2-Methylisoxazolin-5-ones III. Curboxylic. Acids and their Derivatives

Carbethoxy-substituted 12-methylisoxazolin-5-ones and several functional derivatives have been prepared. Spectral properties of the corresponding carboxylic acids are discussed. These acids ant stronger when the carboxy group is in position 3 than when in position 4 of the heterocycle.     

Expanding the Chemical Space of Non-Proteinogenic N4-Substituted Asparagine: Racemic,Enantioenriched, and Deuterated Derivatives

A site-selective carbamoylation strategy to access non-proteinogenic N⁴-modified asparagines has been described. The protocol is characterized by mild reaction conditions, high functional group compatibility, and a wide diversity of functionalized carbamoyl radicals making possible the access to peptides, pharmaceuticals, and natural N⁴-asparagine conjugates, as well as enantioenriched unnatural N⁴-asparagines. Besides that, deuterated analogues were achieved with the insertion of D₂O and enantioenriched derivatives could be obtained in 15 min in continuous-flow conditions.     

Photophysical properties of the lowest excited singlet and triplet states of thio- and seleno-psoralens

The decay processes of the lowest excited singlet and triplet states of five heteropsoralens (HPS) were investigated by steady-state and shift-phase fluorometry and by laser-flash photolysis in different solvents. The emission spectra of HPS are detectable only in trifluoroethanol (TFE), where fluorescence lifetimes (τ_F) and quantum yields (φ_F) were measured. The triplet lifetimes (τ_T), triplet (φ_T) and singlet-oxygen production (φ_Δ) quantum yields were determined in benzene, ethanol and TFE by laser-flash photolysis. Semiempirical (INDO/1-CI) calculations allowed the nature of the lowest excited singlet and triplet states and transition probabilities to be obtained. Theoretical and experimental results indicate that the two lowest excited singlet states S₁ and S₂ of HPS are close-lying and different in nature (π,π* and n,π*). The "proximity effect" between these two states controls the photophysical properties of HPS as it does for the other furocoumarins. However, HPS have a peculiar behavior with respect to the related compounds because they are fluorescent and have, in three cases, detectable intersystem crossing only in TFE. This behavior can be tentatively explained by a different energy gap and/or order between the S₁ and S₂ states.     

Unusual and unexpected reactivity of t-butyl dicarbonate (Boc2O) with alcohols in the presence of magnesium perchlorate. A new and general route to t-butyl ethers

[reaction: see text] A new mild method for protecting alcohols as t-butyl ethers is reported. The reaction proceeds with Mg(ClO4)2 and Boc2O and shows general applicability. The deprotection of t-butyl ethers has also been revisited. Preliminary results indicate the CeCl3 x 7H2O/NaI system is a very suitable catalyst for their removal.     

Direct determination of kallikrein by high-performance liquid chromatography.

A direct and specific identification of porcine pancreatic kallikrein by high-performance hydrophobic chromatography is proposed; the minimum amount which can be injected is 2.5 U. An application to the quantitative determination of the enzyme by high-performance size-exclusion chromatography is reported; the method is precise with a mean coefficient of variation of 2.8% and the minimum amount which can be injected is 0.02 U of kallikrein. The results obtained with determinations in real biological samples (porcine pancreatic powder and human urine) are reported. The method is based on direct and specific chromatographic signals and does not destroy the biological activity of this enzyme.     

Synthesis and inverse virtual screening of new bi-cyclic structures towards cancer-relevant cellular targets

Structural Chemistry - We report here synthetic approaches to access new classes of small molecules based on three heterocyclic scaffolds, i.e. 3,7-dihydropyrimido[4,5-d]pyridazine-4,8-dione,...     

Drug Screening in Human Cells by NMR Spectroscopy Allows the Early Assessment of Drug Potency

Structure‐based drug development is often hampered by the lack of in vivo activity of promising compounds screened in vitro, due to low membrane permeability or poor intracellular binding selectivity. Herein, we show that ligand screening can be performed in living human cells by “intracellular protein‐observed” NMR spectroscopy, without requiring enzymatic activity measurements or other cellular assays. Quantitative binding information is obtained by fast, inexpensive ¹H NMR experiments, providing intracellular dose‐ and time‐dependent ligand binding curves, from which kinetic and thermodynamic parameters linked to cell permeability and binding affinity and selectivity are obtained. The approach was applied to carbonic anhydrase and, in principle, can be extended to any NMR‐observable intracellular target. The results obtained are directly related to the potency of candidate drugs, that is, the required dose. The application of this approach at an early stage of the drug design pipeline could greatly increase the low success rate of modern drug development.