ABSTRACT
There are many great reports of polyamine stabilization of the Z-DNA by bridge conformation between neighboring, symmetry-related Z-DNA in the packing of crystals. However, polyamine binding to the minor groove of Z-DNA and stabilizing the Z-DNA structure has been rarely reported. We proved that the synthesized polyamines bind to the minor groove of Z-DNA and stabilize the conformation under various conditions, by X-ray crystallographic study. These polyamines consist of a polyamine nano wire structure. The modes of the polyamine interaction were changed under different conditions. It is the first example that the crystals consisted of metal free structure. This finding provides a basis for clarifying B-Z transition mechanics.
Subject(s)
DNA, Z-Form/chemistry , DNA, Z-Form/ultrastructure , Models, Chemical , Models, Molecular , Polyamines/chemistry , Computer Simulation , Crystallography, X-Ray , Isomerism , Nucleic Acid Conformation , Nucleic Acid DenaturationABSTRACT
Potassium salts of p-tert-butylcalix[6]arene p-bromophenylalanine derivative formed sizable octameric cages in the solid state that were revealed by X-ray crystallographic analysis.
Subject(s)
Calixarenes/chemical synthesis , Combinatorial Chemistry Techniques/methods , Phenylalanine/analogs & derivatives , Potassium/chemistry , Calixarenes/chemistry , Crystallography, X-Ray , Models, Molecular , Molecular Conformation , Phenylalanine/chemical synthesis , Phenylalanine/chemistry , Salts/chemistryABSTRACT
We succeeded in the crystallization of d(CGCGCG)2 and methylamine Complex. The crystal was clear and of sufficient size to collect the X-ray crystallographic data up to 1.0 A resolution using synchrotron radiation. As a result of X-ray crystallographic analysis of 2Fo-Fc map was much clear and easily traced. It is the first time monoamine co-crystallizes with d(CGCGCG)2. However, methylamine was not found from the complex crystal of d(CGCGCG)2 and methylamine. Five Mg ions were found around d(CGCGCG)2 molecules. These Mg ions neutralized the anion of 10 values of the phosphate group of DNA with five Mg2+. DNA stabilized only by a metallic ion and there is no example of analyzing the X-ray crystal structure like this. Mg ion stabilizes the conformation of Z-DNA. To use monoamine for crystallization of DNA, we found that we can get only d(CGCGCG)2 and Mg cation crystal. Only Mg cation can stabilize the conformation of Z-DNA. The method of using the monoamine for the crystallization of DNA can be applied to the crystallization of DNA of long chain of length in the future like this.
Subject(s)
Methylamines/chemistry , Oligodeoxyribonucleotides/chemistry , Crystallography, X-Ray , DNA, Z-Form/chemistryABSTRACT
In search for potent and selective beta3-adrenergic receptor (beta3-AR) agonists as potential drugs for the treatment of type II diabetes and obesity, a novel series of 1-(3-chlorophenyl)-2-aminoethanol derivatives were prepared and evaluated for their biological activity at human beta1-, beta2-, and beta3-ARs and rat beta3-AR expressed in Chinese hamster ovary (CHO) cells. Replacement of the right-hand side (RHS, benzene ring) in the 'first generation' beta3-AR agonists BRL 37344 and CL 316243 with a 1H-indole ring gave compound 31 with unique pharmacological properties among beta3-AR agonists. Initial in vitro assays showed that 31 possesses modest rat and human beta3-ARs agonistic activity. Introduction of various substituent into the indole nucleus of 31 afforded a number of compounds with good beta3-ARs agonistic activity. In particular, 90 having a carboxylic acid functionality at the 7-position of the indole nucleus showed the most potent human beta3-AR agonistic activity. Finally, optical resolution of 90 led to the identification of the most promising compound, [3-[(2R)-[[(2R)-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1H-indol-7-yloxy]acetic acid (96, AJ-9677). This compound exhibited potent human beta3-AR agonistic activity (EC50=0.062 nM, IA=116%) with 210- and 103-fold selectivity over human beta2-AR and beta1-AR, respectively. Compound 96 also exhibited potent rat beta3-AR agonistic activity (EC50=0.016 nM, IA=110%). Moreover, repeated oral administration of 96 inhibited body weight gain and significantly decreased glucose, insulin, free fatty acid, and triglyceride concentrations in plasma in KK-Ay/Ta mice. On the basis of this pharmacological profile, 96 entered clinical development as a drug for the treatment of type II diabetes and obesity.
Subject(s)
Acetates/chemical synthesis , Acetates/pharmacology , Adrenergic beta-3 Receptor Agonists , Adrenergic beta-Agonists/chemical synthesis , Adrenergic beta-Agonists/pharmacology , Indoles/chemical synthesis , Indoles/pharmacology , Animals , Blood Glucose/metabolism , Body Weight/drug effects , Colon/drug effects , Crystallography, X-Ray , Cyclic AMP/metabolism , Fatty Acids, Nonesterified/blood , Humans , Indicators and Reagents , Insulin/blood , Male , Models, Molecular , Molecular Conformation , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Obesity/drug therapy , Rats , Structure-Activity Relationship , Triglycerides/bloodABSTRACT
It is known that the crystal structure of d(CG)3 become left-handed Z-DNA under high salt concentration and various polyamines stabilize the Z-DNA structure. We have structurally investigated how polyamines stabilize the Z-DNA by the X-ray crystallographic analysis of d(CG)3-polyamine cocrystals. In this study, we determined the Z-DNA structures with di- to pentavalent polyamines at high resolution. Comparison with the structures revealed that the valence of polyamine determined number of the polyamine(s) and metal ion(s) chelating to the Z-DNA. Furthermore, we succeeded in crystallizing d(CG)3-monoamine (methylamine and ethylamine) complexes.
Subject(s)
Amines/chemistry , DNA, Z-Form/chemistry , Polyamines/chemistry , Crystallography, X-Ray , Dinucleotide Repeats , Ethylamines/chemistry , Methylamines/chemistry , Models, MolecularABSTRACT
We have previously found that a pyrazole derivative 1 possesses antibacterial activity and inhibitory activity against DNA gyrase and topoisomerase IV. Here, we synthesized new pyrazole derivatives and found that 5-[(E)-2-(5-chloroindol-3-yl)vinyl]pyrazole 16 possesses potent antibacterial activity and selective inhibitory activity against bacterial topoisomerases. Many of the synthesized pyrazole derivatives were potent against clinically isolated quinolone- or coumarin-resistant Gram-positive strains and had minimal inhibitory concentration values against these strains equivalent to those against susceptible strains.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Indoles/chemical synthesis , Pyrazoles/chemical synthesis , Topoisomerase II Inhibitors , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , DNA Topoisomerase IV/antagonists & inhibitors , Drug Resistance, Bacterial , Enterococcus faecalis/drug effects , Indoles/chemistry , Indoles/pharmacology , Pyrazoles/chemistry , Pyrazoles/pharmacology , Staphylococcus aureus/drug effects , Streptococcus pneumoniae/drug effects , Structure-Activity RelationshipABSTRACT
A novel series of 2-(3-indolyl)alkylamino-1-(3-chlorophenyl)ethanols was prepared and evaluated for in vitro ability to stimulate cAMP production in Chinese hamster ovary cells expressing cloned human beta(3)-AR. The optically active 30a was found to be the most potent and selective human beta(3)-AR agonist in this series with an EC(50) value of 0.062nM. In addition, 30a selectivity for human beta(3)-AR was 210-fold and 103-fold that for human beta(2)-AR and beta(1)-AR, respectively. Furthermore, 30a showed potent agonistic activity at rat beta(3)-AR.
