Cellular delivery of dinucleotides by conjugation with small molecules: targeting translation initiation for anticancer applications

Targeting cap-dependent translation initiation is one of the experimental approaches that could lead to the development of novel anti-cancer therapies. Synthetic dinucleoside 5′,5′-triphosphates cap analogs are potent antagonists of eukaryotic translation initiation factor 4E (eIF4E) in vitro and could counteract elevated levels of eIF4E in cancer cells; however, transformation of these compounds into therapeutic agents remains challenging – they do not easily penetrate into cells and are susceptible to enzymatic cleavage. Here, we tested the potential of several small molecule ligands – folic acid, biotin, glucose, and cholesterol – to deliver both hydrolyzable and cleavage-resistant cap analogs into cells. A broad structure–activity relationship (SAR) study using model fluorescent probes and cap–ligand conjugates showed that cholesterol greatly facilitates uptake of cap analogs without disturbing the interactions with eIF4E. The most potent cholesterol conjugate identified showed apoptosis-mediated cytotoxicity towards cancer cells.

Ligand assisted cellular delivery of negatively charged dinucleotides, which are potential antagonists of the protooncogenic protein eIF4E.     

Diurnal variability of delta13C and delta18O of atmospheric CO2 in the urban atmosphere of Kraków, Poland

This article presents the results of measurements of the isotopic composition and concentration of atmospheric carbon dioxide, performed on air samples from Kraków (Southern Poland) in different seasons of the year. A simple isotope mass balance model has been applied to determine the contributions of different sources of CO2 to the urban atmosphere of Kraków city: the latitudinal/regional background, biospheric contributions and anthropogenic emissions. The calculations show that during the summer and early autumn the dominant contribution to local CO2 peaks is the biosphere, making up to 20% of atmospheric CO2 during the nocturnal temperature inversion in the lower troposphere. During early spring and winter, anthropogenic emissions are the main local source.     

The analysis of the market success of FDA approvals by probing top 100 bestselling drugs

Target-oriented drug discovery is the main research paradigm of contemporary drug discovery. In target-oriented approaches, we attempt to maximize in vitro drug potency by finding the optimal fit to the target. This can result in a higher molecular complexity, in particular, the higher molecular weight (MW) of the drugs. However, a comparison of the successful developments of pharmaceuticals with the general trends that can be observed in medicinal chemistry resulted in the conclusion that the so-called molecular obesity is an important reason for the attrition rate of drugs. When analyzing the list of top 100 drug bestsellers versus all of the FDA approvals, we discovered that on average lower-complexity (MW, ADMET score) drugs are winners of the top 100 list in terms of numbers but that, especially, up to some optimal MW value, a higher molecular complexity can pay off with higher incomes. This indicates that slim drugs are doing better but that fat drugs are bigger fishes to catch.     

A study of chirality in bis(1,2‐dimethoxyethane‐κ2O,O′)sodium bis(tri‐tert‐butoxysilanethiolato‐κ2O,S)sodate

This work presents an analysis of self‐assembly of a complex molecule from simpler ions, some of which are asymmetric, and is an example of a sodium silanethiolate. The tri‐tert‐butoxysilanethiolate anion has two helical conformers (P and M), so aggregation of silanethiolates can proceed with recognition of chirality. Alkali metal silanethiolates can form cyclic solvated oligomers (e.g. dimers) or complexes such as sodates with anions of general formula R₂Na⁻. We note that all known sodates (and lithiates) contain both ligands of the same helicity in the anion, whereas in the dimers the metal atoms are coordinated by silanethiolate ligands of different helicity. The title compound, a new example of a sodate, [Na(C₄H₁₀O₂)₂][Na(C₁₂H₂₇O₃SSi)₂] or [Na{(^tBuO)₃SiS}₂][Na(DME)₂] (DME is 1,2‐dimethoxyethane), is built up of separate ion pairs with no significant interactions. The anion is formed from an Na atom O,S‐chelated by two silanethiolate ligands of the same helicity (both P or both M), while the cation contains an Na atom solvated by two DME molecules. Because the structure is centrosymmetric, equal numbers of both conformational enantiomers are present in the crystal lattice.     

Compact, filtered diode laser system for precision spectroscopy

Stable, narrow-linewidth optical sources are necessary in modern atomic physics. An appealing approach to achieving approximately 10 kHz frequency stability is optical feedback. We have designed a compact external cavity diode laser with optical feedback to a filter cavity mounted on a single baseplate and enclosed inside a vacuum sealed box. The design was implemented for three wavelengths addressing the 422 nm cooling, 1091 nm repumping, and 674 nm clock transition lines of Sr(+). We are able to cool a single, trapped strontium ion to approximately 2 mK and observe motional sidebands of the 5S(1/2) <--> 4D(5/2) transition.     

Conformation‐Family Monte Carlo (CFMC): An Efficient Computational Method for Identifying the Low‐Energy States of a Macromolecule

A highly efficient method, Conformation‐Family Monte Carlo (CFMC), has been developed for searching the conformational space of a macromolecule and identifying its low‐energy conformations. This method maintains a database of low‐energy conformations that are clustered into families. The conformations in this database are improved iteratively by a Metropolis‐type Monte Carlo procedure, together with energy minimization, in which the search is biased towards investigating the regions of the lowest‐energy families. The CFMC method has the advantages of our earlier potential‐smoothing methods (in that it `coarse‐grains' the conformational space and exploits information about nearby low‐energy states), but avoids their disadvantages (such as the displacement of the global minimum at large smoothings). The CFMC method is applied to a test protein, domain B of Staphylococcal protein A. Independent CFMC runs yielded the same low‐energy families of conformations from random starts, indicating that the thermodynamically relevant conformational space of this protein has been explored thoroughly. The CFMC method is highly efficient, performing as well as or better than competing methods, such as Monte Carlo with minimization, conformational‐space annealing, and the self‐consistent basin‐to‐deformed‐basin method.     

Neutron reflectivity study of lipid membranes assembled on ordered nanocomposite and nanoporous silica thin films

Single bilayer membranes of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) were formed on ordered nanocomposite and nanoporous silica thin films by fusion of small unilamellar vesicles. The structure of these membranes was investigated using neutron reflectivity. The underlying thin films were formed by evaporation induced self-assembly to obtain periodic arrangements of silica and surfactant molecules in the nanocomposite thin films, followed by photocalcination to oxidatively remove the organics and render the films nanoporous. We show that this platform affords homogeneous and continuous bilayer membranes that have promising applications as model membranes and sensors.