A linearized path integral description of the collision process between a water molecule and a graphite surface

Quantum effects in the scattering and desorption process of a water molecule from a graphite surface are investigated using the linearized path integral model. The graphite surface is quantized rigorously using the fully quantum many-body Wigner transform of the surface Boltzmann operator, while the water molecule is treated as rigid. Classical dynamics with these quantized initial conditions show that quantizing the surface at 100 and 300 K results in markedly different results, compared to a fully classical analysis. The trapping probability (defined as the probability of multiple encounters with the surface) is not sensitive to the choice of dynamical treatment, but the residence time on the surface is much shorter in the quantum case. At 300 K the transiently trapped molecules desorb from the surface with a rate constant which is 60-70% larger than the corresponding classical value. Lowering the surface temperature to 100 K decreases the quantum rate constant by approximately a factor of 3 while all trapped molecules stick to the surface in the classical case. The stability of the quantum initial state for the highly anisotropic graphite crystal is discussed in detail as well as the dynamical consequences of energy redistribution during the scattering process. The graphite surface application demonstrates that the Boltzmann operator Wigner transform for a system with 900 degrees of freedom can be obtained by the so-called gradient implementation [Poulsen et al. J. Chem. Theory Comput. 2006, 2, 1482] of the underlying Feynman-Kleinert effective frequency theory, an implementation that only requires a force and potential routine for the system at hand, and hence is applicable to any molecule-surface collision problem.     

Structure-based design of Aurora A & B inhibitors

The Aurora family of serine/threonine kinases are mitotic regulators involved in centrosome duplication, formation of the bipolar mitotic spindle and the alignment of the chromosomes along the spindle. These proteins are frequently overexpressed in tumor cells as compared to normal cells and are therefore potential therapeutic oncology targets. An Aurora A high throughput screen revealed a promising sub-micromolar indazole-benzimidazole lead. Modification of the benzimidazole portion of the lead to a C2 linker with a phenyl ring was proposed to achieve novelty. Docking revealed that a conjugated linker was optimal and the resulting compounds were equipotent with the lead. Further structure-guided optimization of substituents on the 5 & 6 position of the indazole led to single digit nanomolar potency. The homology between the Aurora A & Aurora B kinase domains is 71% but their binding sites only differ at residues 212 & 217 (Aurora A numbering). However interactions with only the latter residue may be used for obtaining selectivity. An analysis of published Aurora A and Aurora B X-ray structures reveals subtle differences in the shape of the binding sites. This was exploited by introduction of appropriately sized substituents in the 4 & 6 position of the indazole leading to Aurora B selective inhibitors. Finally we calculate the conformational energy penalty of the putative bioactive conformation of our inhibitors and show that this property correlates well with the Aurora A binding affinity.     

Controlled Double-Bond Migration in Palladium-Catalyzed Intramolecular Arylation of Enamidines

Palladium-catalyzed intramolecular cyclization of N-(N'-tert-butylformimidoyl)-6-[2-(2-iodophenyl)ethyl]-1,2,3,4-tetrahydropyridine (1a) and N-(N'-tert-butylformimidoyl)-6-[3-(2-iodophenyl)propyl]-1,2,3,4-tetrahydropyridine (1b) respectively results in formation of spiro compounds 1'-(N-tert-butylformimidoyl)-3',4'-dihydrospiro[indan-1,2'(1'H)-pyridine] (4a), 1'-(N-tert-butylformimidoyl)-1',6'-dihydrospiro[indan-1,2'(3'H)-pyridine] (5a), and 1'-(N-tert-butylformimidoyl)-5',6'-dihydrospiro[indan-1,2'(1'H)-pyridine] (6a) and 1'-(N-tert-butylformimidoyl)-3,3',4,4'-tetrahydrospiro[naphthalene-1(2H),2'(1'H)-pyridine] (4b), 1'-(N-tert-butylformimidoyl)-1',3,4,6'-tetrahydrospiro[naphthalene-1(2H),2'(3'H)-pyridine] (5b), and 1'-(N-tert-butylformimidoyl)-3,4,5',6'-tetrahydrospiro[naphthalene-1(2H),2'(1'H)-pyridine] (6b). The double-bond migration process can be controlled, and any of the three double-bond isomers can be prepared by employing proper ligands. A combination of BINAP and the amidine function was required to obtain the isomers 5a and 5b with the double bond in the homoallylic position relative to the aryl group. An electrospray ionization mass spectrometric study was conducted to support suggested reaction intermediates.     

Analysis of proteins from a glioma cell line by using micro-scale solution isoelectric focusing in combination with liquid chromatography/tandem mass spectrometry

In this study we have investigated whether micro-solution isoelectric focusing (microsol-IEF) can be used as a pre-fractionation step prior to liquid chromatography/tandem mass spectrometry (LC/MS/MS) and if extensive sample purification of the different fractions is required. We found that, in spite of the high concentrations of buffer and detergents, no clean up of the digested microsol-IEF fractions was necessary before analysis by LC/MS/MS. We also concluded that it is possible to identify at least twice as many proteins in a glioma cell lysate with the combination of microsol-IEF and LC/MS/MS than with LC/MS/MS alone. Furthermore, most of the proteins that were identified from one microsol-IEF fraction by using analytical narrow-range two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and peptide mass fingerprinting with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) were also identified by LC/MS/MS. Finally, we used the combination of microsol-IEF and LC/MS/MS to compare two sample preparation methods for glioma cells and found that several nuclear, mitochondria, and endoplasmic reticulum proteins were only present in the sample that had been subjected to lipid extraction by incubating the homogenized cells in chloroform/methanol/water.     

Persicamidines—Unprecedented Sesquarterpenoids with Potent Antiviral Bioactivity against Coronaviruses

A new family of highly unusual sesquarterpenoids (persicamidines A–E) exhibiting significant antiviral activity was isolated from a newly discovered actinobacterial strain, Kibdelosporangium persicum sp. nov., collected from a hot desert in Iran. Extensive NMR analysis unraveled a hexacyclic terpenoid molecule with a modified sugar moiety on one side and a highly unusual isourea moiety fused to the terpenoid structure. The structures of the five analogues differed only in the aminoalkyl side chain attached to the isourea moiety. Persicamidines A–E showed potent activity against hCoV-229E and SARS-CoV-2 viruses in the nanomolar range together with very good selectivity indices, making persicamidines promising as starting points for drug development.     

Addition of Me3SiCN to trifluoromethyl derivates of N‐(pyridylmethylidene) anilines catalyzed by Lewis acids

A series of novel Shiff bases (1a–h) was synthesized by condensation of pyridinecarboxaldehydes (1–4) with 3‐ and 4‐trifluoromethylanilines (5, 6) in the presence of molecular sieves (4 Å). It was found that AlCl₃ and AlBr₃ catalyzed the addition of Me₃SiCN to the C?N bond of the imines obtained, whereas the other Lewis acids studied (YCl₃, LaCl₃, ZnI₂) were not active. The reactivity of the imines in the title reaction, on the whole, correlated with their basicity. Besides the addition giving the expected α‐amino nitriles (2a,b,d–f,h), an unusual reaction leading to unsaturated nitriles (3a–h) was observed. The structures of saturated and unsaturated products 2d and 3c were determined by X‐ray diffraction. Copyright © 2001 John Wiley & Sons, Ltd.     

A concise route to the macrocyclic core of the rakicidins

An efficient synthesis of the macrolactone core of the rakicidins is described. The rakicidins are cytotoxic lipopeptides with interesting cancer cell selectivities including HIF-1-independent hypoxia-selective cytotoxicity and anti-invasive activity. Access to the core may now allow establishment of preliminary SAR and exploration of routes to several members of rakicidins.