39 research outputs found
disrupting the pcsk9 ldlr protein protein interaction by an imidazole based minimalist peptidomimetic
We report on a tetraimidazole-based β-strand minimalist peptidomimetic as a novel inhibitor of LDLR–PCSK9 protein–protein interaction, a promising target for hypercholesterolemia
Organocatalytic vinylogous Mannich reaction of trimethylsiloxyfuran with isatin-derived benzhydryl-ketimines
A family of chiral quaternary 3-aminooxindole butenolides has been synthesized by BINOL-derived phosphoric acid-catalyzed addition of trimethylsiloxyfuran to isatin-derived ketimines. Such a vinylogous Mannich-type reaction was found to produce diastereoisomeric butenolides in good yields and in most cases high enantiomeric excesses. The configurational assignment of the obtained products was safely performed by chemical correlation. A computational study of the transition state allowed rationalizing the obtained stereochemical outcome, highlighting the possible binding modes of the catalyst-imine-nucleophile transition complex
Efficient Synthesis of Spirooxindole-Fused 3-Thiazoline Derivatives by a One-Pot Asinger-Type Reaction
Synthesis, pharmacological evaluation and conformational investigation of endomorphin-2 hybrid analogues
This study reports on new pharmacologically active endomorphin-2 analogues, incorporating β 2-hPhe, β 3-hPhe and β 3-hTic unnatural amino acids in the place of the Phe 3-Phe 4residues. Such α, β-hybrid analogues were designed to exploit the great potential of β-amino acids in generating conformational variation at the key positions 3 and 4, with the aim of evaluating the effect on the opioid binding affinity. Ligand-stimulated binding assays indicated that some analogues retained a significant affinity, especially for the δ receptor. 1H NMR and molecular modelling suggested the predominance of bent structures for all compounds. The molecular docking with the μ-opioid receptor model was also performed, highlighting a common binding mode for active compounds and helping to rationalize the observed structure-activity data. © 2012 Springer Science+Business Media Dordrecht
RCM strategy for the enantiosynthesis of new polyhydroxylated quinolizidines, indolizidines and pyrrolizidines
Le glicosidasi, enzimi in grado di catalizzare l\u2019idrolisi del legame glicosidico in carboidrati e glicoconiugati, rivestono un ruolo fondamentale in molteplici fenomeni biologici quali, ad esempio, l\u2019assorbimento degli zuccheri a livello intestinale, il catabolismo dei glicoconiugati intracellulari e la regolazione dei processi che riguardano la porzione oligosaccaridica di glicoproteine e glicolipidi di membrana. A partire dagli anni \u201960, sono stati individuati diversi alcaloidi naturali poliossidrilati, tra i quali chinolizidine, indolizidine e pirrolizidine, che hanno dimostrato di poter inibire in modo selettivo le diverse glicosidasi. L\u2019alto potenziale terapeutico di queste molecole a scheletro azabiciclico, dette anche azazuccheri, ha portato alla ricerca di una loro modificazione strutturale che le renda maggiormente attive e selettive, nonch\ue9 alla progettazione di nuove vie di sintesi stereocontrollate di questi composti e di loro isomeri e analoghi non naturali.
In questo lavoro viene descritta una strategia di sintesi a partire da molecole non derivanti da carboidrati, basata su differenti reazioni di ring closing metathesis (RCM) come passaggio chiave
One step access to oxindole-based β-lactams through Ugi four-center three-component reaction
A multicomponent Ugi reaction involving isatin, isocyanide and β-amino acid components has been developed
The diketopiperazine-fused tetrahydro-β-carboline scaffold as a model peptidomimetic with an unusual α-turn secondary structure
Aiming at restricting the conformational freedom of tryptophan-containing peptide ligands, we designed a THBC (tetrahydro-β-carboline)-DKP (diketopiperazine)-based peptidomimetic scaffold capable of arranging in an unusual α-turn conformation. The synthesis is based on a diastereoselective Pictet–Spengler condensation to give the THBC core, followed by an intramolecular lactamization to complete the tetracyclic THBC-DKP fused ring system. The presence of conformers bearing the intramolecular thirteen-membered hydrogen bond that characterizes the α-turn structure is confirmed by 1H NMR conformational studies. To the best of our knowledge, this scaffold represents one of the rare examples of a designed constrained α-turn mimic
Organocatalytic Asymmetric Biginelli-like Reaction Involving Isatin
The first asymmetric, Brønsted acid catalyzed Biginelli-like reaction of a ketone has been developed, employing N-substituted isatins as carbonyl substrates, and urea and alkyl acetoacetates as further components. BINOL-derived phosphoric acid catalysts have been used to achieve the synthesis of a small library of chiral, enantioenriched spiro(indoline-pyrimidine)-diones derivatives. The absolute configuration of the new spiro stereocenter was assessed on diastereoisomeric derivatives through computer-assisted NMR spectroscopy. X-ray diffractometry allowed the disclosure of the overall molecular conformation in the solid state and the characterization of the crystal packing of a Br-substituted Biginelli-like derivative, while computational studies on the reaction transition state allowed us to rationalize the stereochemical outcome