Stacked and continuous helical self-assemblies of guanosine monophosphates detected by vibrational circular dichroism

The aim of this study was to characterize self-assembled structures of guanosine derivatives in aqueous solutions by vibrational circular dichroism (VCD) and electronic circular dichroism (ECD). Three guanosine derivatives were studied [5'-guanosine monophosphate (GMP), diphosphate (GDP), and triphosphate (GTP)] using a broad range of concentrations and various metal/guanosine ratios. VCD was used for the first time in this field and showed itself to be a powerful method for obtaining specific structural information in solution. It can also help to determine the impact that the cations have, when added to the solution, on the versatile structures of guanine derivatives in terms of their association and disassociation. Based on the markedly different intensities and signs of the VCD signals observed for different concentrations of guanosine derivatives, we propose various structures based on guanine quartets for high guanosine concentrations and high K(+)/guanosine ratios (i.e., columnar helical organization of the quartets, which are rearranged into a continuous helix). We performed a degenerate coupled oscillator (DCO) calculation to interpret the VCD spectra obtained and how they vary during the assembly of guanosine derivatives. The calculations correctly predicted the VCD spectra and enabled us to identify the structures of the metal cation/guanosine monophosphate aggregates. ECD in the ultraviolet region was used as a diagnostic tool to characterize the studied systems and as a contact point between the previously defined structures of the guanine derivative assemblies and the molecular systems studied here. These studies revealed that the VCD technique is a powerful new method for determining the structures of optically active guanosine motifs.     

The Crystal Structure of Orthocetamol Solved by 3D Electron Diffraction

Orthocetamol is a regioisomer of the well‐known pain medication paracetamol and a promising analgesic and an anti‐arthritic medicament itself. However, orthocetamol cannot be grown as single crystals suitable for X‐ray diffraction, so its crystal structure has remained a mystery for more than a century. Here, we report the ab‐initio structure determination of orthocetamol obtained by 3D electron diffraction, combining a low‐dose acquisition method and a dedicated single‐electron detector for recording the diffracted intensities. The structure is monoclinic, with a pseudo‐tetragonal cell that favors multiple twinning on a scale of a few tens of nanometers. The successful application of 3D electron diffraction to orthocetamol introduces a new gold standard of total structure solution in all cases where X‐ray diffraction and electron‐microscope imaging methods fail.     

In Vitro Evaluation of In Silico Screening Approaches in Search for Selective ACE2 Binding Chemical Probes

New models for ACE2 receptor binding, based on QSAR and docking algorithms were developed, using XRD structural data and ChEMBL 26 database hits as training sets. The selectivity of the potential ACE2-binding ligands towards Neprilysin (NEP) and ACE was evaluated. The Enamine screening collection (3.2 million compounds) was virtually screened according to the above models, in order to find possible ACE2-chemical probes, useful for the study of SARS-CoV2-induced neurological disorders. An enzymology inhibition assay for ACE2 was optimized, and the combined diversified set of predicted selective ACE2-binding molecules from QSAR modeling, docking, and ultrafast docking was screened in vitro. The in vitro hits included two novel chemotypes suitable for further optimization.     

1-Azaspiro[3.3]heptane as a Bioisostere of Piperidine**

1-Azaspiro[3.3]heptanes were synthesized, characterized, and validated biologically as bioisosteres of piperidine. The key synthesis step was thermal [2+2] cycloaddition between endocyclic alkenes and the Graf isocyanate, ClO₂S−NCO, to give spirocyclic β-lactams. Reduction of the β-lactam ring with alane produced 1-azaspiro[3.3]heptanes. Incorporation of this core into the anesthetic drug bupivacaine instead of the piperidine fragment resulted in a new patent-free analogue with high activity.     

Scanning electrochemical microscopy study of ion transfer process across water/2-nitrophenyloctylether interface supported by hydrophobic carbon ceramic electrode

A carbon ceramic electrode (CCE) modified with the redox probe—decamethylferrocene solution in hydrophobic organic solvent—2-nitrophenyloctyl ether and immersed into an aqueous solution was studied by scanning electrochemical microscopy (SECM). After the electrochemical oxidation of decamethylferrocene, its cations were detected near the electrode surface in the aqueous phase. This indicates that some fraction of the redox-active cations electrochemically produced in the organic phase is transferred across the liquid/liquid interface. They are reduced at the SECM tip and form a solid deposit. The amount of deposited decamethylferrocene was estimated by the anodic reaction at the tip. It is affected by the substrate–tip distance, deposition time, and electrolyte concentration. The SECM images of unmodified and modified CCEs are consistent with their heterogeneous structure.     

Fluorinated bismuth alkoxides: from monomers to polymers and oxo-clusters

A series of new bismuth fluoroalkoxide compounds have been prepared through the treatment of 1,1,1,3,3,3-hexafluoro-2-propanol with BiAr3 (where Ar=Ph, p-Tol). Reactions were conducted without the use of any additional solvent and the reaction products distilled or extracted with non-polar or polar Lewis base solvents. Structural analyses reveal that under variable reaction conditions the interaction of BiAr3 with (CF3)2CHOH can give a mixture of bismuth complexes with varying degrees of substitution, cluster formation and aggregation. Compounds [Bi(OCH(CF3)2)3(pyr)2] () (pyr=pyridine), [Bi(OCH(CF3)2)3(thf)3] () (thf=tetrahydrofuran), [Bi2(OCH(CF3)2)3(dabco)3] () (dabco=1,4-diazabicyclo[2.2.2]octane), [PhBi(OCH(CF3)2)2]n (), [Bi2O(OCH(CF3)2)4(C7H8)]2 () (C7H8=toluene), [Bi9O7(OCH(CF3)2)13] (), [Bi2O(OCH(CF3)2)4(Et2O)]2 (), [Bi2O(OCH(CF3)2)4(thf)]2 () and [Bi2O(OCH(CF3)2)4(tmeda)2] () (tmeda=N,N,N',N'-tetramethylethylenediamine) have been fully characterised including by single crystal X-ray diffraction.     

On-Demand Cell Sheet Release with Low Density Peptide-Functionalized Non-LCST Polymer Brushes

Cell sheet harvesting offers a great potential for the development of new therapies for regenerative medicine. For cells to adhere onto surfaces, proliferate, and to be released on demand, thermoresponsive polymeric coatings are generally considered to be required. Herein, an alternative approach for the cell sheet harvesting and rapid release on demand is reported, circumventing the use of thermoresponsive materials. This approach is based on the end-group biofunctionalization of non-thermoresponsive and antifouling poly(2-hydroxyethyl methacrylate) (p(HEMA)) brushes with cell-adhesive peptide motifs. While the nonfunctionalized p(HEMA) surfaces are cell-repellant, ligation of cell-signaling ligand enables extensive attachment and proliferation of NIH 3T3 fibroblasts until the formation of a confluent cell layer. Remarkably, the formed cell sheets can be released from the surfaces by gentle rinsing with cell-culture medium. The release of the cells is found to be facilitated by low surface density of cell-adhesive peptides, as confirmed by X-ray photoelectron spectroscopy. Additionally, the developed system affords possibility for repeated cell seeding, proliferation, and release on previously used substrates without any additional pretreatment steps. This new approach represents an alternative to thermally triggered cell-sheet harvesting platforms, offering possibility of capture and proliferation of various rare cell lines via appropriate selection of the cell-adhesive ligand.     

Ligand conformation enforces trigonal bipyramidal coordination geometry in a new dinuclear bis(pyrazolato)-bridged copper(II) complex: synthesis, crystal structure, and properties of [Cu(Npy2pz)]2(ClO4)2.2CH3CN

The reaction of Cu(ClO(4))(2).6H(2)O with the new tripodal ligand HNpy(2)pz (N-bis[(pyridin-2-yl)methyl][1H-pyrazol-3-yl)methyl]amine) in the presence of 1 equiv of triethylamine results in the formation of a doubly pyrazolato-bridged dicopper(II) complex, [Cu(Npy(2)pz)](2)(ClO(4))(2).2CH(3)CN (1). The crystal structure of 1 was determined by X-ray crystallography and was found to consist of two nearly identical discrete dinuclear molecules with bis(pyrazolato) bridges. The copper(II) ion has a trigonal bipyramid geometry achieved by the coordination of an aliphatic nitrogen, two pyridine moieties, and two pyrazolato nitrogens. Variable temperature-dependent magnetic data show that antiferromagnetic interactions operate in 1 as a result of the binding angle of the pyrazolato bridge. In solution, the stability of the dinuclear cation, [Cu(py(2)pz)](2)(2+), is highly dependent on the concentration, as indicated by ESI-MS, ligand field, cyclic voltammetry, EPR, and (1)H NMR studies.     

Determination of SLES in Personal Care Products by Colloid Titration with Light Reflection Measurements

The method of colloid titration with poly(diallyldimethylammonium) chloride has been improved to detect the endpoint with an off-vessel light reflectance sensor. The digital color sensor used measures light reflectance by means of light guides, with no immersion into the reaction solution. In such a method, the optical signal is free of disturbances caused by sticky flocs in the solution. The improved automatic titration set was applied for the determination of sodium laureth sulfate (SLES) in industrial batches and commercial personal care products. The sample color and opacity do not disturb the SLES quantification. When the SLES content lies in the range from 5% to 9%, the optimal sample weight is from 6 g to 3 g.