10 research outputs found
Enantioselective Synthesis of Chiral Sulfones by Ir-Catalyzed Asymmetric Hydrogenation: A Facile Approach to the Preparation of Chiral Allylic and Homoallylic Compounds
A highly efficient and enantioselective Ir-catalyzed
hydrogenation
of unsaturated sulfones was developed. Chiral cyclic and acyclic sulfones
were produced in excellent enantioselectivities (up to 98% ee). Coupled
with the RambergâBaĚcklund rearrangement, this reaction
offers a novel route to chiral allylic and homoallylic compounds in
excellent enantioselectivities (up to 97% ee) and high yields (up
to 94%)
On-Water Synthesis of Biaryl Sulfonyl Fluorides
Herein,
we report an efficient, ligand-free, and additive-free
SuzukiâMiyaura coupling that is compatible with the aromatic
sulfonyl fluoride functional group. The protocol proceeds at room
temperature, on water, and offers facile access to a wide range of
biaryl sulfonyl fluorides as bioorthogonal âclickâ reagents
Solid-Phase Synthesis of Pyrrole Derivatives through a Multicomponent Reaction Involving Lys-Containing Peptides
The synthesis of pyrroles has received
considerable attention because
of their biological and pharmaceutical activities. Herein we describe
a solid-phase multicomponent reaction that utilizes Lys as a N donor,
β-nitrostyrenes, 1,3-dicarbonyl compounds, and FeCl<sub>3</sub> as an easily accessible catalyst under microwave irradiation to
afford the subsequent pyrrole derivatives in high conversions. The
strategy combines three of the most powerful tools in modern synthetic
chemistry: the solid-phase mode, microwave activation, and a multicomponent
reaction. The excellent results in terms of rapidity, versatility,
and purity obtained herein support once again that this combined strategy
is efficient for gaining chemical diversity
A Synthesis of âDual Warheadâ βâAryl Ethenesulfonyl Fluorides and One-Pot Reaction to βâSultams
Herein, we report
an operationally simple, ligand- and additive-free
oxidative boron-Heck coupling that is compatible with the ethenesulfonyl
fluoride functional group. The protocol proceeds at room temperature
with chemoselectivity and <i>E</i>-isomer selectivity and
offers facile access to a wide range of β-aryl/heteroaryl ethenesulfonyl
fluorides from commercial boronic acids. Furthermore, we demonstrate
a âone-pot clickâ reaction to directly transform the
products to aryl-substituted β-sultams
6â(Bromomaleimido)hexanoic Acid as a Connector for the Construction of Multiple Branched Peptide Platforms
We
report on a novel and user-friendly platform based on a bromomaleimide
moiety to obtain branched peptides. The platform is stable for all
SPPS conditions. The bromomaleimide core was conjugated to <i>n</i>-copies of thiolâpeptide in-solution to obtain two/four/eight-armed
dendrimers. Using â<i>n</i>â number of bromomaleimide
analogues, 2<sup><i>n</i></sup> ligands were incorporated
at both bromo and ene positions via a thioether bond. This method
has the advantage of high conversion in a short time, thus enabling
effortless purification and characterization processes
The downfall of TBA-354 â a possible explanation for its neurotoxicity <i>via</i> mass spectrometric imaging
<p>1. TBA-354 was a promising antitubercular compound with activity against both replicating and static <i>Mycobacterium tuberculosis</i> (<i>M.tb</i>), making it the focal point of many clinical trials conducted by the TB Alliance. However, findings from these trials have shown that TBA-354 results in mild signs of reversible neurotoxicity; this left the TB Alliance with no other choice but to stop the research.</p> <p>2. In this study, mass spectrometric methods were used to evaluate the pharmacokinetics and spatial distribution of TBA-354 in the brain using a validated liquid chromatography tandem-mass spectrometry (LCMS/MS) and mass spectrometric imaging (MSI), respectively. Healthy female Sprague-Dawley rats received intraperitoneal (i.p.) doses of TBA-354 (20âmg/kgâbw).</p> <p>3. The concentrationtime profiles showed a gradual absorption and tissue penetration of TBA-354 reaching the <i>C</i><sub>max</sub> at 6 h post dose, followed by a rapid elimination. MSI analysis showed a time-dependent drug distribution, with highest drug concentration mainly in the neocortical regions of the brain.</p> <p>4. The distribution of TBA-354 provides a possible explanation for the motor dysfunction observed in clinical trials. These results prove the importance of MSI as a potential tool in preclinical evaluations of suspected neurotoxic compounds.</p
Green Solid-Phase Peptide Synthesis 2. 2âMethyltetrahydrofuran and Ethyl Acetate for Solid-Phase Peptide Synthesis under Green Conditions
<i>N,N</i>-Dimethylformamide
(DMF), <i>N</i>-methyl-2-pyrrolidone, and dichloromethane
(DCM) are the most widely
used solvents for Fmoc solid-phase peptide synthesis (SPPS). These
solvents are considered hazardous chemicals and are normally used
in large amounts for washing, deprotection, and coupling steps. Therefore,
the use of these reagents is indeed in question. Our group recently
reported the use of 2-methyltetrahydrofuran (2-MeTHF), which is a
green solvent, for coupling, but using DMF for the Fmoc removal and
washing steps [Jad et al. Amino Acids 2016, 48 (2), 419â426.]. Herein, total full green solvent protocols in which DMF and DCM
are completely eliminated are reported. Several green solvents, such
as 2-MeTHF, ethyl acetate, and isopropyl alcohol; temperature; solid
supports; and peptide models were evaluated in this study. The best
green protocol established is the use of 2-MeTHF for Fmoc removal,
washing, and coupling steps with some more washing with EtOAc at room
temperature for a short and challenging peptide (Aib-enkephalin pentapeptide).
In the case of a longer and more difficult peptide (Aib-ACP decapeptide),
the best protocol established was similar, except for the Fmoc removal
and coupling steps that were conducted at 40 °C and in combination
with the use of a polyethylene glycol resin (ChemMatrix resin)
A comparative modeling and molecular docking study on <i>Mycobacterium tuberculosis</i> targets involved in peptidoglycan biosynthesis
<p>An alarming rise of multidrug-resistant <i>Mycobacterium tuberculosis</i> strains and the continuous high global morbidity of tuberculosis have reinvigorated the need to identify novel targets to combat the disease. The enzymes that catalyze the biosynthesis of peptidoglycan in <i>M. tuberculosis</i> are essential and noteworthy therapeutic targets. In this study, the biochemical function and homology modeling of MurI, MurG, MraY, DapE, DapA, Alr, and Ddl enzymes of the CDC1551 <i>M. tuberculosis</i> strain involved in the biosynthesis of peptidoglycan cell wall are reported. Generation of the 3D structures was achieved with Modeller 9.13. To assess the structural quality of the obtained homology modeled targets, the models were validated using PROCHECK, PDBsum, QMEAN, and ERRAT scores. Molecular dynamics simulations were performed to calculate root mean square deviation (RMSD) and radius of gyration (Rg) of MurI and MurG target proteins and their corresponding templates. For further model validation, RMSD and Rg for selected targets/templates were investigated to compare the close proximity of their dynamic behavior in terms of protein stability and average distances. To identify the potential binding mode required for molecular docking, binding site information of all modeled targets was obtained using two prediction algorithms. A docking study was performed for MurI to determine the potential mode of interaction between the inhibitor and the active site residues. This study presents the first accounts of the 3D structural information for the selected <i>M. tuberculosis</i> targets involved in peptidoglycan biosynthesis.</p
Synthesis and Biological Evaluation of a Teixobactin Analogue
The
first synthesis and biological activity of a teixobactin analogue
is reported. Substitution of the unusual l-<i>allo</i>-enduracididine residue by the naturally occurring l-arginine
was achieved, and the analogue gave an activity trend similar to that
of teixobactin (against Gram-postive bacteria) and meropenem, which
was approved by the FDA in 1996. The synthetic route used allows for
the synthesis of the natural product as well as the development of
a program of medicinal chemistry
Lysine Scanning of Arg<sub>10</sub>âTeixobactin: Deciphering the Role of Hydrophobic and Hydrophilic Residues
Teixobactin
is a recently discovered antimicrobial cyclodepsipeptide
with good activity against Gram positive bacteria. Taking Arg<sub>10</sub>âteixobactin as
a reference, where the nonproteinogenic residue l-allo-enduracididine
was substituted by arginine, a lysine scan was performed to identify
the importance of keeping the balance between hydrophilic and hydrophobic
amino acids for the antimicrobial activities of this peptide family.
Thus, the substitution of four isoleucine residues present in the
natural sequence by lysine led to a total loss of activity. On the
other hand, the substitution of the polar noncharged residues and
alanine by lysine allowed us to keep and in some cases to improve
the antimicrobial activity