2-Substituted and 2,2-disubstituted adamantane derivatives as models for studying substituent chemical shifts and C-Hax⋯Yax cyclohexane contacts - results from experimental and theoretical NMR spectroscopic chemical shifts and DFT structures

Abstract The complete 1H and 13C NMR chemical shifts assignment for various 2-substituted and 2,2-disubstituted adamantane derivatives 1-38 in CDCl3 solution was realized on the basis of NMR experiments combined with chemical structure information and DFT-GIAO (B3LYP/6-31+G(d,p)-GIAO) calculations of chemical shifts in solution. Substituent-induced 13C NMR chemical shifts (SCS) are discussed. C-Hax⋯Yax contacts are a textbook prototype of steric hindrance in organic chemistry. The nature of these contacts will be further investigated in this work on basis of new adamantane derivatives, which are substituted at C-2 to provide models for 1,4-C-Hax⋯Yax and 1,5-C-Hax⋯Yax contacts. The B3LYP/6-31+G(d,p) calculations predicted the presence of NBO hyperconjugative attractive interactions between C-Hax and Yax groups along C-Hax⋯Yax contacts. The 1H NMR signal separation, Δδ(γ-CH2), reflects the strength of the H-bonded C-Haxa⋯Yax contact. © Elsevier Ltd. All rights reserved

On the mechanism of the Au(I)-mediated addition of alkynes to anthranils to furnish 7-acylindoles

Indole is a very common structural motif in alkaloids with a remarkable history in pharma industry. In the continuous search for more direct and efficient access to these valuable structures, a new and rather elegant approach was found by Jin and coworkers, which involved a gold(I)-mediated addition of alkynes onto anthralins. This approach selectively furnishes 7-acylindoles in a rather expeditious way, and it has been shown to be compatible with a large range of decorated reactants, both at the alkyne side and at the anthralin side. We studied the mechanism of this reaction with a set of different alkynes, including disubstituted ones, to establish similarities and differences between them and to aid in the elucidation of key steps in the reaction pathway. The observed regioselectivity seems to be connected to the irreversible formation of a key α-imino gold carbene intermediate, common to all reaction profiles, through the initial regioselective nucleophilic attack of the anthranil N atom onto the alkyne fragment. © 2022 The Authors. Journal of Physical Organic Chemistry published by John Wiley & Sons Ltd

Approaches to primary tert-alkyl amines as building blocks

Primary tert-alkyl amines include analogues of amantadine, a fragment commonly linked to pharmacophoric groups to enhance biological activity. The preparation of primary tert-alkyl amines is considered to be a difficult problem. Four synthetic procedures, some of which have been previously reported for the synthesis of amines with primary (RCH2NH2) or secondary (RR'CHNH2) alkyl and/or aryl groups, were tested for the synthesis of primary tert-alkyl amines (RR′R″CNH2) in aliphatic series including adamantane adducts. These procedures included the formation and reduction of tert-alkyl azides, the Ritter reaction in standard and modified conditions, the addition of organometallic reagents to N-tert-butyl sulfinyl ketimines and one-pot reactions between nitriles and organometallic reagents in the presence of a Lewis acid, Τi(iPrO)4 or CeCl3. These synthetic routes are unexplored for primary tert-alkyl amines. Studies on the synthetic routes for primary tert-alkyl amines are currently lacking. The reaction conditions and substrate limitations were studied for each procedure, with the first procedure being the most general and applicable also for compounds bearing bulky adducts. © 2019 Elsevier Lt

Classic and non-classic forms of mitral valve prolapse

Objective: To investigate the significance of the established distinction between classic and non-classic forms of mitral valve prolapsed (MVP). Methods: We included in this prospective study all patients examined in our preventive cardiology outpatient clinics during the biannual period October 2004-October 2006. We examined in total 10.818 patients, 238 of whom (2.2%) were diagnosed for MVP. We noted relevant demographic and clinical data (gender, age of diagnosis, symptoms, need for hospitalization) and performed statistical comparisons between patients with the classic and those with the non-classic form. Follow-up controls were performed three years afterwards. Results: Patients with the classic form had an earlier age of first diagnosis, more prominent symptoms, and more frequently diagnosis for other disorders (atrial septal defect, ventricular septal defect, Marfan syndrome, Ehlers-Danlos syndrome) than the rest of the patients; however, there were no significant differences as far as certain major complications (stroke, death, submission to surgery) were concerned. Conclusion: The classic form of mitral valve prolapse is more tightly associated with morbid complications, and a more frequent follow-up control in this group of patients may be useful. (Anadolu Kardiyol Derg 2012; 12:2-4

The balance between side-chain and backbone-driven association in folding of the α-helical influenza A transmembrane peptide

The correct balance between attractive, repulsive and peptide hydrogen bonding interactions must be attained for proteins to fold correctly. To investigate these important contributors, we sought a comparison of the folding between two 25-residues peptides, the influenza A M2 protein transmembrane domain (M2TM) and the 25-Ala (Ala25). M2TM forms a stable α-helix as is shown by circular dichroism (CD) experiments. Molecular dynamics (MD) simulations with adaptive tempering show that M2TM monomer is more dynamic in nature and quickly interconverts between an ensemble of various α-helical structures, and less frequently turns and coils, compared to one α-helix for Ala25. DFT calculations suggest that folding from the extended structure to the α-helical structure is favored for M2TM compared with Ala25. This is due to CH⋯O attractive interactions which favor folding to the M2TM α-helix, and cannot be described accurately with a force field. Using natural bond orbital (NBO) analysis and quantum theory atoms in molecules (QTAIM) calculations, 26 CH⋯O interactions and 22 NH⋯O hydrogen bonds are calculated for M2TM. The calculations show that CH⋯O hydrogen bonds, although individually weaker, have a cumulative effect that cannot be ignored and may contribute as much as half of the total hydrogen bonding energy, when compared to NH⋯O, to the stabilization of the α-helix in M2TM. Further, a strengthening of NH⋯O hydrogen bonding interactions is calculated for M2TM compared to Ala25. Additionally, these weak CH⋯O interactions can dissociate and associate easily leading to the ensemble of folded structures for M2TM observed in folding MD simulations. © 2020 Wiley Periodicals LL

Application of polymerase chain reaction for detection of Legionella pneumophila in serum samples

ObjectiveTo apply the polymerase chain reaction (PCR) to serum samples for the rapid diagnosis of Legionnaire's disease using the L5SL9 and L5SR93 primers designed to generate a 104-base-pair (bp) fragment from the 5S RNA gene of Legionella spp. The amplified product was detected by electrophoresis and by hybridization with the L5S-1-specific probe.MethodsSingle specimens of serum obtained from 24 patients with confirmed legionellosis, at different stages of their disease, were tested by PCR. Additionally, 10 serum samples from patients with no clinical symptoms of pneumonia and 10 samples from patients suffering from pneumonia caused by Mycoplasma pneumoniae, Coxiella bumetii or Chlamydia psittaci were also tested as controls in order to determine the specificity of the method.ResultsOf the 24 examined serum samples, the amplified products from 12 hybridized with the L5S-1 probe (sensitivity 50%). None of the negative controls was positive after PCR. No correlation was found between the day of illness and the positivity in the test.ConclusionsThe PCR technique could be applied as a diagnostic tool for the rapid diagnosis of legionellosis in serum samples after modification, mainly to improve its sensitivity

Binding and Proton Blockage by Amantadine Variants of the Influenza M2WT and M2S31N Explained

While aminoadamantanes are well-established inhibitors of the influenza A M2 proton channel, the mechanisms by which they are rendered ineffective against M2S31N are unclear. Solid state NMR, isothermal titration calorimetry, electrophysiology, antiviral assays, and molecular dynamics simulations suggest stronger binding interactions for aminoadamantanes to M2WT compared to negligible or weak binding to M2S31N. This is due to reshaping of the M2 pore when N31 is present, which, in contrast to wild-type (WT), leads (A) to the loss of the V27 pocket for the adamantyl cage and to a predominant orientation of the ligand’s ammonium group toward the N-terminus and (B) to the lack of a helical kink upon ligand binding. The kink, which reduces the tilt of the C-terminal helical domain relative to the bilayer normal, includes the W41 primary gate for proton conductance and may prevent the gate from opening, representing an alternative view for how these drugs prevent proton conductance. © 2017 American Chemical Society