A Library Approach to the Development of BenzaPhos, Highly Efficient Chiral Supramolecular Ligands for Asymmetric Hydrogenation

A library of chiral supramolecular ligands named BenzaPhos, of straightforward preparation (two steps from commercial or readily available starting materials) and modular structure, was designed and synthesized. The ligands were screened in the search of new rhodium catalysts for the enantioselective hydrogenation of several benchmark and industrially relevant substrates. Once a series of hits were identified, structural modifications were introduced on three of the best ligands and a small second-generation library was created. Members of the latter showed outstanding levels of activity and enantioselectivity in the hydrogenation of challenging olefins such as enamide S4 and beta-dehydroamino ester S5 (> 99% ee: best value ever reported in both cases). A series of control experiments were undertaken in order to clarify the role of hydrogen bonding in determining the catalytic properties of the new ligands. The results of these experiments, together with those of computational studies carried out on four dihydride complexes involved in the catalytic hydrogenation of substrate S4, strongly suggest that a substrate orientation takes place in the catalytic cycle by formation of a hydrogen bond between the ligand amide oxygen and the substrate amide NH

Riding the Wave of Monodentate Ligand Revival : from the A/B Concept to Noncovalent Interactions

The rediscovery of chiral monodentate ligands made in the period 1999\u20132003 had important consequences in enantioselective transition-metal catalysis, such as the introduction of the A/B concept (i.e., use of monodentate ligand mixtures) and, later, a renewed interest in supramolecular ligands capable of ligand\u2013ligand and ligand\u2013substrate interactions. This Personal Account summarizes the contributions made by our research group in this area in the period 2004\u20132015, which reflect the abovementioned developments. Within this area, we introduced some original concepts, such as 1) the use of chiral tropos ligand mixtures; 2) the development of new strategies to maximize heterocomplex formation from combinations of simple monodentate ligands; 3) the investigation of new ligand\u2013ligand interactions to achieve selective heterocomplex formation; and 4) the development of highly efficient and synthetically accessible supramolecular ligands

Rhodium-catalyzed asymmetric hydrogenation of olefins with PhthalaPhos, a new class of chiral supramolecular ligands

A library of 19 binol-derived chiral monophosphites that contain a phthalic acid diamide group (Phthala- Phos) 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. \ua9 2012 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim

Disordering of InGaAs/GaAs strained quantum well structures induced by rare gas ion implantation

In this work we have investigated the effect of various implantation schemes on In(0.2)GaAs/GaAs/AlGaAs Single Quantum Well, where the implanted species are Argon and Helium, with doses in the range 1E12 to 1E14 at cm^2, at energy spanning 270 - 400 KeV and 30 to 50 KeV for Ar and He, respectively. Repetitive annealing processes were carried out between 735 and 870 degree(s)C and the interdiffusion was deduced by photoluminescence measurements. A maximum of 20 nm shift from He ion implanted Quantum Well with an high degree of reconstruction has been recorded, thus allowing the application of this disordering scheme for the realization of optoelectronic devices

Taking care of systemic sclerosis patients during COVID-19 pandemic : rethink the clinical activity

COVID-19 outbreak has quickly spread worldwide, causing a high pressure on the health-care system. In Italy, from March 8, 2020, all the deferrable clinical activities have been suspended to increase the health care offer for COVID-19 patients. The hospital organization has been modified also in order to assure non-COVID-19 patients assistance. The Scleroderma Unit of ASST Pini-CTO Hospital, in Milan, in the region mostly hit by SARS-CoV-2 in Italy, follows more than 600 patients affected by systemic sclerosis (SSc). Patients with SSc need a close follow-up with a regular screening of organ involvement and frequent intravenous treatments. All SSc patients have been educated about ministerial directives to limit COVID-19 spread. The organization of our Scleroderma Unit has been quickly rethought to assure SSc patients assistance in safety for them and for health-care workers during urgent visits or infusion therapies. Using electronic way of communication with frequent virtual contact and guarantying home deliveries of some therapies, we allowed a continuity of care also outside the Hospital

Istruzione terziaria e finanziamenti pubblici: un’opportunità di crescita?

Luca Bonacini, Giuseppe Pignataro e Cristina Specchi in relazione alle politiche universitarie, centrali anche per il PNRR, sottolineano l’importanza di un loro orientamento ad accrescere l’attrattività dell’università e, in questa prospettiva, della riduzione del divario tra Nord e Sud, tra centro e periferia

New Insight on Medieval Painting in Sicily: The Virgin Hodegetria Panel in Monreale Cathedral (Palermo, Italy)

: The Virgin Hodegetria, located in the Cathedral of Santa Maria Nuova in Monreale, near Palermo (Italy), probably dating the first half of the 13th century, is one of the earliest examples of medieval panel painting in Sicily. A diagnostic campaign was carried out on the panel aiming to identify the constituting materials and the executive technique, as well as to assess the state of conservation for supporting the methodological choice of the restoration intervention. Both non invasive (X-ray radiography, digital microscope, multispectral imaging, ED-X-ray fluorescence) and micro-invasive (polarised light microscopy, ESEM-EDX, ATR-FTIR spectroscopy and micro-Raman spectroscopy) analyses were performed. According to the results, the executive technique followed the 13th–14th-century Italian painting tradition. A complex structure was applied on the wooden support, consisting of a double layer of canvas and several ground layers of gypsum and glue based binder. The underdrawing was made by a brush using carbonaceous black pigment. The original palette includes red ochre, red lead, azurite, carbon black and bone black. During the several restorations, mercury-based red, indigo, smalt blue, orpiment and synthetic mars were used. The original silver leaf of the frame was covered with red tin-based lake and subsequently regilded with gold leaf. Proteinaceous and oil binders were also detecte

Yeast-Derived Formulations Are Differentially Fermented by the Canine and Feline Microbiome As Assessed in a Novel in Vitro Colonic Fermentation Model

The current study evaluated the effect of five yeast-derived formulations (T1-T5) on microbial metabolism and composition of the canine and feline gut microbiota using a novel in vitro colonic incubation approach. This novel in vitro model allowed for growth of the entire spectrum of dog- and cat-derived bacteria from the inoculum, thus offering an excellent platform to evaluate effects of nutritional interventions on the gut microbiota. Further, yeast-derived ingredients differentially increased production of acetate, propionate, butyrate, ammonium, and branched short-chain fatty acids, with T5 and T1 consistently stimulating propionate and butyrate, respectively. 16S-targeted Illumina sequencing coupled with flow cytometry provided unprecedented high-resolution quantitative insights in canine and feline microbiota modulation by yeast-derived ingredients, revealing that effects on propionate production were related to Prevotellaceae, Tannerellaceae, Bacteroidaceae, and Veillonellaceae members, while effects on butyrate production were related to Erysipelotrichaceae, Lachnospiraceae, Ruminococcaceae, and Fusobacteriaceae. Overall, these findings strengthen the health-promoting potential of yeast-derived ingredients

β-Glucuronidase triggers extracellular MMAE release from an integrin-targeted conjugate

A non-internalizing \u3b1v\u3b23 integrin ligand was conjugated to the anticancer drug MMAE through a \u3b2-glucuronidase-responsive linker. In the presence of \u3b2-glucuronidase, only the conjugate bearing a PEG4 spacer inhibited the proliferation of integrin-expressing cancer cells at low nanomolar concentrations, indicating important structural requirements for the efficacy of these therapeutics

Targeted acetylation of NF-kappaB/RelA and histones by epigenetic drugs reduces post-ischemic brain injury in mice with an extended therapeutic window.

Nuclear factor-kappaB (NF-κB) p50/RelA is a key molecule with a dual effect in the progression of ischemic stroke. In harmful ischemia, but not in preconditioning insult, neurotoxic activation of p50/RelA is characterized by RelA-specific acetylation at Lys310 (K310) and deacetylation at other Lys residues. The derangement of RelA acetylation is associated with activation of Bim promoter. Objective: With the aim of producing neuroprotection by correcting altered acetylation of RelA in brain ischemia, we combined the pharmacological inhibition of histone deacetylase (HDAC) 1-3, the enzymes known to reduce global RelA acetylation, and the activation of sirtuin 1, endowed with a specific deacetylase activity on the K310 residue of RelA. To afford this aim, we tested the clinically used HDAC 1-3 inhibitor entinostat (MS-275) and the sirtuin 1 activator resveratrol. Methods: We used the mouse model of transient middle cerebral artery occlusion (MCAO) and primary cortical neurons exposed to oxygen glucose deprivation (OGD). Results: The combined use of MS-275 and resveratrol, by restoring normal RelA acetylation, elicited a synergistic neuroprotection in neurons exposed to OGD. This effect correlated with MS-275 capability to increase total RelA acetylation and resveratrol capability to reduce RelA K310 acetylation through the activation of an AMP-activated protein kinase-sirtuin 1 pathway. The synergistic treatment reproduced the acetylation state of RelA peculiar of preconditioning ischemia. Neurons exposed to the combined drugs totally recovered the optimal histone H3 acetylation.Neuroprotection was reproduced in mice subjected to MCAO and treated with MS-275 (20μg/kg and 200μg/kg) or resveratrol (6800μg/kg) individually. However, the administration of lowest doses of MS-275 (2μg/kg) and resveratrol (68μg/kg) synergistically reduced infarct volume and neurological deficits. Importantly, the treatment was effective even when administered 7h after the stroke onset. Chromatin immunoprecipitation analysis of cortices harvested from treated mice showed that the RelA binding and histone acetylation increased at the Bcl-x L promoter and decreased at the Bim promoter. Conclusion: Our study reveals that epigenetic therapy shaping acetylation of both RelA and histones may be a promising strategy to limit post-ischemic injury with an extended therapeutic window