In this work we have investigated hydration properties of aqueous solutions up to a solute molar fraction X 2 ¼ 0.125 of two isosteric molecules -the bioprotectant trimethylamine-N-oxide (TMAO) and the denaturant tert-butyl alcohol (TBA) -using molecular dynamics simulation at 298 K. Statistical analyses of the trajectories show in particular that as the solute concentration increases the number of the water molecules in the first hydration shell decreases uniformly for TMAO, while for TBA it decreases more rapidly in a concentration range where experiments indicate that TBA starts to self-aggregate. No appreciable solute segregation occurs for TMAO even in the most concentrated solution, where on the average each water molecule is shared by two solutes. This result parallels what has been recently found for glycine betaine, an organic osmolyte closely related to TMAO.

A novel series of β-lactam derivatives that was designed and synthesized to target RGD-binding and leukocyte integrins is reported. The compound library was evaluated by investigating the effects on integrin-mediated cell adhesion and cell signaling in cell lines expressing αβ, αβ, αβ, αβ, αβ, αβ, and αβ integrins. SAR analysis of the new series of azetidinones enabled the recognition of structural elements associated with integrin selectivity. We obtained selective and potent agonists that could induce cell adhesion and promote cell signaling mediated by αβ, αβ, αβ, or αβ integrin, and antagonists for the integrins αβ and αβ as well as αβ and αβ, preventing the effects elicited by the respective endogenous agonists.

Orbitals which are extremely localized on molecular fragments represent a powerful tool for a number of purposes: just to cite a few examples, they allow to strongly reduce the complexity of calculations on large systems and they are easily transferable from one molecule to another one, providing a suitable and efficient way to build up the electronic structure of large molecules. Recently, we have developed efficient algorithms to determine Extremely Localized Molecular Orbitals (ELMOs) that will be reviewed in this paper.As a rigorous localization is strictly connected to a reduction in the number of variational parameters, which reflects into an increased value of the associated energy with respect to the Hartree Fock value, we have developed a number of strategies to relax the wavefunction built up using transferred localized orbitals.The extreme localization has also been exploited in connection with the 'Divide & Conquer' technique to determine large polypeptides electron densities assembled from orbitals computed on small model molecules.Moreover, we will discuss the recent application of the ELMOs in the framework of the hybrid QM/MM methods to describe the frontier region.We will also show that the ELMOs can be used to extract chemical interpretations from numerical results.A variety of applications will be presented.

We report the synthesis of novel chelates of Gd and (68)Ga with DPTA, DOTA, HP-DOA3, as well as with AAZTA, a novel chelating agent developed by our research group. These chelating agents were appropriately conjugated, prior to metal complexation, with DB58, an RGD peptidomimetic, conformationally constrained on an azabicycloalkane scaffold and endowed with high affinity for integrin α(ν)β(3) . Because α(ν)β(3) is involved in neo-angiogenesis in solid tumors and is also directly expressed in cancer cells (e.g. glioblastomas, melanomas) and ovarian, breast, and prostate cancers, these constructs could prove useful as molecular imaging probes in cancer diagnosis by MRI or PET techniques. Molecular modeling, integrin binding assays, and relaxivity assessments allowed the selection of compounds suitable for multiple expression on dendrimeric or nanoparticulate structures. These results also led us to an exploratory investigation of (68)Ga complexation for the promising (68)Ga-PET technique; the AAZTA complex 15((68)Ga) exhibited uptake in a xenograft model of glioblastoma, suggesting potentially useful developments with new probes with improved affinity.

Cyclic RGD-containing functionalized azabicycloalkane peptides were synthesized with the aim of developing high-affinity selective integrin ligands as carriers for therapeutic and diagnostic purposes. Herein we describe the synthesis and in vitro screening of these RGD derivatives, as well as the determination of their conformational properties in solution by spectroscopic and computational methods. Docking studies with the X-ray crystal structure of the extracellular domain of integrin alpha(v)beta(3) were also performed to elucidate the structural binding requirements and to rationalize the biological results. One compound in particular was found to be the best alpha(v)beta(3) integrin binder (IC(50)=53.7 nM) among the new functionalized RGD cyclic peptides, thus emerging as a promising candidate for covalent bonding and selective homing of useful functional units.

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A library of 19 binol-derived chiral monophosphites that contain a phthalic acid diamide group (PhthalaPhos) has been designed and synthesized in four steps. These new ligands were screened in the rhodium-catalyzed enantioselective hydrogenation of prochiral dehydroamino esters and enamides. Several members of the library showed excellent enantioselectivity with methyl 2-acetamido acrylate (6 ligands gave >97% ee), methyl (Z)-2-acetamido cinnamate (6 ligands gave >94% ee), and N-(1-phenylvinyl)acetamide (9 ligands gave >95% ee), whilst only a few representatives afforded high enantioselectivities for challenging and industrially relevant substrates N-(3,4-dihydronaphthalen-1-yl)-acetamide (96% ee in one case) and methyl (E)-2-(acetamidomethyl)-3-phenylacrylate (99% ee in one case). In most cases, the new ligands were more active and more stereoselective than their structurally related monodentate phosphites (which are devoid of functional groups that are capable of hydrogen-bonding interactions). Control experiments and kinetic studies were carried out that allowed us to demonstrate that hydrogen-bonding interactions involving the diamide group of the PhthalaPhos ligands strongly contribute to their outstanding catalytic properties. Computational studies carried out on a rhodium precatalyst and on a conceivable intermediate in the hydrogenation catalytic cycle shed some light on the role played by hydrogen bonding, which is likely to act in a substrate-orientation effect.