DataSheet1_An unprecedented palladium-arsenic catalytic cycle for nitriles hydration.docx

An unprecedented palladium/arsenic-based catalytic cycle for the hydration of nitriles to the corresponding amides is here described. It occurs in exceptionally mild conditions such as neutral pH and moderate temperature (60°C). The versatility of this new catalytic cycle was tested on various nitriles from aliphatic to aromatic. Also, the effect of ring substitution with electron withdrawing and electron donating groups was investigated in the cases of aromatic nitriles, as well as the effect of potentially interferent functional groups such as hydroxy group or pyridinic nitrogen. Furthermore, a pilot study on the potential suitability of this approach for its scale-up is presented, revealing that the catalytic cycle could be potentially and quickly scaled up.</p

Structural Characterization of a Gold/Serum Albumin Complex

The medicinal gold­(III) dithiocarbamato complex AuL12 forms a stable adduct with bovine serum albumin. The crystal structure reveals that a single gold­(I) center is bound to Cys34, with the dithiocarbamato ligand being released. To the best of our knowledge, this is the first structure for a gold adduct of serum albumin

Dioxygen Oxidation Cu(II) → Cu(III) in the Copper Complex of <i>cyclo</i>(Lys‑dHis-βAla-His): A Case Study by EXAFS and XANES Approach

A former spectroscopic study of Cu­(II) coordination by the 13-membered ring cyclic tetrapeptide <i>c</i>(Lys-dHis-βAla-His) (DK13), revealed the presence, at alkaline pH, of a stable peptide/Cu­(III) complex formed in solution by atmospheric dioxygen oxidation. To understand the nature of this coordination compound and to investigate the role of the His residues in the Cu­(III) species formation, Cu K-edge XANES, and EXAFS spectra have been collected for DK13 and two other 13-membered cyclo-peptides: the diastereoisomer <i>c</i>(Lys-His-βAla-His) (LK13), and <i>c</i>(Gly-βAla-Gly-Lys) (GK13), devoid of His residues. Comparison of pre-edge peak features with those of Cu model compounds, allowed us to get information on copper oxidation state in two of the three peptides, DK13 and GK13: DK13 contains only Cu­(III) ions in the experimental conditions, while GK13 binds only with Cu­(II). For LK13/Cu complex, EXAFS spectrum suggested and UV–vis analysis confirmed the presence of a mixture of Cu­(II) and Cu­(III) coordinated species. Theoretical XANES spectra have been calculated by means of the MXAN code. The good agreement between theoretical and experimental XANES data collected for DK13, suggests that the refined structure, at least in the first coordination shell around Cu, is a good approximation of the DK13/Cu­(III) coordination species present at strongly alkaline pH. All the data are consistent with a slightly distorted pyramidal CuN₄ unit, coming from the peptide bonds. Surprisingly, the His side-chains seemed not involved in the final, stable, Cu­(III) scaffold

Biotin Derivatives Carrying Two Chelating DOTA Units. Synthesis, in Vitro Evaluation of Biotinidases Resistance, Avidin Binding, and Radiolabeling Tests

The synthesis of four biotin derivatives carrying two DOTA moieties for each ligand (BisDOTA set) is reported, for increasing radiation/dose ratio and improving efficiency in the pretargeted avidin−biotin radioimmunotherapy. The biotin-containing scaffold of two BisDOTA was similar to the mono-DOTA derivative previously described. Then the scaffold was elongated by trifunctionalized spacers of different length and conjugated with one of the COOH groups of two DOTA. Two others were prepared starting from a on-resin lysine residue. The lysine α-NH2 was bonded to biotin, and then spacers were appended to the ε-NH2 and conjugated with two DOTA molecules. One compound contained a p-aminobenzoic acid spacer, which ensured higher head-to-tail distance and increased rigidity of the chain. These last two compounds had a very high ability to bond avidin and were labeled with 90Y at high specific activity. All the compounds were resistant to the action of serum biotinidases

Mechanistic Evaluations of the Effects of Auranofin Triethylphosphine Replacement with a Trimethylphosphite Moiety

Auranofin, a gold(I)-based complex, is under clinical trials for application as an anticancer agent for the treatment of nonsmall-cell lung cancer and ovarian cancer. In the past years, different derivatives have been developed, modifying gold linear ligands in the search for new gold complexes endowed with a better pharmacological profile. Recently, a panel of four gold(I) complexes, inspired by the clinically established compound auranofin, was reported by our research group. As described, all compounds possess an [Au{P(OMe)3}]+ cationic moiety, in which the triethylphosphine of the parent compound auranofin was replaced with an oxygen-rich trimethylphosphite ligand. The gold(I) linear coordination geometry was complemented by Cl–, Br–, I–, and the auranofin-like thioglucose tetraacetate ligand. As previously reported, despite their close similarity to auranofin, the panel compounds exhibited some peculiar and distinctive features, such as lower log P values which can induce relevant differences in the overall pharmacokinetic profiles. To get better insight into the P–Au strength and stability, an extensive study was carried out for relevant biological models, including three different vasopressin peptide analogues and cysteine, using 31P NMR and LC-ESI-MS. A DFT computational study was also carried out for a better understanding of the theoretical fundamentals of the disclosed differences with regard to triethylphosphine parent compounds

New Copper(II)/Cyclic Tetrapeptide System That Easily Oxidizes to Copper(III) under Atmospheric Oxygen

A 13-membered ring cyclic tetrapeptide was synthesized by the solid-phase peptide synthesis method, and its copper(II) coordination properties were analyzed by optical spectroscopy, mass spectrometry, and electrochemistry. All collected data strongly support the presence, at alkaline pH, of a stable peptide/copper(III) complex that is formed in solution by atmospheric dioxygen oxidation. On the basis of previous studies on cyclic peptide/copper systems, we suggest that the copper(III) ion is at the center of the ligand's cavity being coordinated to four deprotonated amide nitrogen atoms. This donor set would greatly lower the redox potential for the CuIII/CuII couple, thus allowing easy oxidation of the coordinated copper(II) by atmospheric oxygen

Neurotrophic Activity and Its Modulation by Zinc Ion of a Dimeric Peptide Mimicking the Brain-Derived Neurotrophic Factor N‑Terminal Region

Brain-derived neurotrophic factor (BDNF) is a neurotrophin (NT) essential for neuronal development and synaptic plasticity. Dysregulation of BDNF signaling is implicated in different neurological disorders. The direct NT administration as therapeutics has revealed to be challenging. This has prompted the design of peptides mimicking different regions of the BDNF structure. Although loops 2 and 4 have been thoroughly investigated, less is known regarding the BDNF N-terminal region, which is involved in the selective recognition of the TrkB receptor. Herein, a dimeric form of the linear peptide encompassing the 1–12 residues of the BDNF N-terminal (d-bdnf) was synthesized. It demonstrated to act as an agonist promoting specific phosphorylation of TrkB and downstream ERK and AKT effectors. The ability to promote TrkB dimerization was investigated by advanced fluorescence microscopy and molecular dynamics (MD) simulations, finding activation modes shared with BDNF. Furthermore, d-bdnf was able to sustain neurite outgrowth and increase the expression of differentiation (NEFM, LAMC1) and polarization markers (MAP2, MAPT) demonstrating its neurotrophic activity. As TrkB activity is affected by zinc ions in the synaptic cleft, we first verified the ability of d-bdnf to coordinate zinc and then the effect of such complexation on its activity. The d-bdnf neurotrophic activity was reduced by zinc complexation, demonstrating the role of the latter in tuning the activity of the new peptido-mimetic. Taken together our data uncover the neurotrophic properties of a novel BDNF mimetic peptide and pave the way for future studies to understand the pharmacological basis of d-bdnf action and develop novel BDNF-based therapeutic strategies