Pyridin-2-yl Guanidine Derivatives: Conformational Control Induced by Intramolecular Hydrogen-Bonding Interactions

The synthesis and conformational analysis of a series of pyridin-2-yl guanidine derivatives using NMR, X-ray crystallography, and B3LYP/6-31+G** theoretical studies are reported. A remarkable difference was observed in the ¹H NMR spectra of the guanidinium salts as compared with their <i>N</i>,<i>N</i>′-di-Boc protected and neutral analogues. This difference corresponds to a 180° change in the dihedral angle between the guanidine/ium moiety and the pyridine ring in the salts as compared to the Boc-protected derivatives, a conclusion that was supported by theoretical studies, X-ray data, and NMR analysis. Moreover, our data sustain the existence of two intramolecular hydrogen-bonding systems: (i) between the pyridine N1 atom and the guanidinium protons in the salts and (ii) within the <i>tert</i>-butyl carbamate groups of the Boc-protected derivatives. To verify that the observed conformational control arises from these intramolecular interactions, a new series of <i>N</i>-Boc-<i>N</i>′-propyl-substituted pyridin-2-yl guanidines were also prepared and studied

Additional file 3: of Composition and dynamics of the respiratory tract microbiome in intubated patients

Closed-reference OTU table. Closed-reference OTU taxonomic assignments. Sequence data was analyzed using the Quantitative Insights Into Microbial Ecology (QIIME) bioinformatics pipeline, version 1.8.0. Sequence alignment was performed via PyNAST, closed-reference operational taxonomic unit (OTU) formation, and taxonomic assignment was based on the Greengenes (13.8) taxonomy. Closed-reference OTUs were used in all comparisons between intubated subjects and healthy controls. (ZIP 90.8 KB

Additional file 1: Figure S1. of Composition and dynamics of the respiratory tract microbiome in intubated patients

Comparison of beta diversity among intubated subjects and healthy controls. Principal coordinate analysis was performed on pairwise weighted Jaccard distances for samples from intubated subjects (blue) and healthy control subjects (red), based on sequence read counts aggregated at family-level taxonomy (as in Fig. 2). Panel A depicts upper respiratory tract samples. Panel B depicts lower respiratory tract samples. The proportion of variance explained by each principal coordinate is noted parenthetically along the horizontal and vertical axes. (PDF 45.8 KB

Non-Covalent Interactions: Complexes of Guanidinium with DNA and RNA Nucleobases

Considering that guanidine-based derivatives are good DNA minor groove binders, we have theoretically studied, using the Polarizable Continuum model mimicking water solvation, the complexes formed by the biologically relevant guanidinium cation and the DNA and RNA nucleobases (adenine, guanine, cytosine, thymine, and uracil). The interactions established within these complexes both by hydrogen bonds and by cation−π interactions have been analyzed by means of the Atoms in Molecules and Natural Bond Orbital approaches. Moreover, maps of electron density difference have been produced to understand the cation−π complexes. Finally, the NICS and three-dimensional NICS maps of the cation−π complexes have been studied to understand the effect of the guanidinium cation on the aromaticity of the nucleobases

Structure–Activity Relationships in Non-Ligand Binding Pocket (Non-LBP) Diarylhydrazide Antiandrogens

We report the synthesis and a study of the structure–activity relationships of a new series of diarylhydrazides as potential selective non-ligand binding pocket androgen receptor antagonists. Their biological activity as antiandrogens in the context of the development of treatments for castration resistant prostate cancer was evaluated using <i>in vitro</i> time resolved fluorescence resonance energy transfer and fluorescence polarization on target assays. Additionally, a theoretical study combining docking and molecular dynamics methods was performed to provide insight into their mechanism of action as a basis for further lead optimization studies

α₂‑Adrenoceptor Antagonists: Synthesis, Pharmacological Evaluation, and Molecular Modeling Investigation of Pyridinoguanidine, Pyridino-2-aminoimidazoline and Their Derivatives

We have previously identified phenylguanidine and phenyl-2-aminoimidazoline compounds as high affinity ligands with conflicting functional activity at the α₂-adrenoceptor, a G-protein-coupled receptor with relevance in several neuropsychiatric conditions. In this paper we describe the design, synthesis, and pharmacological evaluation of a new series of pyridine derivatives [para substituted 2- and 3-guanidino and 2- and 3-(2-aminoimidazolino)­pyridines, disubstituted 2-guanidinopyridines and N-substituted-2-amino-1,4-dihydroquinazolines] that were found to be antagonists/inverse agonists of the α₂-adrenoceptor. Furthermore, the compounds exert their effects at the α₂-adrenoceptor both in vitro in human prefrontal cortex tissue and in vivo in rat brain as shown by microdialysis experiments. We also provide a docking study at the α_2A- and α_2C-adrenoceptor subtypes demonstrating the structural features required for high affinity binding to the receptor

Single-Molecule Analysis of the Supramolecular Organization of the M₂ Muscarinic Receptor and the Gα_i1 Protein

G protein-coupled receptors constitute the largest family of transmembrane signaling proteins and the largest pool of drug targets, yet their mechanism of action remains obscure. That uncertainty relates to unresolved questions regarding the supramolecular nature of the signaling complex formed by receptor and G protein. We therefore have characterized the oligomeric status of eGFP-tagged M₂ muscarinic receptor (M₂R) and G_i1 by single-particle photobleaching of immobilized complexes. The method was calibrated with multiplexed controls comprising 1–4 copies of fused eGFP. The photobleaching patterns of eGFP-M₂R were indicative of a tetramer and unaffected by muscarinic ligands; those of eGFP-G_i1 were indicative of a hexamer and unaffected by GTPγS. A complex of M₂R and G_i1 was tetrameric in both, and activation by a full agonist plus GTPγS reduced the oligomeric size of G_i1 without affecting that of the receptor. A similar reduction was observed upon activation of eGFP-Gα_i1 by the receptor-mimic mastoparan plus GTPγS, and constitutively active eGFP-Gα_i1 was predominantly dimeric. The oligomeric nature of G_i1 in live CHO cells was demonstrated by means of Förster resonance energy transfer and dual-color fluorescence correlation spectroscopy in studies with eGFP- and mCherry-labeled Gα_i1; stochastic FRET was ruled out by means of non-interacting pairs. These results suggest that the complex between M₂R and holo-G_i1 is an octamer comprising four copies of each, and that activation is accompanied by a decrease in the oligomeric size of G_i1. The structural feasibility of such a complex was demonstrated in molecular dynamics simulations