Dimethylarginine dimethylaminohydrolase (DDAH) is a highly conserved hydrolytic enzyme found in numerous species, including bacteria, rodents, and humans. In humans, the DDAH-1 isoform is known to metabolize endogenous asymmetric dimethylarginine (ADMA) and monomethyl arginine (L-NMMA), with ADMA proposed to be a putative marker of cardiovascular disease. Current literature reports identify the DDAH family of enzymes as a potential therapeutic target in the regulation of nitric oxide (NO) production, mediated via its biochemical interaction with the nitric oxide synthase (NOS) family of enzymes. Increased DDAH expression and NO production have been linked to multiple pathological conditions, specifically, cancer, neurodegenerative disorders, and septic shock. As such, the discovery, chemical synthesis, and development of DDAH inhibitors as potential drug candidates represent a growing field of interest. This review article summarizes the current knowledge on DDAH inhibition and the derived pharmacokinetic parameters of the main DDAH inhibitors reported in the literature. Furthermore, current methods of development and chemical synthetic pathways are discussed.
Molecular tweezers were synthesised by using a microwave accelerated alkene plus cyclobutane epoxide reaction between norbornyl appended porphyrin moieties and a diepoxide functionalised phenyl diimide spacer. The tweezers contain several rotational degrees of freedom; about the porphyrin with respect to the norbornyl linker, and between the two norbornyl backbone sections. The ability of ZnII metallated tweezer 1 to complex 1,4‐diazabicyclo[2.2.2]octane (DABCO) was studied by UV/Vis and 1H NMR spectroscopy and multivariate global spectral analysis. The system was found to form a strong 1:1 intramolecular complex (1:DABCO) with an association constant of K11 = 8.1 × 107 M–1, transforming to a 1:2 open complex [1:(DABCO)2] with K12 = 2.7 × 109 M–2 at high concentrations of DABCO.
Deuterium isotope effects in the keto-enol tautomerism of β-dicarbonyl compounds (malonaldehyde, acetylacetone, dibenzoylmethane, and avobenzone) have been studied using a B3LYP+D functional level of multi-component density functional theory (MC_DFT), which can directly take nuclear quantum effects (NQEs) of the hydrogen nuclei into account. We clearly show that the keto-enol energy difference becomes smaller by deuterium substitution, which is in reasonable agreement with the corresponding experimental evidence. Our MC_DFT study also reveals the hydrogen/deuterium (H/D) isotope effect in geometries and shows that the deuterium substitution weakens the intramolecular hydrogen-bonded interaction in the enol form. Direct treatment of NQEs of hydrogen nuclei via the MC_DFT method is essential for analyzing the H/D isotope effect in keto-enol tautomerism of β-dicarbonyl compounds. Such isotope effects cannot be reproduced in the conventional DFT scheme with harmonic zero-point vibrational corrections.
A capillary electrophoresis coupled to tandem mass spectrometry (CE-MS/MS) has been used to make a qualitative determination of hercynine-the main precursor of L-ergothioneine biosynthesis-in some key human biological specimens, such as urine, whole blood, plasma, and saliva. From semiquantitative analysis results, the highest concentrations of hercynine were detected in saliva and whole blood, whereas much lower concentrations were measured in urine and plasma. Whole blood was the biological matrix with the highest concentration of L-ergothioneine followed by plasma, saliva, and urine. The antioxidant effects attributed to L-ergothioneine, along with its peculiar antioxidant mechanism, offer a possible explanation for the presence of the hercynine, as well as its concentration, in the considered biological matrices.
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