New Anticancer Agents Mimicking Protein Recognition Motifs

Abstract

The novel tetrasubstituted pyrrole derivatives 8g, 8h, and 8i showed selective cytotoxicity against M14 melanoma cells at low micromolar concentration. Structure-activity relationships (SARs) indicated the presence of three aromatic substituents on the pyrrole core as necessary for biological activity. Computational studies strongly suggest that the peculiar 3D orientation of these substituents is able to reproduce the hydrophobic side chains in LxxLL-like protein recognition motifs. Biological results showed altered p53 expression and nuclear translocation in cells sensitive to the compounds, suggesting p53 involvement in their anticancer mechanism of action. Unfortunately, because of poor solubility of the active analogues, it was not possible to perform further investigation by NMR techniques. Pharmacophore models were generated and used to perform 3D searches in molecular databases. Results indicated that two compounds share the same pharmacological profile and the same pharmacophoric features with our new derivatives, and one of them inhibited MDM2-MDM4 heterodimer formation.

Investigating the Neuroprotective Effects of Turmeric Extract: Structural Interactions of β-Amyloid Peptide with Single Curcuminoids

“…Computational studies provided a molecular model for this interaction and a possible explanation for the peculiar ability of CYC, unlike CUR and THC, to interact directly with A β (25–35), either in solution or in the liposomal environment. Indeed, according to the results of our molecular modeling studies, this result is due to the constrained “semi-folded” conformation of CYC, which allows it to mimic the orientation of the hydrophobic side chains of short peptide motifs, similarly to our previous observations for other small ligands6869. Thus, by mimicking the orientation of the i, i + 4, and i + 7 residues of an α-helix, CYC could interact with A β (25–35), reproducing the pattern observed in α-helical coiled-coil structures, the latter being characterized by the presence of one of the principal dimerization motifs in proteins70.…”

Apoptosis Therapy in Cancer: The First Single-molecule Co-activating p53 and the Translocator Protein in Glioblastoma

“…AIDA makes use of two-dimensional 15 N-HSQC spectra, however, in the presence of flexible protein residues, 1D proton NMR spectra may be sufficient for monitoring the states of the complex upon addition of ligands. Since the N-terminal domain of p53 is highly flexible, MDM2/p53 complex is suitable for 1D proton NMR application262829. Particularly, the signals from N H ε side chains of W23 and W53 are sharp in the free p53 1D proton spectrum.…”

“…The assay was also validated using different concentration of human recombinant MDM2/p53 complex (Figure 5B). As reference compounds, the two characterized MDM2 inhibitors, Nutlin-3 and ISA27 were used1629. As depicted in Figure 5C, both Nutlin-3 and ISA27 dissociated the MDM2/p53 complex, with IC 50 values of 108.0 ± 4.5 nM and 121.7 ± 14.5 nM, respectively.…”

Discovery of Novel Isatin-Based p53 Inducers

“…The p53-binding part of MDM2 is rigid, and its solved structure is widely used in molecular docking studies. 13 Most of the MDM2 inhibitors mimic the structure of the TAD1 α-helix 14 and hence form the same intermolecular contacts with the hydrophobic MDM2 pocket as the original p53. An alternative concept of stapled peptides was shown to be a successful strategy in attempts to inhibit MDM2.…”