Keywords: 2-Aminobenzothiazole / Dibenzothiazolyltetraazathiapentalene / Electrophilic and nucleophilic sulfur atoms Reactions between CS 2 and the exocyclic amino groups of 2-aminobenzothiazoles gave series of molecules bearing thiourea, isothiourea, dithiocarbamate, dithiocarboimine, dimethyldithiocarbamate, methyldithiocarbamate, S-CH 3 and O-alkyl thiocarbamic ester, and guanidine groups. Preferred tautomers and conformers were determined. Most compounds present coordinative bonds between the endocyclic sulfur atom, which behaves as a Lewis acid, and oxygen, ni-
The
mechanochemically induced complexation between diethyl N,N′-1,3-phenyldioxalamate tweezers
and resorcinol, orcinol, 4,6-di-tert-butyl-1,3-benzenediol,
and 4-hexyl-1,3-benzenediol is described. IR-spectroscopy, X-ray powder
diffraction, 13C CPMAS, and single X-ray diffraction allowed
establishing the structures of the complexes as hydrogen-bonded heterodimers
and heterotetramers. Complexation occurs through O–H···OC
hydrogen-bonding interactions with the participation of phenolic OH
and amide carbonyl groups. The initial conformation and steric factors
coming from the 1,3-benzenediols exert a strong influence on the final
structure of the complex formed. Complexation twists both oxalyl arms
by 180°, strengthens the intramolecular (amide)CO···H(Csp
2)···OC(amide) three-centered
hydrogen bond, and moves apart the oxalyl arms to allow the accommodation
of the 1,3-benzenediol inside the cavity. The supramolecular architectures
of the complexes in 1-D are directed by R
1
2(6), R
2
2(10),
and R
1
2(6) adjacent hydrogen-bonding
ring motifs; meanwhile, the 2-D and 3-D arrays are driven by multipolar
interactions. Theoretical DFT calculations at the B3LYP/6-31G(d,p) level of theory were performed to
support the experimental findings. The complexes herein reported constitute
the first examples of molecular complexes with phenyldioxalamate.
Here, we describe the first systematic
study on the mechanism of
substrate-selective inhibition of mammalian ALOX15 orthologs. For
this purpose, we prepared a series of N-substituted
5-(1H-indol-2-yl)anilines and found that (N-(5-(1H-indol-2-yl)-2-methoxyphenyl)sulfamoyl)carbamates
and their monofluorinated analogues are potent and selective inhibitors
of the linoleate oxygenase activity of rabbit and human ALOX15. Introduction
of a 2-methoxyaniline moiety into the core pharmacophore plays a crucial
role in substrate-selective inhibition of ALOX15-catalyzed oxygenation
of linoleic acid at submicromolar concentrations without affecting
arachidonic acid oxygenation. Steady-state kinetics, mutagenesis studies,
and molecular dynamics (MD) simulations suggested an allosteric mechanism
of action. Using a dimer model of ALOX15, our MD simulations suggest
that the binding of the inhibitor at the active site of one monomer
induces conformational alterations in the other monomer so that the
formation of a productive enzyme–linoleic acid complex is energetically
compromised.
Arachidonic acid lipoxygenases (ALOXs) have been suggested to function as monomeric enzymes, but more recent data on rabbit ALOX15 indicated that there is a dynamic monomer-dimer equilibrium in aqueous solution. In the presence of an active site ligand (the ALOX15 inhibitor RS7) rabbit ALOX15 was crystalized as heterodimer and the X-ray coordinates of the two monomers within the dimer exhibit subtle structural differences. Using native polyacrylamide electrophoresis, we here observed that highly purified and predominantly monomeric rabbit ALOX15 and human ALOX15B are present in two conformers with distinct electrophoretic mobilities. In silico docking studies, molecular dynamics simulations, site directed mutagenesis experiments and kinetic measurements suggested that in aqueous solutions the two enzymes exhibit motional flexibility, which may impact the enzymatic properties.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.