ABSTRACT
This review summarizes for the first time data on the design and synthesis of biologically active compounds of a new generation - mitochondria-targeted antioxidants, which are natural (or synthetic) p-benzoquinones conjugated via a lipophilic linker with (triphenyl)phosphonium or ammonium cations with delocalized charge. It also describes the synthesis of mitochondria-targeted antioxidants - uncouplers of oxidative phosphorylation - based on fluorescent dyes.
Subject(s)
Antioxidants/chemical synthesis , Drug Design , Mitochondria/metabolism , Ammonium Compounds/chemistry , Antioxidants/pharmacology , Antioxidants/therapeutic use , Benzoquinones/chemistry , Dry Eye Syndromes/drug therapy , Dry Eye Syndromes/pathology , Fluorescein/chemistry , Humans , Mitochondria/drug effects , Oxidative Phosphorylation , Plastoquinone/analogs & derivatives , Plastoquinone/chemical synthesis , Plastoquinone/chemistry , Reactive Oxygen Species/chemistry , Reactive Oxygen Species/metabolismABSTRACT
Novel fluorescent derivatives of macrolide antibiotics related to tylosin bearing rhodamine, fluorescein, Alexa Fluor 488, BODIPY FL, and nitrobenzoxadiazole (NBD) residues were synthesized. The formation of complexes of these compounds with 70S E. coli ribosomes was studied by measuring the fluorescence polarization depending on the ribosome amount at constant concentration of the fluorescent substance. With the synthesized fluorescent tylosin derivatives, the dissociation constants for ribosome complexes with several known antibiotics and macrolide analogs previously obtained were determined. It was found that the fluorescent tylosin derivatives containing BODIPY FL and NBD groups could be used to screen the binding of novel antibiotics to bacterial ribosomes in the macrolide-binding site.
Subject(s)
Escherichia coli/chemistry , Fluorescent Dyes/chemistry , Ribosomes/chemistry , Tylosin/analogs & derivatives , Tylosin/chemistryABSTRACT
Chloramphenicol amine peptide derivatives containing tripeptide fragments of regulatory "stop peptides" - MRL, IRA, IWP - were synthesized. The ability of the compounds to form ribosomal complexes was studied by displacement of the fluorescent erythromycin analog from its complex with E. coli ribosomes. It was found that peptide chloramphenicol analogs are able to bind to bacterial ribosomes. The dissociation constants were 4.3-10 µM, which is 100-fold lower than the corresponding values for chloramphenicol amine-ribosome complex. Interaction of the chloramphenicol peptide analogs with ribosomes was simulated by molecular docking, and the most probable contacts of "stop peptide" motifs with the elements of nascent peptide exit tunnel were identified.
Subject(s)
Chloramphenicol/chemistry , Oligopeptides/metabolism , Ribosomes/metabolism , Binding Sites , Boron Compounds/chemistry , Crystallography, X-Ray , Escherichia coli/metabolism , Kinetics , Molecular Docking Simulation , Oligopeptides/chemical synthesis , Oligopeptides/chemistry , Protein Structure, Tertiary , Ribosomes/chemistryABSTRACT
Using a method of static simulation, a series of erythromycin A analogs was designed with aldehyde functions introduced instead of one of the methyl substituents in the 3'-N-position of the antibiotic that was potentially capable of forming a covalent bond with an amino group of one of the nucleotide residues of the 23S rRNA in the ribosomal exit tunnel. Similar interaction is observed for antibiotics of the tylosin series, which bind tightly to the large ribosomal subunit and demonstrate high antibacterial activity. Binding of novel erythromycin derivatives with the bacterial ribosome was investigated with the method of fluorescence polarization. It was found that the erythromycin analog containing a 1-methyl-3-oxopropyl group in the 3'-N-position demonstrates the best binding. Based on the ability to inhibit protein biosynthesis, it is on the same level as erythromycin, and it is significantly better than desmethyl-erythromycin. Molecular dynamic modeling of complexes of the derivatives with ribosomes was conducted to explain the observed effects.
Subject(s)
Erythromycin/metabolism , RNA, Ribosomal/metabolism , Binding Sites , Drug Design , Erythromycin/analogs & derivatives , Erythromycin/pharmacology , Escherichia coli/genetics , Escherichia coli/metabolism , Kinetics , Molecular Conformation , Molecular Dynamics Simulation , Protein Biosynthesis/drug effects , RNA, Ribosomal/chemistryABSTRACT
This review describes the results of recent studies of the ribosomal tunnel (RT), the major function of which is to allow the smooth passage of nascent polypeptides with different sequences from the peptidyl transferase center of the ribosome to the tunnel exit, where the folding of protein molecules begins. The features of structural organization of RT and their role in modulation and stabilization of the nascent chain conformation are discussed. Structural features of macrolide binding sites as well as application of macrolide antibiotics and their derivatives as tools to investigate ligand-tunnel wall interactions are also considered. Several examples of strong and specific interactions of regulatory polypeptides with nucleotide and amino acid residues of RT that lead to ribosome stalling and translational arrest are described in detail. The role of these events in regulation of expression of certain genes is discussed on the basis of recent high-resolution structural studies of nascent chains in the RT.
Subject(s)
Protein Biosynthesis/physiology , Ribosomes/chemistry , Ribosomes/metabolism , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Humans , Macrolides/chemistry , Macrolides/pharmacology , Peptides/chemistry , Peptides/metabolism , Peptidyl Transferases/chemistry , Peptidyl Transferases/metabolism , Protein Conformation/drug effects , Ribosomes/drug effectsABSTRACT
Fenotropil and its structural analog--compound RGPU-95 to a greater extent reduce the severity of anxious and depressive behavior in male rats than in females. On expression of the anxiolytic compound RGPU-95 significantly exceeds Fenotropil, but inferior to Diazepam; of antidepressant activity--comparable to Melipramin and exceeds Fenotropil.
Subject(s)
Anxiety/physiopathology , Behavior, Animal/drug effects , Depression/physiopathology , GABA Modulators/pharmacology , Sex Characteristics , Animals , Anxiety/drug therapy , Depression/drug therapy , Female , Male , Rats , Rats, WistarABSTRACT
Approaches to the synthesis of model compounds based on the tylosin-related macrolides desmycosin and O-mycaminosyltylonolide were developed using specially designed peptide derivatives of macrolide antibiotics to study the conformation and topography of the nascent peptide chain in the ribosome tunnel. A method for selective bromoacetylation of desmycosin at the hydroxyl group of mycinose was developed, which involves preliminary acetylation of mycaminose. The reaction of the 4"-bromoacetyl derivative of the antibiotic with cesium salts of the dipeptide Boc-Ala-Ala-OH and the hexapeptide MeOTr-Gly-Pro-Gly-Pro-Gly-Pro-OH led to the corresponding peptide derivatives of desmycosin. The protected peptides Boc-Ala-Ala-OH, Boc-Ala-Ala-Phe-OH, and Boc-Gly-Pro-Gly-Pro-Gly-Pro-OH were condensed with the C23-hydroxyl group of O-mycaminosyltylonolide.