[18F]-Radiolabelled Nanoplatforms: A Critical Review of Their Intrinsic Characteristics, Radiolabelling Methods, and Purification Techniques.

A wide range of nano-objects is found in many applications of our everyday life. Recognition of their peculiar properties and ease of functionalization has prompted their engineering into multifunctional platforms that are supposed to afford efficient tools for the development of biomedical applications. However, bridging the gap between bench to bedside cannot be expected without a good knowledge of their behaviour in vivo, which can be obtained through non-invasive imaging techniques, such as positron emission tomography (PET). Their radiolabelling with [18F]-fluorine, a technique already well established and widely used routinely for PET imaging, with [18F]-FDG for example, and in preclinical investigation using [18F]-radiolabelled biological macromolecules, has, therefore, been developed. In this context, this review highlights the various nano-objects studied so far, the reasons behind their radiolabelling, and main in vitro and/or in vivo results obtained thereof. Then, the methods developed to introduce the radioelement are presented. Detailed indications on the chemical steps involved are provided, and the stability of the radiolabelling is discussed. Emphasis is then made on the techniques used to purify and analyse the radiolabelled nano-objects, a point that is rarely discussed despite its technical relevance and importance for accurate imaging. The pros and cons of the different methods developed are finally discussed from which future work can develop.

Chiral Benzothiazole Monofluoroborate Featuring Chiroptical and Oxygen-Sensitizing Properties: Synthesis and Photophysical Studies.

Advances in personalized medicine are prompting the development of multimodal agents, that is, molecules that combine properties promoting various diagnostic and therapeutic applications. General approaches exploit chemical conjugation of therapeutic agents with contrast agents or the design of multimodal nanoplatforms. Herein, we report the design of a single molecule that exhibits potential for different diagnostic modes as well as the ability to sensitize oxygen, thus offering potential for photodynamic therapy. Exceptionally, this work involves the synthesis and chiral resolution of an enantiomeric pair of chiral monofluoroborates that contain a stereogenic boron atom. Combining experimental and theoretical chiroptical studies allowed the unambiguous determination of their absolute configuration. Photophysical investigations established the ability of this compound to sensitize oxygen even in the absence of heavy atoms within its structure. The synthesis of a chiral benzothiazole monofluoroborate paves a way to multimodal diagnostic tools (fluorescence and nuclear imaging) while also featuring potential therapeutic applications owing to its ability to activate oxygen to its singlet state for use in photodynamic therapy.

Expanding the Balz-Schiemann Reaction: Organotrifluoroborates Serve as Competent Sources of Fluoride Ion for Fluoro-Dediazoniation.

The Balz-Schiemann reaction endures as a method for the preparation of (hetero)aryl fluorides yet is eschewed due to the need for harsh conditions or high temperatures along with the need to isolate potentially explosive diazonium salts. In a departure from these conditions, we show that various organotrifluoroborates (RBF3 - s) may serve as fluoride ion sources for solution-phase fluoro-dediazoniation in organic solvents under mild conditions. This methodology was successfully extended to a one-pot process obviating aryl diazonium salt isolation. Sterically hindered (hetero)anilines are fluorinated under unprecedentedly mild conditions in good-to-excellent yields. Taken together, this work expands the repertoire of RBF3 - s to act as fluorine ion sources in an update to the classic Balz-Schiemann reaction.

Metal-Free Intermolecular Azide-Alkyne Cycloaddition Promoted by Glycerol.

Metal-free intermolecular Huisgen cycloadditions using nonactivated internal alkynes have been successfully performed in neat glycerol, both under thermal and microwave dielectric heating. In sharp contrast, no reaction occurs in other protic solvents, such as water, ethanol, or diols. DFT calculations have shown that the BnN3/glycerol adduct promotes a more important stabilization of the corresponding LUMO than that produced in the analogous BnN3/alcohol adducts, favoring the reactivity with the alkyne in the first case. The presence of copper salts in the medium did not change the reaction pathway (Cu(I) acts as spectator), except for disubstituted silylalkynes, for which desilylation takes place in contrast to the metal-free system.

The benzazole scaffold: a SWAT to combat Alzheimer's disease.

Neurodegenerative disorders including Alzheimer's disease (AD) are drawing scientists' attention within various fields, being one of the most serious diseases mankind will have to fight against in the very near future. AD is multi-factorial and is characterized by two histopathological hallmarks: the senile plaques made of amyloid-ß (Aß) peptide fibrils which also contain high levels of transition metal ions and the neurofibrillary tangles of Tau protein. Aß aggregation, possibly modulated by metal ions, is now considered as an important factor in AD aetiology. Hence, chemists are studying the details of molecular features at the origin of the disease with special interest in Aß aggregation and in the design of new molecules for the early diagnosis of AD or with curative properties. In this context, the benzazole molecular scaffold, included for instance in Thioflavin-T, an Aß fibril specific dye, or the PIB imaging agent, appears to be very attractive and exhibits multiple uses. In the present review, we have thus focused our interest on the applications of benzazole derivatives for understanding, diagnosing and curing AD. After having analysed the synthetic access to 2-arylbenzazoles, we have described a selection of recent applications of such compounds aiming to combat AD. They include the use of Thioflavin-T for the monitoring of Aß aggregation, the investigations of new PET and SPECT imaging agents for the detection of the senile plaques, the development of bi-functional molecules, encompassing the 2-arylbenzazole moiety for Aß binding and a chelating unit for metal ions coordination for instance.

2-Azahetaryl-2-(oxoindolin-2-ylidene)acetonitriles as Colorimetric Probes for Zn: Synthesis and Optical Properties.

A new one-pot approach for the synthesis of the Zn2+-sensitive probes 2-azahetaryl-2-(oxoindolin-2-ylidene)acetonitriles 3a-c and 4 is described. The method includes the in situ formation of imidoylchloride and its further condensation with azahetarylacetonitrile 1. The structure of the obtained compounds is studied using 1H nuclear magnetic resonance (NMR), 13C NMR, infrared (IR), high-resolution mass spectrometry (HRMS), and UV-Vis spectroscopy techniques. Two model ligands both exhibiting the highest extinction coefficient and the best solubility in a Tris buffer pH 7.2/dimethyl sulfoxide (DMSO) solution, namely 5-methyl-benzothiazole derivative 3b and benzoxazole derivative 4, are thoroughly studied as colorimetric probes for Zn2+. The probe 3b has the highest sensitivity to Zn2+, showing a limit of ion detection (LOD) calculated by the 3S criterion of 0.43 µM and selectivity upon masking Cu2+ ions with Na2S2O3. The composition of the complexes in the solution was determined by the limited logarithm method. The stability constant (lg K) values of 3b-Zn of 10.27 ± 0.02 and 4-Zn of 12.5 ± 0.2 indicate the formation of complexes of average stability.

Dioxazaborocanes: old adducts, new tricks.

Dioxazaborocanes are boronic adducts obtained by condensation of diethanolamine derivatives with boronic compounds. They were first described in the mid-1950's as a practical way to isolate a boronic adduct. Their use has for a long time been restricted to this purpose for the isolation and characterisation of either a final product or a boronic intermediate. Only recently have they been directly involved in chemical transformations in which they proved equivalent or superior to their acid counterpart. In the meantime they have also been used as protected boronic acids. We wish to show in this report that they will likely represent a fluoride-free alternative to organotrifluoroborate salts and therefore an area of intense development.

Ethyl 2-[N-(tert-butyl-sulfin-yl)carbamo-yl]benzoate.

The title compound, C(14)H(19)NO(4)S, was obtained in quanti-tative yield by Lewis acid-catalysed alcoholysis of a phtalimide precursor. An intra-molecular C-H⋯O hydrogen bond occurs. In the crystal, centrosymmetric dimers are formed by pairs of N-H⋯O hydrogen bonds between the sulfinyl O atoms and the carbamoyl N-H group of a neighboring mol-ecule. C-H⋯O inter-actions feature in the crystal structure.

Crystal structure of catena-poly[[[di-chlorido-copper(II)]-{µ-tert-butyl N-methyl-N-[4-(6-{[4-(pyridin-2-yl-κN)-1H-1,2,3-triazol-1-yl-κN3]meth-yl}-1,3-benzo-thia-zol-2-yl)phen-yl]carbamato}] aceto-nitrile monosolvate].

In the title coordination polymer, {[CuCl2(C27H26N6O2S)]·CH3CN} n , the copper(II) ion is fivefold coordinated, with an almost perfect square-pyramidal coordination sphere. In the equatorial plane, it is ligated to a pyridine N atom and an N atom of the triazole unit and to two Cl- ions, while the apical position is occupied by the carbonyl O atom of the tert-butyl carbamate group. In the crystal, the polymer chains propagate in the [11-1] direction, with the aceto-nitrile solvent mol-ecules linked to the chain by C-H⋯N hydrogen bonds. The chains are linked by C-H⋯Cl hydrogen bonds forming sheets parallel to the plane (011). The crystal packing is further consolidated by C-H⋯π inter-actions and offset π-π stacking inter-actions [inter-centroid distance = 3.6805 (15) Å], forming a three-dimensional supra-molecular structure.

Correction: A Robust and Efficient Production and Purification Procedure of Recombinant Alzheimers Disease Methionine-Modified Amyloid-ß Peptides.

[This corrects the article DOI: 10.1371/journal.pone.0161209.].

The Forgotten Nitroaromatic Phosphines as Weakly Donating P-ligands: An N-Aryl-benzimidazolyl Series in RhCl(CO) Complexes.

The coordination chemistry of a priori weakly σ-donating nitroaromatic phosphines is addressed through a series of nitro-substituted (N-phenyl-benzimidazol-1-yl)diphenylphosphines in RhI complexes. From a set of seven such phosphines L=Lxyz(') (x, y, z=0 or 1=number of NO2 substituents at the 5, 6 and N-Ph para positions, respectively), including the non-nitrated parent L000 and its dicationic N-methyl counterpart L000 ', three LRhCl(COD) and seven L2 RhCl(CO) complexes have been obtained in 72-95 % yield. Despite of a cis orientation of the L and CO ligands, the C=O IR stretching frequency νCO varies in the expected sense, from 1967±1 cm-1 for Lxy0 to 1978±1 cm-1 for Lxy1 , and 2005 cm-1 for L000 '. The 103 Rh NMR chemical shift δRh varies from -288 ppm for L000 to -316±1 ppm for L10z or L01z , and -436 ppm for L000 '. The νCO and δRh probes thus reveal moderate but systematic variations, and act as "orthogonal" spectroscopic indicators of the presence of nitro groups on the N-Ph group and the benzimidazole core, respectively. For the dicationic ligand L000 ', a tight electrostatic sandwiching of the Rh-Cl bond by the benzimidazole moities is evidenced by X-ray crystallography (RhClδ- ⋅⋅⋅CN2+ ≈3.01 Å). Along with the LRhCl(CO) complexes, dinuclear side-products (µ-CO)(RhClL)2 were also obtained in low spectroscopic yield: for the dinitro ligand L=L011 , a unique 1:6.7 clathrate structure, with dichloromethane as solvate, is also revealed by X-ray crystallography.

Expedited Route to Fully Substituted Amino-Pyrazole Building Blocks and Their Further Transformations.

We report here an efficient and easily reproducible two-step approach to heterocycle-substituted amino-pyrazoles from heterocyclic acetonitriles and their unprecedented subsequent transformations to fully substituted pyrazoles. Such transformations include regioselective derivatization from polyamino derivatives, formation of tetracyclic compounds in up to 45% overall yield, and deaminative transformations through diazotization, followed by arylation through Suzuki-Miyaura cross-coupling and C-H activation, providing arylated pyrazoles in up to 71% yield over four steps. This strategy allows the swift introduction of significant molecular complexity to a range of scaffolds.

[18F]-Fluoride capture and release: azeotropic drying free nucleophilic aromatic radiofluorination assisted by a phosphonium borane.

[18F]-Fluoride ready for aromatic nucleophilic substitution was prepared according to a simple process including trapping of aqueous [18F]-fluoride on a cartridge pre-loaded with the phosphonium borane [(Ph2MeP)C6H4(BMes2)]+, then releasing by elution of TBACN in dry acetonitrile. Subsequent radiofluorination was successfully applied to a model reaction and to the radiosynthesis of [18F]-setoperone.

A Robust and Efficient Production and Purification Procedure of Recombinant Alzheimers Disease Methionine-Modified Amyloid-ß Peptides.

An improved production and purification method for Alzheimer's disease related methionine-modified amyloid-ß 1-40 and 1-42 peptides is proposed, taking advantage of the formation of inclusion body in Escherichia coli. A Thioflavin-S assay was set-up to evaluate inclusion body formation during growth and optimize culture conditions for amyloid-ß peptides production. A simple and fast purification protocol including first the isolation of the inclusion bodies and second, two cycles of high pH denaturation/ neutralization combined with an ultrafiltration step on 30-kDa cut-off membrane was established. Special attention was paid to purity monitoring based on a rational combination of UV spectrophotometry and SDS-PAGE analyses at the various stages of the process. It revealed that this chromatography-free protocol affords good yield of high quality peptides in term of purity. The resulting peptides were fully characterized and are appropriate models for highly reproducible in vitro aggregation studies.

Naphthylaminoborane: from structural switches to frustrated Lewis pair reactivity.

A series of naphthyl-bridged amino-borane derivatives, namely 1-(dimethylamino)-8-naphthylboranes (1, 3, 5, 7) and 5-(dimethylamino)-6-acenaphthylboranes (2, 4, 6, 8, 10, 11), differing in the steric and electronic properties of the boryl moiety, have been synthesized and fully characterized by spectroscopic and crystallographic means. Structural X-ray analysis of the peri-atom displacement and ring torsion angles served to experimentally assess the presence and magnitude of the B-N interactions. The reversible quaternarization of nitrogen has been explored and was found to provide an efficient switch corresponding to different molecular organizations. The electronic characteristics of the nature of B-N interactions were further studied by Natural Bonding Orbital analysis derived from the theoretically calculated electron densities. This real-space bonding indicator discriminates the bonding B-N contact in 5 from the nonbonding in 8, which correlates with the flexibility of the naphthyl scaffold to respond to the Lewis acidity of boron allowing shorter peri interactions. Whereas, the steric shielding imposed by the two mesityl groups, and/or the rigidity of the acenaphthene framework disrupt B-N interaction. Thus, this communication reports on the modulation of the B-N bonding continuum by means of structural tuning leading to a molecular switch, as well as its implications towards revealing FLP reactivities through the isolation of intermediates of a stepwise mechanism.

A new water-soluble Cu(II) chelator that retrieves Cu from Cu(amyloid-ß) species, stops associated ROS production and prevents Cu(II)-induced Aß aggregation.

The synthesis of the H(2)L(2-) ligand (N,N'-Bis[(5-sulfonato-2-hydroxy)benzyl]-N,N'-dimethyl-ethane-1,2-diamine) and characterizations of the corresponding Cu(II) complex [Cu(L)(H(2)O)](2-) (1) by X-ray diffraction, EPR, UV-Visible and potentiometry are described. At pH 7.4, the affinity of Cu(II) for this ligand is approximately 4 × 10(14)M(-1). Coordination of redox active metal ions such as copper or iron to the amyloid-ß (Aß) peptide has been linked to deleterious processes encountered in the etiology of Alzheimer disease (AD), such as Aß aggregation and reactive oxygen species (ROS) production. In this context, the ability of the H(2)L(2-) to extract Cu(II) from Cu(Aß) species where Aß is the peptide involved in AD, is reported as well as its capacity to redox silence the Cu(Aß) induced ROS formation and to prevent Cu(II)-induced Aß aggregation. Such water soluble sulfonato-derivatives of Cu(II) chelators are very interesting counterparts for in vitro study of chelators' properties required to attend further biological applications as therapeutic tools against AD.

Base free aryl coupling of diazonium compounds and boronic esters: self-activation allowing an overall highly practical process.

Boronic esters have long been considered as poor partners in cross-coupling reactions with arene diazoniums. Here is reported an unprecedented application of self-activated boronic esters in a base-free cross-coupling reaction with diazonium salts under mild and user friendly conditions.