Recently a series of 2-amino-5-sulfanyl-1,3,4-thiadiazole derivatives bearing different substituents were synthesized and screened pharmacologically in order to evaluate their central nervous system activity. The purpose of this study was to evaluate the effects of the title compounds on CNS activity by varying the substituents in the thiadiazole moiety. It was found that some of these compounds possess marked antidepressant and anxiolytic properties comparable in efficiency to the reference drugs Imipramine and Diazepam. The most potent compound 3k was further investigated to complete its pharmacological profile with respect to undesired side effects. Behavioral results showed that 3k is a very promising compound, characterized by a mixed antidepressant-anxiolytic activity accompanied by a therapeutic dose range that is essentially 2 orders of magnitude less than that at which side effects such as sedation and amnesia are evident.
Rac1 protein is implicated in several events of atherosclerotic plaque development and represents a new potential pharmacological target for cardiovascular diseases. In this paper we describe a pharmacophore virtual screening followed by molecular docking calculations leading to the identification of five new Rac1 inhibitors. These compounds were shown to be more effective than the reference compound NSC23766 in reducing the intracellular levels of Rac1-GTP, thus supporting this approach for the development of new Rac1 inhibitors.
The use of the 2-amino-3-(phenylsulfanyl)norbornane-2-carboxylate scaffold has been exploited for the de novo design of potent Rac1 inhibitors acting as modulators of the protein-protein interaction between Rac1 and Tiam1. A series of compounds differing in regio- and stereochemistry has been prepared by way of a multistep synthesis based on cycloaddition reactions and Pd chemistry. Pharmacological analyses showed that all the prepared compounds were active and selective for Rac1, and the most effective compound 13 was capable of inhibiting smooth muscle cell migration. The synthesis of this derivative was successfully scaled up to 1 g.
A very efficient synthesis of orthogonally protected 1H-azepine-4-amino-4-carboxylic acid, abbreviated as Azn, a conformationally restricted analogue of ornithine, was realized. It was obtained on a gram scale in good overall yield in five steps, three of which did not require isolation of the intermediates, starting from the readily available 1-amino-4-oxo-cyclohexane-4-carboxylic acid. Both enantiomers were used for the preparation of pentapeptide models containing Ala, Aib, and Azn. Conformational studies using both spectroscopic techniques (NMR, CD) and molecular dynamics on model 5-mer peptides showed that the (R)-Azn isomer possesses a marked helicogenic effect.
Through a computational approach, five new compounds with potent and selective Rac inhibitory activity were identified. In particular, compound 4 was shown to selectively inhibit Rac activity in a concentration-dependent manner by 10 affecting the GEF-dependent GDP-GTP exchange. This compound was more potent than the original inhibitors previously identified.
A new cyclic enantiopure b-amino acid, named b-Morph, containing the morpholino ring, was obtained in gram scale starting from a-D-glucopyranose enantiopure material, focusing on the "environmental sustainability" concept. A series of ultrashort model peptides containing b-Morph were prepared. b-Morph was found able to induce an inverse g-turn in Leu-Val containing sequences. Key element for the g-turn formation might be the oxygen atom of morpholino ring that could drive the spatial orientation of NH of amino acid i+1, through an unusual hydrogen bond. This datum was confirmed by QTAIM calculations. Interestingly, when two b-Morph-Leu-Val repeats are present in the peptide, two g-turns can be formed, as supported by NMR experiments and aMD and H-REMD calculations. Introduction g-Turns is a very short motif able to reverse the main chain of a peptide/protein. It is stabilized by the formation of a hydrogen bond between the C=O of residue i and the NH of residue i+2 forming a pseudo-seven-membered ring. Depending on the f and y angles, two different type of turns can be designed defined as inverse [φ (-75°); y (+65°)] and classical φ (+75°); y (-65°)] g-turns. In the first one, the R substituent of the a-amino acid lies in the equatorial position, while in the second one in axial position. Inverse g-turns are generally located at a position of reversal in chain direction (180°) and often within b-strands associated to b-sheets. On the other hand, classical g-turns are less common in proteins, and in most cases, they lie at the loop end of a β-hairpin. 1 A new cyclic enantiopure b-amino acid, named b-Morph, containing the morpholino ring, was obtained in gram scale starting from a-D-glucopyranose enantiopure material, focusing on the "environmental sustainability" concept. A series of ultrashort model peptides containing b-Morph were prepared. b-Morph was found able to induce an inverse g-turn in Leu-Val containing sequences. Key element for the g-turn formation might be the oxygen atom of morpholino ring that could drive the spatial orientation of NH of amino acid i+1, through an unusual hydrogen bond. This datum was confirmed by QTAIM calculations. Interestingly, when two b-Morph-Leu-Val repeats are present in the peptide, two g-turns can be formed, as supported by NMR experiments and aMD and H-REMD calculations.
An expedient chemical synthesis of a 75mer peptide corresponding to the DNA binding domain (DBD, 227-301) of the human MafA leucine zipper transcription factor is reported. The application of microwave-assisted solid phase peptide synthesis (MW-SPPS) with a protocol modified respect to the standard one allowed obtaining the desired 75mer peptide in a short time with high quantity and optimal purity. MW-SPPS methodology was thus demonstrated as a valuable alternative to recombinant methods to obtain protein domains. Considering that recent findings suggest an involvement of MafA in the pathogenesis of diabetes mellitus, we also performed circular dichroism studies both on DBD folding and its interaction with MafA recognition element (MARE) on insulin enhancer. From our results, it was evicted that a disorder to order transition occurs after DBD interaction with insulin MARE which is mediated by specific structural elements on the N-terminus of the DBD.
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