Discovery of novel anti-HIV active G-quadruplex-forming oligonucleotides

A series of d((5')TGGGAG(3')) sequences, 5'-conjugated with a variety of aromatic groups through phosphodiester linkages, were synthesized, showing CD spectra diagnostic of parallel-stranded, tetramolecular G-quadruplex structures. When tested for anti-HIV-1 and HIV-2 activity, potent inhibition of HIV-1 infection in CEM cell cultures was found, associated with high selectivity index values. Surface Plasmon Resonance assays revealed specific binding to HIV-1 gp120 and gp41.     

Molecular modeling of alkyl and alkenyl monolayers on hydrogen-terminated Si(111)

On H-Si(111) surfaces monolayer formation with 1-alkenes results in alkyl monolayers with a Si-C-C linkage, while 1-alkynes yield alkenyl monolayers with a Si-C═C linkage. Recently, considerable structural differences between both types of monolayers were observed, including an increased thickness, improved packing, and higher surface coverage for the alkenyl monolayers. The precise origin thereof could experimentally not be clarified yet. Therefore, octadecyl and octadecenyl monolayers on Si(111) were studied in detail by molecular modeling via PCFF molecular mechanics calculations on periodically repeated slabs of modified surfaces. After energy minimization the packing energies, structural properties, close contacts, and deformations of the Si surfaces of monolayers structures with various substitution percentages and substitution patterns were analyzed. For the octadecyl monolayers all data pointed to a substitution percentage close to 50-55%, which is due the size of the CH(2) groups near the Si surface. This agrees with literature and the experimentally determined coverage of octadecyl monolayers. For the octadecenyl monolayers the minimum in packing energy per chain is calculated around 60% coverage, i.e., close to the experimentally observed value of 65% [Scheres et al. Langmuir 2010, 26, 4790], and this packing energy is less dependent on the substitution percentage than calculated for alkyl layers. Analysis of the chain conformations, close contacts, and Si surface deformation clarifies this, since even at coverages above 60% a relatively low number of close contacts and a negligible deformation of the Si was observed. In order to evaluate the thermodynamic feasibility of the monolayer structures, we estimated the binding energies of 1-alkenes and 1-alkynes to the hydrogen-terminated Si surface at a range of surface coverages by composite high-quality G3 calculations and determined the total energy of monolayer formation by adding the packing energies and the binding energies. It was shown that due to the significantly larger reaction exothermicity of the 1-alkynes, thermodynamically even a substitution percentage as high as 75% is possible for octadecenyl chains. However, because sterically (based on the van der Waals footprint) a coverage of 69% is the maximum for alkyl and alkenyl monolayers, the optimal substitution percentage of octadecenyl monolayers will be presumably close to this latter value, and the experimentally observed 65% is likely close to what is experimentally maximally obtainable with alkenyl monolayers.     

Ruthenium-Decorated Lipid Vesicles: Light-Induced Release of [Ru(terpy)(bpy)(OH(2))](2+) and Thermal Back Coordination

Electrostatic forces play an important role in the interaction between large transition metal complexes and lipid bilayers. In this work, a thioether-cholestanol hybrid ligand (4) was synthesized, which coordinates to ruthenium(II) via its sulfur atom and intercalates into lipid bilayers via its apolar tail. By mixing its ruthenium complex [Ru(terpy)(bpy)(4)](2+) (terpy = 2,2';6',2'-terpyridine; bpy = 2,2'-bipyridine) with either the negatively charged lipid dimyristoylphosphatidylglycerol (DMPG) or with the zwitterionic lipid dimyristoylphosphatidylcholine (DMPC), large unilamellar vesicles decorated with ruthenium polypyridyl complexes are formed. Upon visible light irradiation the ruthenium-sulfur coordination bond is selectively broken, releasing the ruthenium fragment as the free aqua complex [Ru(terpy)(bpy)(OH(2))](2+). The photochemical quantum yield under blue light irradiation (452 nm) is 0.0074(8) for DMPG vesicles and 0.0073(8) for DMPC vesicles (at 25 °C), which is not significantly different from similar homogeneous systems. Dynamic light scattering and cryo-TEM pictures show that the size and shape of the vesicles are not perturbed by light irradiation. Depending on the charge of the lipids, the cationic aqua complex either strongly interacts with the membrane (DMPG) or diffuses away from it (DMPC). Back coordination of [Ru(terpy)(bpy)(OH(2))](2+) to the thioether-decorated vesicles takes place only at DMPG bilayers with high ligand concentrations (25 mol %) and elevated temperatures (70 °C). During this process, partial vesicle fusion was also observed. We discuss the potential of such ruthenium-decorated vesicles in the context of light-controlled molecular motion and light-triggered drug delivery.     

Composition depth profile analysis of electrodeposited alloys and metal multilayers: the reverse approach

The reverse depth profile analysis is a recently developed method for the study of a deposit composition profile in the near-substrate zone. The sample preparation technique enables one to separate the deposit and a thin cover layer from its substrate, and the initial roughness of the sample is much smaller than in the conventional sputtering direction. This technique is particularly suitable to study the zones being formed in the early phase of the electrodeposition of alloys. It has been demonstrated with the reverse depth profile analysis that in many cases when one component of an alloy is preferentially deposited, an initial zone is formed that is rich in the preferentially deposited component. This phenomenon is demonstrated for Ni–Cd, Ni–Sn, Fe–Co–Ni, Co–Ni, and Co–Ni–Cu alloys. The composition change is confined to the initial 150-nm-thick deposit, and it is the result of the interplay of the deposition preference and the depletion of the electrolyte near the cathode with respect to the ion reduced preferentially. The reverse depth profile analysis made it possible to compare the measured and the calculated composition depth profile of electrodeposited multilayers. It has been shown that the decay in the composition oscillation intensity in Co/Cu multilayers with the increase of the sputtering depth can be derived from the roughness measured as a function of the deposit thickness.     

Synthesis and in vitro antiproliferative activity of novel androst-5-ene triazolyl and tetrazolyl derivatives

A straightforward and reliable method for the regioselective synthesis of steroidal 1,4-disubstituted triazoles and 1,5-disubstituted tetrazoles via copper(I)-catalyzed cycloadditions is reported. Heterocycle moieties were efficiently introduced onto the starting azide compound 3β-acetoxy-16β-azidomethylandrost-5-en-17β-ol through use of the "click" chemistry approach. The antiproliferative activities of the newly-synthesized triazoles were determined in vitro on three human gynecological cell lines (HeLa, MCF7 and A2780) using the microculture tetrazolium assay.     

Self-consistent field modeling of adsorption from polymer/surfactant mixtures

We report on the development of a self-consistent field model that describes the competitive adsorption of nonionic alkyl-(ethylene oxide) surfactants and nonionic polymer poly(ethylene oxide) (PEO) from aqueous solutions onto silica. The model explicitly describes the response to the pH and the ionic strength. On an inorganic oxide surface such as silica, the dissociation of the surface depends on the pH. However, salt ions can screen charges on the surface, and hence, the number of dissociated groups also depends on the ionic strength. Furthermore, the solvent quality for the EO groups is a function of the ionic strength. Using our model, we can compute bulk parameters such as the average size of the polymer coil and the surfactant CMC. We can make predictions on the adsorption behavior of either polymers or surfactants, and we have made adsorption isotherms, i.e., calculated the relationship between the surface excess and its corresponding bulk concentration. When we add both polymer and surfactant to our mixture, we can find a surfactant concentration (or, more precisely, a surfactant chemical potential) below which only the polymer will adsorb and above which only the surfactant will adsorb. The corresponding surfactant concentration is called the CSAC. In a first-order approximation, the surfactant chemical potential has the CMC as its upper bound. We can find conditions for which CMC < CSAC . This implies that the chemical potential that the surfactant needs to adsorb is higher than its maximum chemical potential, and hence, the surfactant will not adsorb. One of the main goals of our model is to understand the experimental data from one of our previous articles. We managed to explain most, but unfortunately not all, of the experimental trends. At the end of the article we discuss the possibilities for improving the model.     

Efficient approach to novel 1α-triazolyl-5α-androstane derivatives as potent antiproliferative agents

Stereoselective 1,4-Michael addition of azoimide to 17β-acetoxy-5α-adrost-1-en-3-one was carried out to furnish a 1α-azido-3-ketone, which was reduced to give the 3β- and 3α-hydroxy epimers in a ratio of 5 : 2. The Cu(I)-catalyzed 1,3-dipolar cycloaddition of the major isomer to terminal alkynes afforded 1α-triazolyl derivatives, which were deacetylated to the corresponding 3β,17β-diols or oxidized to the analogous 3-ketones. However, the ability of the minor 1α,3α-azidoalcohol to undergo similar cyclization was found to be affected significantly by the steric bulk of the substituents on the alkyne reaction partner. All triazolyl compounds were tested in vitro on three malignant gynecological cell lines (HeLa, MCF7 and A2780).     

Synthesis and characterization of (smif)2M(n) (n = 0, M = V, Cr, Mn, Fe, Co, Ni, Ru; n = +1, M = Cr, Mn, Co, Rh, Ir; smif =1,3-di-(2-pyridyl)-2-azaallyl)

A series of Werner complexes featuring the tridentate ligand smif, that is, 1,3-di-(2-pyridyl)-2-azaallyl, have been prepared. Syntheses of (smif)(2)M (1-M; M = Cr, Fe) were accomplished via treatment of M(NSiMe(3))(2)(THF)(n) (M = Cr, n = 2; Fe, n = 1) with 2 equiv of (smif)H (1,3-di-(2-pyridyl)-2-azapropene); ortho-methylated ((o)Mesmif)(2)Fe (2-Fe) and ((o)Me(2)smif)(2)Fe (3-Fe) were similarly prepared. Metatheses of MX(2) variants with 2 equiv of Li(smif) or Na(smif) generated 1-M (M = Cr, Mn, Fe, Co, Ni, Zn, Ru). Metathesis of VCl(3)(THF)(3) with 2 Li(smif) with a reducing equiv of Na/Hg present afforded 1-V, while 2 Na(smif) and IrCl(3)(THF)(3) in the presence of NaBPh(4) gave [(smif)(2)Ir]BPh(4) (1(+)-Ir). Electrochemical experiments led to the oxidation of 1-M (M = Cr, Mn, Co) by AgOTf to produce [(smif)(2)M]OTf (1(+)-M), and treatment of Rh(2)(O(2)CCF(3))(4) with 4 equiv Na(smif) and 2 AgOTf gave 1(+)-Rh. Characterizations by NMR, EPR, and UV-vis spectroscopies, SQUID magnetometry, X-ray crystallography, and DFT calculations are presented. Intraligand (IL) transitions derived from promotion of electrons from the unique CNC(nb) (nonbonding) orbitals of the smif backbone to ligand π*-type orbitals are intense (ε ≈ 10,000-60,000 M(-1)cm(-1)), dominate the UV-visible spectra, and give crystals a metallic-looking appearance. High energy K-edge spectroscopy was used to show that the smif in 1-Cr is redox noninnocent, and its electron configuration is best described as (smif(-))(smif(2-))Cr(III); an unusual S = 1 EPR spectrum (X-band) was obtained for 1-Cr.