Synthesis and Characterization of a Luminescent Cyclic Poly(ethylene oxide)-Polypyridyl Ruthenium Complex.

We report the synthesis of a macrocyclic poly(ethylene oxide) (PEO) connected by one [Ru(bpy)3]2+ unit (where bpy = 2,2'-bipyridine), a photoactive metal complex that provides photosensitivity and potential biomedical applications to this polymer structure. The PEO chain provides biocompatibility, water solubility, and topological play. The macrocycles were successfully synthesized by copper-free click cycloaddition between a bifunctional dibenzocyclooctyne (DBCO)-PEO precursor and 4,4'-diazido-2,2'-bipyridine, followed by complexation with [Ru(bpy)2Cl2]. The cyclic product accumulated efficiently in MCF7 cancer cells and exhibited a longer fluorescence lifetime than its linear analogue, likely due to differences in the accessibility of the ligand-centered/intraligand states of Ru polypyridyls in both topologies.

Discovery of a novel family of FKBP12 "reshapers" and their use as calcium modulators in skeletal muscle under nitro-oxidative stress.

The hypothesis of rescuing FKBP12/RyR1 interaction and intracellular calcium homeostasis through molecular "reshaping" of FKBP12 was investigated. To this end, novel 4-arylthioalkyl-1-carboxyalkyl-1,2,3-triazoles were designed and synthesized, and their efficacy was tested in human myotubes. A library of 17 compounds (10a-n) designed to dock the FKBP12/RyR1 hot-spot interface contact residues, was readily prepared from free α-amino acids and arylthioalkynes using CuAAC "click" protocols amenable to one-pot transformations in high overall yields and total configurational integrity. To model nitro-oxidative stress, human myotubes were treated with the peroxynitrite donor SIN1, and evidence was found that some triazoles 10 were able to normalize calcium levels, as well as FKBP12/RyR1 interaction. For example, compound 10 b at 150 nM rescued 46% of FKBP12/RyR1 interaction and up to 70% of resting cytosolic calcium levels in human myotubes under nitro-oxidative stress. All compounds 10 analyzed showed target engagement to FKBP12 and low levels of cytotoxicity in vitro. Compounds 10b, 10c, 10h, and 10iR were identified as potential therapeutic candidates to protect myotubes in muscle disorders with underlying nitro-oxidative stress, FKBP12/RyR1 dysfunction and calcium dysregulation.

Fluorescent bicolour sensor for low-background neutrinoless double ß decay experiments.

Observation of the neutrinoless double ß decay is the only practical way to establish that neutrinos are their own antiparticles1. Because of the small masses of neutrinos, the lifetime of neutrinoless double ß decay is expected to be at least ten orders of magnitude greater than the typical lifetimes of natural radioactive chains, which can mimic the experimental signature of neutrinoless double ß decay2. The most robust identification of neutrinoless double ß decay requires the definition of a signature signal-such as the observation of the daughter atom in the decay-that cannot be generated by radioactive backgrounds, as well as excellent energy resolution. In particular, the neutrinoless double ß decay of 136Xe could be established by detecting the daughter atom, 136Ba2+, in its doubly ionized state3-8. Here we demonstrate an important step towards a 'barium-tagging' experiment, which identifies double ß decay through the detection of a single Ba2+ ion. We propose a fluorescent bicolour indicator as the core of a sensor that can detect single Ba2+ ions in a high-pressure xenon gas detector. In a sensor made of a monolayer of such indicators, the Ba2+ dication would be captured by one of the molecules and generate a Ba2+-coordinated species with distinct photophysical properties. The presence of such a single Ba2+-coordinated indicator would be revealed by its response to repeated interrogation with a laser system, enabling the development of a sensor able to detect single Ba2+ ions in high-pressure xenon gas detectors for barium-tagging experiments.

1,3-Dioxa-[3,3]-sigmatropic Oxo-Rearrangement of Substituted Allylic Carbamates: Scope and Mechanistic Studies.

An unexpected 1,3-dioxa-[3,3]-sigmatropic rearrangement during the treatment of aryl- and alkenyl-substituted allylic alcohols with activated isocyanates is reported. The reorganization of bonds is highly dependent on the electron density of the aromatic ring and the nature of isocyanate used. This metal-free tandem reaction from branched allyl alcohols initiated by a carbamoylation reaction and followed by a sigmatropic rearrangement thus offers a new access to ( E)-cinnamyl and conjugated ( E, E)-diene carbamates, such as N-acyl and N-sulfonyl derivatives. A computational study was conducted in order to rationalize this phenomenon, and a rearrangement progress kinetic analysis was performed.

Alkaloids Reactivity: DFT Analysis of Selective Demethylation Reactions.

All possible demethylation reactions of a diverse family of quaternary alkaloids by means of DFT calculations are here described. We aim to develop a rational model that allows the explanation of the high selectivity observed experimentally and predicts the occurrence of new alkaloid derivatives. To this end, we have performed a detailed analysis of the initial reagents and products. In addition, as a proof of concept, an experimentally unknown demethylation reaction of coralyne has been carried out, thus verifying the reliability of the theoretical model presented here.

Cooperative Catalysis with Coupled Chiral Induction in 1,3-Dipolar Cycloadditions of Azomethine Ylides.

1,3-Dipolar cycloadditions (1,3-DC) between imino esters (as precursors of N-metallated azomethine ylides) and π-deficient alkenes are promoted by cooperative asymmetric Lewis acid/Brønsted base catalysis. The components of these catalytic pairs are silver salts derived from enantiopure commercially available BINOL-based phosphoric acids and Cinchona alkaloids. Chiral phosphoric silver(I) salts promote HOMO raising of in situ formed 1,3-dipoles, whereas protonated cinchona alkaloids generate a LUMO lowering for the dipolarophiles resulting in a global acceleration of the 1,3-DC. The best results were obtained with BINOL-derived silver phosphate and hydrocinchonine. Matching between both cooperative metallo- and organocatalyst results in an enhanced enantiomeric excess, superior to that reached by both separate components. NOESY experiments and DFT calculations are compatible with a non-covalent interaction (hydrogen bond) between both catalysts, which results in close contacts and mutually coupled chiral environments.

Catalysis of a 1,3-dipolar reaction by distorted DNA incorporating a heterobimetallic platinum(ii) and copper(ii) complex.

A novel catalytic system based on covalently modified DNA is described. This catalyst promotes 1,3-dipolar reactions between azomethine ylides and maleimides. The catalytic system is based on the distortion of the double helix of DNA by means of the formation of Pt(ii) adducts with guanine units. This distortion, similar to that generated in the interaction of DNA with platinum chemotherapeutic drugs, generates active sites that can accommodate N-metallated azomethine ylides. The proposed reaction mechanism, based on QM(DFT)/MM calculations, is compatible with thermally allowed concerted (but asynchronous) [π4s + π2s] mechanisms leading to the exclusive formation of racemic endo-cycloadducts.

Linear and Cyclic Depsipeptidomimetics with ß-Lactam Cores: A Class of New αv ß3 Integrin Receptor Inhibitors.

The αv ß3 integrin receptor plays an important role in tumor metastasis and tumor-induced angiogenesis. The inhibition of this receptor with diverse ligands, antibodies, or cyclic peptides is a promising research field for the treatment of a variety of tumors. The replacement of Phe-(Me)Val dipeptide by a ß-lactam ring in Cilengitide has led to new products that show higher inhibitory activity than the parent cyclopeptide. In particular, substitution of a peptide bond ß-lactam-NH-Asp linkage by a ß-lactam-O-Asp ester linkage increases the activity of the new cyclodepsipeptide. In the same way it has been found that open-chain compounds of the form Asp-ß-lactam-Arg can interact with the receptor and inhibit its activity moderately. The integrin inhibitory activity of the synthesized compounds has been established by using the CGH array, a method that appears to be a more reliable trial than the classical adhesion test.

The underlying mechanisms for self-healing of poly(disulfide)s.

Recently, self-healing polymers based on disulfide compounds have gained attention due to the versatile chemistry of disulfide bonds and easy implementation into polymeric materials. However, the underlying mechanisms of disulfide exchange which induce the self-healing effect in poly(disulfide)s remain unclear. In this work, we elucidate the process of disulfide exchange using a variety of spectroscopic techniques. Comparing a model exchange reaction of 4-aminophenyl disulfide and diphenyl disulfide with modified reactions in the presence of additional radical traps or radical sources confirmed that the exchange reaction between disulfide compounds occurred via a radical-mediated mechanism. Furthermore, when investigating the effect of catalysts on the model exchange reaction, it could be concluded that catalysts enhance the disulfide exchange reaction through the formation of S-based anions in addition to the radical-mediated mechanism.

Site-Selective N-Dealkylation of 1,2,3-Triazolium Salts: A Metal-Free Route to 1,5-Substituted 1,2,3-Triazoles and Related Bistriazoles.

N3-Alkylation of 1-(pivaloyloxymethyl)-1,2,3-triazoles with alkyl triflates carrying latent "click" functionality, followed by a nucleophile-promoted N1-dealkylation of the resulting strongly electrophilic intermediate triazolium salts, provides an efficient route to 1,5-disubstituted 1,2,3-triazoles. The azide and alkyne groups incorporated by N-alkylation can be submitted to further copper-catalyzed azide-alkyne and Huisgen cycloadditions to provide bis(1,2,3-triazoles) with unprecedented 1,5/1,4 substitution patterns.

Cationic 1,2,3-Triazolium Alkynes: Components To Enhance 1,4-Regioselective Azide-Alkyne Cycloaddition Reactions.

4-Alkynyl-1,2,3-triazolium cations undergo thermal [3 + 2] cycloaddition reactions with azides roughly 50- to 100-fold faster than comparable noncharged alkynes. Further, the reaction is highly 1,4-regioselective (dr up to 99:1) owing to the selective stabilization of 1,4-TS transition states via conjugative π-acceptor assistance of the alkyne triazolium ring. The novel cationic triazolium alkynes also accelerate the CuAAC reaction to provide bis(1,2,3-triazoles) in an "ultrafast" way (<5 min).

Introducing axial chirality into mesoionic 4,4'-bis(1,2,3-triazole) dicarbenes.

Mesoionic 4,4'-bis(1,2,3-triazole-5,5'-diylidene) Rh(I) complexes having a C2 chiral 4,4'-axis were accessed from 3-alkyltriazolium salts in virtually complete de. Their structure and configurational integrity were assessed by NMR spectroscopy, X-ray crystallography, and chiral HPLC. Computational analysis of the MICs involved in the reaction suggested the formation of a highly stable and unprecedented cation-carbene intermediate species, which could be evidenced experimentally by cyclic voltammetry analysis.

Determination of additives in an electrolytic zinc bath by q1H-NMR spectroscopy.

The use of proton nuclear magnetic resonance ((1)H-NMR) for the quantification of additives in an electrolytic Zn bath is reported. A simple and quick method is described that does not need any prior sample preparation. Contrary to other analytical methods, the three additives in the bath, benzylidene acetone (BDA), benzoic acid (BA) and poly(ethylene glycol) (PE400), can be quantified. Two calibration methods were tried: integration of NMR signals with the use of an internal standard and partial least squares (PLS) regression applied to the characteristic NMR peaks. Both methods are compared and the univariate method was preferred because of simplicity, accuracy and precision. The following limits of detection were found: 0.30 g L(-1) BA, 0.08 g L(-1) BDA and 0.7 g L(-1) PE400 with dynamic ranges of at least 1.0-6.0, 0.1-0.6 and 3.0-18.0 g L(-1) respectively. Those concentration ranges are suitable to follow the concentration of additives in the bath in real time. (1)H-NMR spectra provide evidence for the BDA degradation pattern.

"Click" synthesis of nonsymmetrical bis(1,2,3-triazoles).

Unsymmetrically 1,1'-disubstituted 4,4'-bis-1H-1,2,3-triazoles 4 have been prepared from 4-ethynyl-1,2,3-triazoles 5 and azides. Following a "double-click" strategy, two complementary approaches were implemented for the preparation of the key 4-ethynyltriazole intermediates 5: (a) the stepwise Swern oxidation/Ohira-Bestman alkynylation of readily available 4-hydroxymethyl-1,2,3-triazoles 8 and (b) the stepwise cycloaddition of TMS-1,4-butadiyne 9. The method is highlighted by its compatibility with orthogonally protected and functionalized saccharide-peptide hybrids and its ability to be extended to the trisubstituted counterparts 12.

Mechanistic insights on the magnesium(II) ion-activated reduction of methyl benzoylformate with chelated NADH peptide beta-lactam models.

Mechanistic details of the Mg(2+) ion-activated enantioselective reduction of methyl benzoylformate have been investigated at a B3LYP/6-31G* theory level, using peptide NADH models 1 rigidified with a beta-lactam ring. Computation of the reaction pathway revealed important structural differences between the intermediate NADH/Mg(2+)/ArCOCO(2)R ternary complexes 3 and the corresponding transition states leading to enantiomeric methyl mandelates. Thus, ternary complexes showed the dihydronicotinamide moiety placed quasiequatorial to a seven-membered chelation pseudoplane including the two amide carbonyls and the Mg(2+) cation, whereas productive transition states were strongly deformed with the dihydronicotinamide group oriented quasiaxial to the chelation pseudoplane. This chelation model was further applied to acyclic nonrigidified NADH models and, based on the fluxional mobility of the peptide chain bonds, experimental enantioselectivities were correctly predicted. Parallel experiments were also conducted in deuterated acetonitrile, using NMR techniques, to study the structure of the binary complexes 2 (NADH/Mg(2+)) and ternary complexes 3 (NADH/Mg(2+)/PhCOCO(2)Me). Finally, owing to the incorporation of two diastereotopic trimethylsilyl NMR-tags in the beta-lactam-NADH peptidomimetics, a nonproductive ternary complex predicted by calculations could be observed and its structure characterized on the basis of ROESY experiments and molecular modeling.

Meningioma del surco olfatorio / Olfactory groove meningioma

Los meningiomas del surco olfatorio son tumores intracraneales infrecuentes. Suelen alcanzar gran tamaño antes de manifestarse clínicamente, siendo los síntomas más frecuentes los relacionados con la alteración de funciones corticales superiores. Es esencial llegar a un diagnóstico precoz cuando el tumor es relativamente pequeño (3 a 4 cm), para reducir su alta morbi-mortalidad, puesto que el avance en las técnicas de neuro-imagen no han sido suficientes para mejorar el pronóstico. Los signos precoces como edema de papila y/o cambios mentales, la anosmia permanente y la cefalea, desde el punto de vista del especialista de ORL, nos deben hacer sospechar una patología orgánica, descartando la presencia de una masa ocupante de espacio.

Meningiomas of the olfactory sulcus are rare intracranial tumors. They tend to reach a large size before showing clinically. Their most frequent symptoms are related to superior cortical functions. Early diagnose is essential when the tumor is still relatively small (3 to 4 cm), in order to reduce its high morbid-mortality rate, since the advance in neuro-image techniques has not been good enough to improve its prognosis. Early signs such as papilladema and/or cognitive changes and permanent anosmia and headache, from the ENT point of view should make us suspect an organic pathology, ruling out the presence of a space occupying mass.

Functionalization of N-[(silyl)methyl]-beta-lactam carbanions with carbon electrophiles.

Latent acidity of alpha-alkyl-alpha-amino-N-[(silyl)methyl]-beta-lactams enabled a concise entry to lithium nonenolate N-methyl-azetidinone carbanions lithiated alpha' to the beta-lactam nitrogen, owing to the stabilizing "alpha-effect" of one or two trimethylsilyl groups. (n)BuLi/TMEDA and (t)BuLi/TMEDA were the bases of choice for complete deprotonation of di- and monosilylated beta-lactams, respectively. Trapping of the resulting carbanions with alkyl halides provided the corresponding N-[(alpha'-silyl)-alkyl]-beta-lactams, while carbon dioxide and related electrophiles such as benzyl chloroformates or isocyanates, afforded the corresponding silicon-free N-carboxymethyl-, N-benzyloxycarbonylmethyl-, and N-amidomethyl-beta-lactams in a single synthetic step. Likely structures of these unprecedented lithiated N-[(silyl)methyl]-beta-lactams were studied by MO calculations (B3LYP/6-31G**), and the origin of their relative stability was briefly discussed.

Adenoma pleomorfo del paladar duro / Pleomorphic adenoma of the hard palate

Se expone el caso de un adenoma pleomorfo del paladarduro donde se verifica su incidencia familiar, lo que suponeel único caso publicado con estas características enla literatura universal

We report a case of a pleomorphic adenoma of the hardpalate with incidente in the same family. Such case esunique in the universal literature

Synthesis of type II beta-turn surrogate dipeptides based on syn-alpha-amino-alpha,beta-dialkyl-beta-lactams.

The achiral bis(trimethylsilyl)methyl group acts as an efficient stereochemical determinant of the alpha-alkylation reaction in beta-branched alpha-phenyloxazolidinyl- or alpha-diphenyloxazolidinyl-beta-lactams and provides the first stereocontrolled access to syn-alpha-amino-alpha,beta-dialkyl(aryl)-beta-lactams. These products are readily transformed into type II beta-turn mimetic surrogates 2B. [reaction: see text]

Practical Synthesis of alpha-Amino Acid N-Carboxy Anhydrides of Polyhydroxylated alpha-Amino Acids from beta-Lactam Frameworks. Model Studies toward the Synthesis of Directly Linked Peptidyl Nucleoside Antibiotics.

A straightforward method for the synthesis of polyhydroxylated alpha-amino acid N-carboxy anhydrides (NCAs) is described as the means by which short peptide segments comprised of a polyhydroxylated chain are easily affordable. The entire sequence lies in the preparation of nonracemic 3-hydroxy beta-lactams through the highly diastereoselective Staudinger reaction of hydroxyketene equivalents with chiral alpha-oxyaldehyde-derived imines, followed by TEMPO radical assisted cycloexpansion to the corresponding NCA and subsequent peptide coupling with alpha-amino acid esters. The method has been applied to the synthesis of short peptide segments derived from carbamoylpolyoxamic acid, some glycoglycines, as well as C(2) symmetric hydroxy amino acids.