Alessandra Tolomelli

Targeting integrins αvβ3 and α5β1 with new β-lactam derivatives.

The αvβ3 and α5β1 integrins are widely expressed in different cancer types and recognize the tripeptide Arg-Gly-Asp (RGD) motif present in several extracellular matrix proteins. We report here the design, synthesis and biological activity of some new β-lactam derivatives specifically designed to target integrins. The new molecules contain the azetidinone as the only cyclic framework armed with carboxylic acid and amine terminals spaced from 9 to 14 atoms to switch on recognition by integrins. All tested molecules showed a concentration-dependent enhancement in fibronectin-mediated adhesion of K562 and SK-MEL-24xa0cells; in particular 1, expressed a higher affinity towards α5β1 integrin (EC50 of 12xa0nM) and 2 was more selective for integrin αvβ3 (EC50 of 11xa0nM).

Spectroscopic fingerprints of DNA/RNA pyrimidine nucleobases in third-order nonlinear electronic spectra

Accurate ab initio modeling of spectroscopic signals in nonlinear electronic spectra, such as bidimensional (2D) spectra, requires the computation of the electronic transitions induced by the incoming pump/probe pulses, resulting in a challenging calculation of many electronic excited states. A protocol is thus required to evaluate the variations of spectral properties, like transition energies and dipole moments, with the computational level, and to estimate the sensitivity of the spectra to these variations. Such a protocol is presented here within the framework of complete and restricted active space self-consistent field (CASSCF/RASSCF) theory and its second-order perturbation theory extensions (CASPT2/RASPT2). The electronic excited-state manifolds of pyrimidine nucleobases (thymine, uracil, and cytosine) are carefully characterized in vacuo employing high-level RAS(0,0|10,8|2,12)//SS-RASPT2 calculations. The results provide a reference data set that can be used for optimizing computational efforts and costs, as required for studying computationally more demanding multichromophoric systems (e.g., di- and oligonucleotides). The spectroscopic signatures of the 2D electronic spectrum of a perfectly stacked uracil–cytosine dimer model are characterized, and experimental setups are proposed that can resolve non-covalent interchromophoric interactions in canonical pyrimidine nucleobase-stacked dimers.

Integrin Ligands with α/β-Hybrid Peptide Structure: Design, Bioactivity, and Conformational Aspects.

Integrins are cell surface receptors for proteins of the extracellular matrix and plasma‐borne adhesive proteins. Their involvement in diverse pathologies prompted medicinal chemists to develop small‐molecule antagonists, and very often such molecules are peptidomimetics designed on the basis of the short native ligand‐integrin recognition motifs. This review deals with peptidomimetic integrin ligands composed of α‐ and β‐amino acids. The roles exerted by the β‐amino acid components are discussed in terms of biological activity, bioavailability, and selectivity. Special attention is paid to the synthetic accessibility and efficiency of conformationally constrained heterocyclic scaffolds incorporating α/β‐amino acid span.

Synthesis and assay of retro-α4β1 integrin-targeting motifs

In recent years, several research groups proposed new peptidomimetic antagonists of integrins αvβ3, α5β1, αIIbβ3, αvβ6, αvβ5, etc. based on retro sequences of the classic integrin-binding motif RGD. The retro strategy is still largely ignored for the non-RGD-binding α4β1 integrin. Herein we present the first examples of retro sequences for targeting this integrin, composed of Asp or isoAsp equipped with an aromatic cap at the N-terminus, (S)-pyrrolidine-3-carboxylic acid (β(2)-Pro) as a constrained core, and the amino variant (AMPUMP) of the well-known α4-targeting diphenylurea MPUPA. We discuss α4β1 receptor affinity (SPA), cell adhesion assays, stability in mouse serum, and conformational analysis. For their significant ability to inhibit cell adhesion and remarkable stability, the retro-peptide mimetics BnCO-Asp-β-Pro-AMPUMP (3) and BnCO-isoAsp-β-Pro-AMPUMP (4) represent promising candidates for designing small molecules as potential anti-inflammatory agents.

In-peptide synthesis of di-oxazolidinone and dehydroamino acid–oxazolidinone motifs as β-turn inducers

Small and easy-to-do mimetics of β-turns are of great interest to interfere with protein-protein recognition events mediated by β-turn recognition motifs. We propose a straightforward procedure for constraining the conformation of tetrapeptides lacking a pre-formed scaffold. According to the stereochemistry array, N-Ts tetrapeptides including Thr or PhSer (phenylserine) at the positions 2 or 3 gave rise in a single step to the sequences Oxd(2)-Oxd(3) or ΔAbu(2)-Oxd(3) (Oxd, oxazolidin-2-one; ΔAbu, 2,3-dehydro-2-aminobutyric). These pseudo-Pro residues displayed highly constrained ϕ, ψ, and χ dihedral angles, and induced clear β-turns or inverse turns of type I or II, as determined by extensive spectroscopic and computational analyses.

New isoxazolidinone and 3,4-dehydro-β-proline derivatives as antibacterial agents and MAO-inhibitors: A complex balance between two activities

Among the different classes of antibiotics, oxazolidinone derivatives represent important drugs, since their unique mechanism of action overcomes commonly diffused multidrug-resistant bacteria. Anyway, the structural similarity of these molecules to monoamino oxidase (MAO) inhibitors, like toloxatone and blefoxatone, induces in many cases loss of selectivity as a major concern. A small library of compounds based on isoxazolidinone and dehydro-β-proline scaffold was designed with the aim to obtain antibacterial agents, evaluating at the same time the potential effects of structural features on MAO inhibitory behaviour. The structural modification introduced in the backbone, starting from Linezolid model, lead to a significant loss in antibiotic activity, while a promising inhibitory effect could be observed on monoamino oxidases. These interesting results are also in agreement with docking experiments suggesting a good binding pose of the synthesized compounds into the pocket of the oxidase enzymes, in particular of MAO-B.

Can Integrin Agonists Have Cards to Play against Cancer? A Literature Survey of Small Molecules Integrin Activators

The ability of integrins to activate and integrate intracellular communication illustrates the potential of these receptors to serve as functional distribution hubs in a bi-directional signal transfer outside-in and inside-out of the cells. Tight regulation of the integrin signaling is paramount for normal physiological functions such as migration, proliferation, and differentiation, and misregulated integrin activity could be associated with several pathological conditions. Because of the important roles of integrins and their ligands in biological development, immune responses, leukocyte traffic, haemostasis, and cancer, their potential as therapeutic tools is now widely recognized. Nowadays extensive efforts have been made to discover and develop small molecule ligands as integrin antagonists, whereas less attention has been payed to agonists. In recent years, it has been recognized that integrin agonists could open up novel opportunities for therapeutics, which gain benefits to increase rather than decrease integrin-dependent adhesion and transductional events. For instance, a significant factor in chemo-resistance in melanoma is a loss of integrin-mediated adhesion; in this case, stimulation of integrin signaling by agonists significantly improved the response to chemotherapy. In this review, we overview results about small molecules which revealed an activating action on some integrins, especially those involved in cancer, and examine from a medicinal chemistry point of view, their structure and behavior.