ABSTRACT
The synthesis of a series of vinylated analogues of sphingosine-1-phosphate together with their unambiguous configurational assignment by VCD methods is reported. Among them, compound RBM10-8 can irreversibly inhibit human sphingosine-1-phosphate lyase (hS1PL) while behaving also as an enzyme substrate. These findings, together with the postulated mechanism for S1PL activity, reinforce the role of RBM10-8 as a new mechanism-based hS1PL inhibitor.
Subject(s)
Aldehyde-Lyases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Aldehyde-Lyases/chemistry , Amino Acid Sequence , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Molecular Structure , StereoisomerismABSTRACT
Prochloraz is a widely used imidazole fungicide that has to be analyzed together with its metabolites or transformation products for food safety monitoring purposes in the European Union. Although the focus in food of plant origin has been set on metabolites BTS 44595 and BTS 44596, we consider relevant the study of BTS 40348 metabolite, too, because it has been detected in both raw and processed foods based on citrus fruits in the EU. Metabolite BTS 40348 should be monitored in surface water due to its ecotoxicological effects. In this work, the synthesis and structural characterization of BTS 40348 metabolite of fungicide prochloraz is presented, because the structure is closely related to the chemistry and biological activity of the substance. Characterization using 13C and 1H NMR, infrared (IR), and Raman spectroscopy is detailed, together with confirmation by electrospray mass spectrometry analysis.
Subject(s)
Fungicides, Industrial/chemistry , Fungicides, Industrial/metabolism , Imidazoles/chemistry , Imidazoles/metabolism , European Union , Fast Foods/analysis , Food Contamination/analysis , Magnetic Resonance Spectroscopy , Molecular Structure , Pesticide Residues/chemistry , Pesticide Residues/metabolism , Spectrum Analysis, Raman , Water Pollutants/chemistryABSTRACT
Thermochemical kinetics of hydrolysis reactions of compounds with transannular intramolecular M N bonds, i.e., atranes RM(OCH2CH2)3N and ocanes R2M(OCH2CH2)2NH (M = Si, Ge; R = F, Cl, Me), is studied at the B3LYP/aug-cc-pVDZ theoretical level. Several DFT methods are assessed for the reproduction of the experimental activation barrier for the Si-O bond cleavage of 1-methylsilatrane. Activation barriers for atranes and ocanes show the tendency for their growth with the decrease of the electronegativity of a substituent R on going from F to Me and their decrease from Si to Ge. Hydrolysis activation barriers of atranes and ocanes are compared with those of their acyclic analogs RM(OCH3)3 and R2M(OCH2)2NH in order to study the role of transannular M N bonds in the stability of these molecules to hydrolysis. Substantially larger barriers for atranes support the opinion that stability of atranes may be explained by the formation of intramolecular bonds; however, the strengthening of transannular M N bonds results in lower M-O cleavage barriers. It was proposed that the M-O cleavage barrier height is determined not by a weak M N bonding itself, but rather by the contribution of a nitrogen lone pair to the antibonding orbitals of M-O bonds. The NBO analysis show that this interaction increases with the decrease of the electronegativity of a substituent R and decreases on going from atranes to ocanes. In ocanes, the presence of M N bonds does not kinetically hinder the hydrolytic process; M-O cleavage activation barriers for acyclic analogs are higher. M-Hal cleavage barriers are substantially higher than those for M-O cleavage for R = F, but lower for R = Cl. Graphical Abstract The experimental barrier height of the Si-O bond cleavage in 1-methylsilatrane is well reproduced when three explicit water molecules are included in the B3LYP/aug-cc-pVDZ theoretical model.
ABSTRACT
The implementation of a strategy comprising the use of vibrational circular dichroism spectroscopy and DFT calculations allows determination of the solution-state conformational distribution in (-)-S-cotinine, giving further proof of the extra conformer-discriminating potential of this experimental technique, which may offer unique molecular fingerprints of subtly dissimilar molecular conformers of chiral samples. Natural bond orbital electronic structure calculations of the rotational barrier height between the two main conformers of the species indicate that hyperconjugative effects are the key force governing the conformational equilibrium. The negligible effect of the solvent's polarity over both structure and conformational energy profile supports this result.
