Synthesis of N-1-(Indanyloxymethyl) and N-1-(4-Hydroxybut-2-enyloxymethyl) Analogues of the HIV Drugs Emivirine and GCA-186

A series of Emivirine and GCA-186 analogues substituted at N-1 with indan-1-yloxymethyl (6a–6c) and indan-2-yloxymethyl (6d–6f) were synthesized by reaction of the corresponding bis(indanyloxy)methans with uracils having 5-ethyl or 5-isopropyl and 6-benzyl or 6-(3,5-dimethylbenzyl) substituents. A route to the corresponding N-1 substituted 4-hydroxybut-2-enyloxymethyl analogue was also devised. All newly synthesized compounds showed potent activity against wild-type HIV-1, the most active compound being 5-ethyl-1-(indan-1-yloxymethyl)-6-(3,5-dimethylbenzyl)uracil (6b), which was 50-fold more active than Emivirine.     

Effect of bending and torsion rigidity on self-diffusion in polymer melts: a molecular-dynamics study

Extensive molecular-dynamics simulations have been performed to study the effect of chain conformational rigidity, controlled by bending and torsion potentials, on self-diffusion in polymer melts. The polymer model employs a novel torsion potential that avoids computational singularities without the need to impose rigid constraints on the bending angles. Two power laws are traditionally used to characterize the dependence of the self-diffusion coefficient on polymer length: D proportional to N(-nu) with nu=1 for NNe (reptation regime), Ne being the entanglement length. Our simulations, at constant temperature and density, up to N=250 reveal that, as the chain rigidity increases, the exponent nu gradually increases towards nu=2.0 for NNe. The value of Ne is slightly increased from 70 for flexible chains, up to the point where the crossover becomes undefined. This behavior is confirmed also by an analysis of the bead mean-square displacement. Subsequent investigations of the Rouse modes, dynamical structure factor, and chain trajectories indicate that the pre-reptation regime, for short stiff chains, is a modified Rouse regime rather than reptation.     

Synthesis of imidazoles as novel emivirine and S‐DABO analogues

5‐Alkyl‐4‐benzyl‐1,3‐dihydroimidazol‐2‐ones ( 3a‐d ) and 5‐alkyl‐4‐benzyl‐1,3‐dihydroimidazole‐2‐thiones (7a‐d) were prepared via Dakin West reaction on DL‐phenylalanine with the appropriate aliphatic acid anhydrides followed by hydrolysis and reaction with potassium cyanate or potassium thiocyanate. Compounds 3a‐d were alkylated with ethoxymethyl chloride to give the alkylated imidazoles 5a‐d which were considered analogues of Emivirine with deletion of carbonyl group at the 4‐position. Alkylation of 7a‐d afforded the corresponding S‐alkylated derivatives 8a‐p which in a similar way were considered analogues of S‐DABO. However all the imidazole derivatives were devoid of activity against HIV.     

Four levels of pattern recognition

Problems of pattern recognition in chemistry and other subjects can be divided conveniently into four different types depending on the level of scope of the problem.(1) Classification into one of a number of defined classes. As an example blood samples taken from persons known to be either controls or welders are considered. The problem is whether trace element concentrations in these samples contain information on whether or not a person is a welder.(2) Level 1 plus the possibility that an object is an outlier, i.e. does not belong to any of the defined classes. As an example, the üse of ¹³C-n.m.r. data to decide whether 2-substituted norbornanes have the exo or endo structure is discussed. (2A) Level 2, asymmetric. This situation occurs when one class does not have a systematic structure, but another class is homogeneous and can be described by a level 2 model. This occurs in the classification of materials or compounds as good or bad, active or inactive, and in binary classifications. As an example the use of trace element data to classify steel samples as having good or poor properties of strength is discussed.(3) Level 2 plus the ability to relate the variables measured to external properties of continuous character. As an example, the classification of a series of chemical compounds as β -receptor blockers, β -receptor stimulants, or neither, on the basis of their structural variables is discussed. In addition, relations between these structural variables and the measured biological activity are sought within each of the two classes.(4) Level 3 with the difference that several external property variables in the objects are measured. It may be desirable to use variables of the objects both for classification and for relations to several property variables: such examples are numerous in analytical chemistry.     

Synthesis and antiviral activity of monofluorinated cyclopropanoid nucleosides

Diastereopure monofluorinated cyclopropanoid nucleosides were synthesized for biological studies. As key intermediates cis- and trans-(+/-)-[1-fluoro-2-(acetoxymethyl)cyclopropyl]methanol were prepared starting from diastereopure fluorinated cyclopropanecarboxylates. The latter were synthesized by copper(i)-catalyzed cyclopropanation of [small alpha]-fluorostyrene with ethyl diazoacetate. After reduction and O-acetylation the diastereomeric (2-fluoro-2-phenylcyclopropyl)methyl acetates were obtained. Oxidative degradation using RuO(4) and reduction of the formed carboxyl group with borane gave the fluorinated alcohols, which were coupled with different nucleobases. After deprotection, the corresponding cyclopropanoid nucleosides of adenine, cytosine, guanine, thymine and uracil were obtained. Antiviral tests revealed for the cis-configured guanosine a low, but specific activity against HSV-1 and HSV-2. In addition low affinities of the adenine derivatives to adenosine receptors were detected.     

Macrocyclization of bis-indole quinolines for selective stabilization of G-quadruplex DNA structures

The recognition of G-quadruplex (G4) DNA structures as important regulatory elements in biological mechanisms, and the connection between G4s and the evolvement of different diseases, has sparked interest in developing small organic molecules targeting G4s. However, such compounds often lack drug-like properties and selectivity. Here, we describe the design and synthesis of a novel class of macrocyclic bis-indole quinolines based on their non-macrocyclic lead compounds. The effects of the macrocyclization on the ability to interact with G4 DNA structures were investigated using biophysical assays and molecular dynamic simulations. Overall, this revealed compounds with potent abilities to interact with and stabilize G4 structures and a clear selectivity for both G4 DNA over dsDNA and for parallel/hybrid G4 topologies, which could be attributed to the macrocyclic structure. Moreover, we obtained knowledge about the structure–activity relationship of importance for the macrocyclic design and how structural modifications could be made to construct improved macrocyclic compounds. Thus, the macrocyclization of G4 ligands can serve as a basis for the optimization of research tools to study G4 biology and potential therapeutics targeting G4-related diseases.

Macrocyclization improves the selectivity, affinity, and ability to stabilize G4 DNA structures.     

On-line coupling of supercritical fluid extraction with high-performance liquid chromatography for the determination of explosives in vapour phases

An investigation into the selectivity of an iminodiacetic acid (IDA) modified silica gel column for transition and heavy metal ions using non-chelating inorganic eluents has been carried out. A number of eluent parameters were investigated to determine the exact retention mechanism taking place and to control selectivity. The parameters studied were eluent ionic strength and the nature of the inorganic salt used, eluent pH and eluent temperature. The results obtained showed how despite certain metal ions exhibiting similar stability constants with the bonded IDA groups, careful control of each of the above parameters, in particular eluent chloride ion concentration and eluent temperature, could result in large changes in selectivity. Optimal conditions for the isocratic and gradient separation of Mg(II), Ca(II), Mn(II), Cd(II), Co(II), Zn(II) and Pb(II) were determined. An isocratic method using a 0.035 M KCl, 0.065 M KNO3 (pH 2.5) eluent was successfully applied to the determination of Mn(II), Cd(II), Co(II) and Zn(II) at concentrations between 20 and 121 microg/l in a freshwater certified reference material (NIST 1640).     

Association of bound states of the coulomb potential with resonances of the coulomb potential perturbed by a barrier

In the present article we show how the bound states of the Coulomb potential may be associated with resonances that occur when this potential is perturbed by a barrier potential. The main idea is to trace the bound states on successive switching on of the barrier perturbation. It is found that those bound states that are localized inside the barrier are highly sensitive to variation with respect to the barrier height, whereas those that are localized outside are less sensitive. However, there are certain intervals for the barrier height when the role of being “a state localized inside the barrier” is shifted from one bound state to another. The result can be pictured as a “relay race,” where the “deliveries of the baton” are carried out over corresponding avoided crossings. The baton is ultimately handed over to a shape-type resonance state.     

Multiple binding modes of the camptothecin family to DNA oligomers

The binding constants of camptothecin, topotecan and its lactone ring-opened carboxylate derivative to DNA octamers were measured by UV and NMR spectroscopy. The self-association of topotecan (TPT) was also measured. The carboxylate form of TPT binds in the same way as the lactone, but more weakly. Titration of TPT into d(GCGATCGC)2 shows a preferred location stacked onto the terminal G1 base. However, the intermolecular NOEs cannot be reconciled with a single conformation of the complex, and suggest a model of a limited number of conformations in fast exchange. MD calculations on four pairs of starting structures with TPT stacked onto the G1-C8 base pair in different orientations were therefore performed. The use of selected experimental "docking" restraints yielded ten MD trajectories covering a wide conformational space. From a combination of calculated free energies, NOEs and chemical shifts, some of the structures produced could be eliminated, and it is concluded that the data are consistent with two major families of conformations in fast exchange. One of these is the conformation found in a crystal of a TPT/DNA/topoisomerase I ternary complex [Proc. Natl. Acad. Sci. USA 2002, 99, 15 387-15 392].     

pH sensitivity of Si--C linked organic monolayers on crystalline silicon surfaces.

The electrochemical behavior of Si--C linked organic monolayers is studied in electrolyte-insulator-Si devices, under conditions normally encountered in potentiometric biosensors, to gain fundamental knowledge on the behavior of such Si electrodes under practical conditions. This is done via titration experiments, Mott-Schottky data analysis, and data fitting using a site-binding model. The results are compared with those of native SiO(2) layers and native SiO(2) layers modified with hexamethyldisilazane. All samples display pH sensitivity. The number of Si--OH groups on the alkylated samples is calculated to be less than 0.7 % of that of a pure SiO(2) insulator, which still causes a pH sensitivity of approximately 25 mV per pH unit in the pH range: 4-7. The alkylated samples hardly suffer from response changes during up- and down-going titrations, which indicates that very little oxide is additionally formed during the measurements. The pK(a) values of all samples with monolayers (4.0-4.4) are lower than that of native SiO(2) (6.0). The long-term drift (of approximately 1 mV h(-1)) is moderate. The results indicate that biosensors composed of alkylated Si substrates are feasible if a cross-sensitivity towards pH in the sensor signal is taken into account.