Subject(s)
Antineoplastic Agents/chemistry , Benzofurans/chemistry , Pancreatic Neoplasms/drug therapy , Receptors, Leukotriene B4/antagonists & inhibitors , Thiazoles/chemistry , Animals , Antineoplastic Agents/therapeutic use , Benzofurans/therapeutic use , CHO Cells , Cell Line, Tumor , Cricetinae , Cricetulus , Drug Screening Assays, Antitumor , Humans , Inhibitory Concentration 50 , Molecular Structure , Receptors, Leukotriene B4/drug effectsABSTRACT
Several 2-alkylcarbamoyl-1-alkylvinylbenzo[b]furans were designed to find a selective leukotriene B4 (LTB4) receptor antagonist. 2-(2-Alkylcarbamoyl-1-alkylvinyl)benzo[b]furans having a substituent group at the 3-position, 4-(2-alkylcarbamoyl-1-methylvinyl)benzo[b]furans having a substituent group at the 3-position, and 7-(2-alkylcarbamoyl-1-methylvinyl)benzo[b]furans and 3-(2-alkylcarbamoyl-1-alkylvinyl)benzo[b]furans were prepared and evaluated for LTB4 receptor (BLT1 and BLT2) inhibitory activities. (E)-3-Amino-4-[2-[2-(3,4-dimethoxyphenyl)ethylcarbamoyl]-1-methylvinyl]benzo[b]furan ((E)-17c) showed potent and selective inhibitory activity for BLT2. On the other hand, (E)-7-(2-diethylcarbamoyl-1-methylvinyl)benzo[b]furan ((E)-27a) showed potent inhibitory activity for both BLT1 and BLT2.
Subject(s)
Benzofurans/chemical synthesis , Benzofurans/pharmacology , Receptors, Leukotriene B4/antagonists & inhibitors , Animals , Benzofurans/chemistry , CHO Cells , Cricetinae , Cricetulus , Crystallography, X-Ray , Drug Evaluation, Preclinical , Humans , Models, Molecular , Molecular Structure , Receptors, Leukotriene B4/biosynthesis , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A novel seven-membered lactam formation method has been established by intramolecular ring closure reaction of 4-bromo-(E)-3-[(2-alkylvinyl)carbonylamino]benzo[b]furans under Heck coupling conditions. A number of furo[2,3,4-jk][2]benzazepin-4(3H)-ones, tricyclicbenzo[b]furans, have been prepared by this method and evaluated for their leukotriene B(4) (LTB(4)) receptor and poly(ADP-ribose)polymerase-1 (PARP-1) inhibitory activities.
Subject(s)
Benzazepines/chemical synthesis , Benzazepines/pharmacology , Benzofurans/chemical synthesis , Benzofurans/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors , Animals , Benzazepines/chemistry , Benzofurans/chemistry , CHO Cells , Cricetinae , Cricetulus , Enzyme Activation/drug effects , Humans , Molecular Structure , Poly (ADP-Ribose) Polymerase-1 , Receptors, Leukotriene B4/antagonists & inhibitors , Stereoisomerism , Structure-Activity RelationshipABSTRACT
We have been actively involved in the development of parallel approaches for the discovery of phosphine ligands. Our approach has been based on the incorporation of phosphine-containing amino acids into peptide sequences that are designed to have stable secondary structures. We have examined helical and turn secondary structures and have reported that alkylation of cyclopentenyl acetate with dimethylmalonate can be catalyzed in high enantiomeric excess (ee) with a beta-turn-based ligand. The importance of the peptide secondary structure was demonstrated through the synthesis of a series of peptide ligands where the nature of the turn-forming residues was probed. Additionally, other turn-forming units and a variety of different phosphine-containing amino acids have been examined for their ability to control the selectivity of the allylation reaction. This paper reports the results obtained through the examination of different turn motifs as well as different phosphine substitutions on the "best" turn sequence, Pps-Pro-d-Xxx-Pps.
Subject(s)
Amino Acids/chemistry , Oligopeptides/chemistry , Phosphines/chemistry , Amino Acid Sequence , Catalysis , Ligands , Models, Molecular , Oligopeptides/chemical synthesis , Protein Structure, Secondary , StereoisomerismABSTRACT
Cox17p, essential for the assembly of functional cytochrome c oxidase (CCO) in Saccharomyces cerevisiae, has been believed to deliver copper ions to the mitochondrion for insertion into the enzyme. We have recently isolated an approximately 20 kb genomic fragment of the mouse COX17. Reporter assay experiments have shown that most of the promoter activity was restricted to a 0.85 kb fragment flanking the first exon. Further intensive deletion and detailed mutation analysis suggested that the minimal essential region for transactivation was located at bases -155 to -70. This 5'-flanking region did not possess a TATA box, but contained putative Sp1, NRF-1 and NRF-2 binding sites. COX17 basal promoter activity was abrogated by site-directed mutagenesis of Sp1, NRF-1 and NRF-2 binding sites. Electrophoretic mobility shift assays with AtT-20 and NIH3T3 cell nuclear extract revealed that this region binds both a Sp1-like protein and NRF-1 transcription factors. These results indicated that Sp1, NRF-1 and NRF-2 are involved in basal transcription of the COX17 gene, similar to the transcription mechanism of other CCO-related genes.
