General method for the synthesis of 8-arylsulfanyl adenine derivatives

We report a general method for the synthesis of 8-arylsulfanyl adenine derivatives using a mild protocol of coupling 8-mercaptoadenine with a variety of aryl iodides.     

Study on the properties of dextran-linked adenine nucleotide derivatives

A simple method is described for the preparation of dextran-linked coenzyme derivatives. Several different 8-(6-aminohexyl)amino-adenine nucleotide coenzymes and their derivatives were covalently attached to dextran by incubation with bromohydroxypropyl derivatives of dextran at room temperature in an alkaline medium. The polymer-linked adenine nucleotide derivatives were separated from the free coenzyme derivatives by a Sephadex G-50 column. The prepared dextran derivatives have ligand densities ranging from 20 to 100 μmol/g of dextran derivatives depending on the conditions of coupling and derivatives. NMR studies revealed that proton resonances of the polymer-linked coenzymes exhibit short transverse relaxation times (T₂) but long longitudinal relaxation times (T₁) This phenomenon was interpreted in terms of the anisotropic motions of the dextran-bound coenzyme derivatives in which the fast axial motions and slow restricted transverse motions of the bound coenzyme derivatives are postulated. These observations could properly explain why the polymer-linked coenzymes exhibit lower biological activity, but similar binding affinity to most enzymes.     

Spectral properties of coumarin derivatives in various environments

The structural and spectral properties of coumarin derivatives in complex environments were investigated within the time-dependent density functional theory (TD DFT). Absorption spectra calculations were obtained at TD PBE0/6-31+G(d,p) level of theory for coumarin47 in the gas-phase and in various polar and non-polar organic solvents. The geometries of coumarins 6, 30, 47 and 522 in the gas phase and in inclusion complexes with the β-cyclodextrin (βCD) were determined by PM3 and DFT (HCTH/6-31G) calculations. Encapsulation of coumarin in βCD and associated changes in electronic structure produced either a red or blue shift in the absorption spectra of coumarins. A proposed cavity model for βCD-coumarin complex in water solution allowed identification of various contributions to the overall shift in the absorption spectra of coumarin upon complex formation in a solvent environment      

Spectral and photochemical properties of hydroxylated 2-styrylquinoline derivatives

The spectral and photochemical properties of 2-(4-hydroxystyryl)quinoline 1 and 2-(2-hydroxystyryl)quinoline 2 have been studied. The trans-cis photoisomerization quantum yield for 1 and 2 in the neutral form is 0.2–0.5, and it is reduced by a factor of 6–7 by protonation, presumably, owing to the competitive process of hydroxyl group deprotonation in the excited state and the formation of quinoid tautomers. The quantum yield of the back cis-trans photoisomerization in the protonated form varies insignificantly. The neutral, protonated, and deprotonated forms of 1 have been used for to simulate a molecular logic gate, the half-adder with chemical inputs and absorbance as outputs.     

Gas-phase hydrogen/deuterium exchange of adenine nucleotides

Gas-phase hydrogen/deuterium exchange reactions of (de)protonated (sodiated) adenosine-5'-mono-, di- and triphosphate ions with CD(3)OD, CD(3)CO(2)D and ND(3) were achieved using a combination of electrospray ionization and Fourier transform ion cyclotron resonance mass spectrometry. The reaction kinetics are dependent on factors such as the charge state, the phosphate chain length, the properties of the exchange reactants and the sodium content. The results indicate that the overall H/D exchange may involve specific sites even if endowed with high energetic barriers. The enhanced reactivity exhibited by adenosine polyphosphate ions compared with adenosine-5'-monophosphate suggests a critical role of the polyphosphate chain in rendering conformationally accessible remote H-donor sites. Low-energy collision-induced dissociation of (sodiated) adenine nucleotides anions supports the aptitude of the (poly)phosphate chain in probing distant sites via the intermediacy of a cyclic structure.     

Spectral characteristics,structure, and properties of phenanthridone derivatives

On the basis of IR and electronic spectra and quantum-chemical calculations, a conclusion has been drawn regarding the structure of phenanthridone and its derivatives: It has been confirmed that in the crystalline state and in solutions, phenanthridones exist primarily in the lactam form. An interpretation is given for the longwave bands in the electronic absorption spectra. Certain spectral criteria are proposed for determining the positions of substituents in the phenyl rings of phenanthridones, and the direction of aromatic substitution of the lactim and cationic forms of phenanthridone have been evaluated. Acid association constants of phenanthridone and its derivatives have been determined.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1361–1368, October, 1992.     

Structures of ferrocenylalkyl derivatives of adenine

9-(α-Ferrocenylethyl)adenine was prepared by the reaction of adenine with α-hydroxyethylferrocene in a two-phase aqueous-organic medium in the presence of HBF₄. The structure of the resulting compound was established by X-ray diffraction analysis. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1828–1831, September, 1998.     

Spectral and self-assembly properties of a series of asymmetrical pyrene derivatives

A series of pyrene derivatives with different asymmetrical substituents were successfully synthesized and characterized. The geometrical electronic structures of the asymmetrical pyrene derivatives were performed by density functional theory （DFT） calculations. The results of photophysical spectra and electrochemical analysis indicated that the optical or electric properties of the pyrene derivatives could be tuned by adjust the π-conjugation lengths of the substituents. Furthermore, through a phase exchange self-assembly method, the highly organized morphologies were observed by SEM.     

Gas-phase acidity studies of multiple sites of adenine and adenine derivatives

The acidities of multiple sites in the purine nucleobase adenine (1) and adenine alkyl derivatives 9-ethyladenine (2), 3-methyladenine (3), 1-methyladenine (4), and N,N-dimethyladenine (5) have been investigated for the first time, using computational and experimental methods to provide an understanding of adenine reactivity. We have previously measured two acidic sites on adenine, with the N9 site being 19 kcal mol(-)(1) more acidic than the N10 site (333 +/- 2 versus 352 +/- 4 kcal mol(-)(1), respectively). In this work, we have established that 9-ethyladenine has two sites more acidic than water: the N10 (352 +/- 4 kcal mol(-)(1)) and the C8 (374 +/- 2 kcal mol(-)(1)). We have likewise measured two acidities for 3-methyladenine, the N10 (347 +/- 4 kcal mol(-)(1)) and the C2 (370 +/- 3 kcal mol(-)(1)). For 1-methyladenine and N,N-dimethyladenine, we measure the N9H acidity to be 331 +/- 2 and 333 +/- 2 kcal mol(-)(1), respectively. We believe that the bracketing of only one site for the latter species is a kinetic effect, which we discuss further in the paper. Computationally, we have found the interesting result that some of the vinylic C-H sites in these purine bases are predicted to be much more acidic than water (DeltaH(acid) = 390.7 kcal mol(-)(1)) in the gas phase, on the order of 373 kcal mol(-)(1). The acidic vinylic C-H sites are always adjacent to an N-R group, and this pattern is maintained regardless of whether the site is on the five- or six-membered ring of the purine. Vinylic C-H sites elsewhere on the purine have calculated acidities of about 400 kcal mol(-)(1). The differing acidities are interpreted through electrostatic potential calculations. We also relate our results to the intriguing biochemical decarboxylation of orotate ribose monophosphate, which involves a vinylic anion adjacent to an N-R group; this decarboxylation is the last step in the de novo biosynthesis of pyrimidine nucleotides, and the enzyme that catalyzes the reaction, orotate ribose monophosphate decarboxylase, has been the subject of intense study recently, as its mechanism remains elusive.     

Syntheses and biological properties of new 8-fluorocarbapenem derivatives

8-Fluorocarbapenem derivatives having various C-3 side chains were synthesized to study for the structure-activity relationship of carbapenems by in vitro biological evaluation. The introduction of fluorine at C-8 of racemic PS-5 led to slight improvements of the antimicrobial activity and the stability to renal dehydropeptidase-I. When D-cysteine was additionally introduced to the C-3 position of (+/-)-8-fluorocarbapenem, the diastereomeric separation of the 8-fluorocarbapenems became feasible. As expected from penicillins and cephalosporins, (+)-8-fluoro-3-D-cysteinylcarbapenem (+)-7a was antimicrobially active, whereas (-)-7b was inactive. It is worth noting, however, that (+)-7a was significantly more sensitive to renal dehydropeptidase-I than (-)-7b. Irrespective of the presence of fluorine at C-8, basic S-side chains at C-3, such as the pyridyl and pyrrolidyl groups, significantly improved in antimicrobial activity and dehydropeptidase-I stability. The combination of 8-fluorination with C-3 basic side chains in 7c--g resulted in a marked improvement of antimicrobial activity and dehydropeptidase-I stability.     

Synthesis and antibacterial properties of new 8-nitrofluoroquinolone derivatives

The objective of this research was the preparation of new 8-nitrofluoroquinolone models and investigation of their antibacterial properties. The work initially involved large scale preparation of the synthon 7-chloro-1-cyclopropyl-6-fluoro-8-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (3), followed by introduction of substituted primary amine appendages at the C-7 position to give derivatives 9a-g, in which the amino group is appended to substituted benzenes or aromatic heterocycles, is part of a primary alpha-amino acid or just a simple primary aliphatic amine. This nucleophilic aromatic substitution step was a very simple procedure since the 8-nitro group of the above synthon facilitated the addition of weak nucleophiles at C-7. All compounds prepared were fully identified and characterized using NMR, IR, EA and MS, and were consistent with expected structures. The prepared targets and the intermediates have shown interesting antibacterial activity against gram positive and/or gram negative strains. In particular, the p-toluidine, p-chloroaniline and aniline derivatives showed good activity against S. aureus with MIC range approximately 2-5 microg/mL. In conclusion, more lipophilic groups seem to enhance activity against gram positive strains.     

Protonation studies of modified adenine and adenine nucleotides by theoretical calculations and (15)N NMR

The acid/base character of nucleobases affects phenomena such as self-association, interaction with metal ions, molecular recognition by proteins, and nucleic acid base-pairing. Therefore, the investigation of proton-transfer equilibria of natural and synthetic nucleos(t)ides is of great importance to obtain a deeper understanding of these phenomena. For this purpose, a set of ATP prototypes was investigated using (15)N NMR spectroscopy, and the corresponding adenine bases were investigated by theoretical calculations. (15)N NMR measurements provided not only acidity constants but also information on the protonation site(s) on the adenine ring and regarding the ratio of the singly protonated species in equilibrium. Substituents of different nature and position on the adenine ring did not change the preferred protonation site, which remained N1. However, for 2-thioether-ATP derivatives a mixed population of N1 and N7 singly protonated species was observed. Reduction of basicity of 0.4-1 pK(a) units relative to ATP was also observed for all evaluated ATP derivatives, except for 2-Cl-ATP, for which K(a) was ca. 10,000-fold lower. To explain the substitution-dependent variations in the experimental pK(a) values of the ATP analogues, gas-phase proton affinities (PA), Delta Delta G(hyd), and pK(a) values of the corresponding adenine bases were calculated using quantum mechanical methods. The computed PA and Delta Delta G(hyd) values successfully explained the experimental pK(a) values. A computational procedure for the prediction of accurate pK(a) values was developed using density functional theory and polarizable continuum model calculations. In this procedure, we developed a set of parameters for the polarizable continuum model that was fitted to reproduce experimental pK(a) values of nitrogen heterocycles. This method is proposed for the prediction of pK(a) values and protonation site(s) of purine analogues that have not been synthesized or analyzed.     

Some intramolecular michael additions of adenine derivatives

In our attempts to prepare polymerizable derivatives of nucleic acid bases, we investigated the reaction of adenine ( 1 ) and 9-(cyanoethyl)adenine ( 4 ) with acrylic anhydride and acryloyl chloride. Reactions of adenine with methyl acrylate and vinyl acrylate were also examined. The results show that these reactions are solvent dependent and the intermediate acryloyladenine 3 can undergo a facile intramolecular Michael reaction to form 7.     

Methods for the determination of adenosine triphosphate and other adenine nucleotides

The following methods for the determination of adenosine triphosphate reported in the past 25 years are considered: bioluminescence methods with the use of the firefly luciferase enzyme (with sensitivity to 10^?14 M); chromatographic methods (ion-exchange, thin-layer, and high performance liquid chromatography) for the determination of adenine nucleotides in mixtures with other nucleotides, nucleosides, and nitrogen bases; and fluorescence, spectrophotometric, and electrochemical techniques (including those with the use of sensors), which are promising but not commonly used for the determination of adenine nucleotides. The advantages and disadvantages of these methods are demonstrated.