1,721,489 research outputs found
SALICYLALDEHYDE-TAGGED PEPTIDES FOR THE REVERSIBLE-COVALENT ENGAGEMENT OF PROTEIN LYSINE RESIDUES
Full text linkInserting electrophilic species into small molecule ligands or peptides is a well-established method for enhancing binding affinity to target proteins. The amino acid Lysine (Lys) is highly abundant in the proteome and one of the most frequent residues on the outer structural layers of proteins. For these reasons, the derivatization of synthetic ligands with aldehyde tags capable of imine bond formation with Lys ɛ-amino groups may represent a general strategy for the discovery of potent small-molecule inhibitors.
Ortho-hydroxy aldehydes such as pyridoxal or salicylaldehyde (SA) derivatives have been used to form imines in aqueous media, stabilized by an intramolecular H-bond between the imine N atom and the ortho-phenolic proton. By virtue of this reactivity, SA derivatives are being installed into various classes of protein ligands, aimed at the reversible-covalent engagement of protein Lys residues.1,2
This talk will describe our recent contribution to this field, with focus on the installation of the Lys-engaging SA module into peptide ligands.3,4
Figure 1. Left: Binding mechanism of a reversible-covalent ligand equipped with a salicylaldehyde (SA) tag. Ideally, SA forms a remarkably stable imine bond with a Lys(ε-NH2) residue proximal to the ligand binding site. This covalent ligand-protein connection is stabilized by a H bond between the OH phenolic proton and the imine N atom. As a result, the final ligand-protein complex is stabilized by a combination of non-covalent and covalent interactions. Right: Current options for the SA tag installation at different peptide positions, recently developed by our group.
References
1. A. Dal Corso, M. Catalano, A. Schmid, J. Scheuermann, D. Neri, Angew. Chem. Int. Ed. 2018, 57, 17178.
2. M. Mason, L. Belvisi, L. Pignataro, A. Dal Corso, ChemBioChem 2023, e202300743.
3. G. Sacco, D. Arosio, M. Paolillo, A. Gloger, J. Scheuermann, L. Pignataro, L. Belvisi, A. Dal Corso, C. Gennari, Chem. Eur. J. 2023, e202203768.
4. M. Mason, B. Nava, L. Belvisi, L. Pignataro, A. Dal Corso, Eur. J. Org. Chem. 2024, 27, 202400229
A library approach to the development of chiral supramolecular ligands for asymmetric hydrogenation
No full textThe creation of chiral ligands of simple structure and truly easy preparation is the condition for supramolecular catalysis to become of practical industrial use. To this end, we developed a library of chiral monodentate phosphites, named BenzaPhos,[1] which can be prepared in only two simple steps from readily available compounds. The new ligands, containing a benzoic acid primary amide group capable of hydrogen bonding interactions, showed excellent activity and stereocontrol in the enantioselective hydrogenation of both benchmark substrates and ‘challenging’ olefins.
A series of experiments and computational studies strongly suggest that ligand-substrate H-bonding crucially affects these outstanding catalytic properties.
[1] L. Pignataro, C. Bovio, M. Civera, U. Piarulli, C. Gennari, Chem. Eur. J. 2012, 18, DOI: 10.1002/chem.201201032
A Highly Stereoselective Total Synthesis of (–)-Dictyostatin
No full textThe sponge-derived macrolide (-)-dictyostatin (1) has been reported to exhibit paclitaxel-like effects on cellular microtubules and to inhibit human cancer cell proliferation (even of paclitaxel-resistant cancer cell lines) at low nanomolar concentrations, with activity somewhat superior to the already very active discodermolide.1 Although four total syntheses of (-)-dictyostatin were recently completed,2 the development of a practical and flexible synthesis remains an important goal, particularly as its natural supply is extremely scarce.
Here we report a highly stereoselective total synthesis of (-)-dictyostatin, achived by coupling two key-fragments,3 C1-C9 (2) and C10-C26 (3), followed by Yamaguchi macrolactonization and global deprotection. The reported synthetic route offers the possibility of introducing variations in the dictyostatin skeleton, which will allow for the preparation of novel analogs.
We thank the Ministero dell’Università e della Ricerca for financial support (PRIN prot. 2008J4YNJY) and for a PhD fellowship (Borsa di dottorato ‘Progetto giovani’ to C. Zanato). L. Pignataro thanks Milan University for a postdoctoral fellowship (‘Assegno di ricerca’). Z. Hao (Lanzhou University, PRC) thanks the China Scholarship Council for a PhD mobility grant. We thank Master student A. Ambrosi for the scale-up of several intermediates
Aspetti innovativi della clinica del cancro laringeo : ruolo del path-way Cicline-CDK nel cancro laringeo
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