Combining BNCT with carbonic anhydrase inhibition for mesothelioma treatment: Synthesis, in vitro, in vivo studies of ureidosulfamido carboranes.

Mesothelioma is a malignant neoplasm of mesothelial cells caused by exposure to asbestos. The average survival time after diagnosis is usually nine/twelve months. A multi-therapeutic approach is therefore required to treat and prevent recurrence. Boronated derivatives containing a carborane cage, a sulfamido group and an ureido functionality (CA-USF) have been designed, synthesised and tested, in order to couple Boron Neutron Capture Therapy (BNCT) and the inhibition of Carbonic Anhydrases (CAs), which are overexpressed in many tumours. In vitro studies showed greater inhibition than the reference drug acetazolamide (AZ). To increase solubility in aqueous media, CA-USFs were used as inclusion complexes of hydroxypropyl ß-cyclodextrin (HP-ß-CD) in all the inhibition and cell experiments. BNCT experiments carried out on AB22 (murine mesothelioma) cell lines showed a marked inhibition of cell proliferation by CA-USFs, and in one case a complete inhibition of proliferation twenty days after neutron irradiation. Finally, in vivo neutron irradiation experiments on a mouse model of mesothelioma demonstrated the efficiency of combining CA IX inhibition and BNCT treatment. Indeed, a greater reduction in tumour mass was observed in treated mice compared to untreated mice, with a significant higher effect when combined with BNCT. For in vivo experiments CA-USFs were administered as inclusion complexes of higher molecular weight ß-CD polymers thus increasing the selective extravasation into tumour tissue and reducing clearance. In this way, boron uptake was maximised and CA-USFs demonstrated to be in vivo well tolerated at a therapeutic dose. The therapeutic strategy herein described could be expanded to other cancers with increased CA IX activity, such as melanoma, glioma, and breast cancer.

Inexpensive and bench stable diarylmethylium tetrafluoroborates as organocatalysts in the light mediated hydrosulfonylation of unactivated alkenes.

In this paper, we present the synthetic potential of diarylmethylium tetrafluoroborates as catalysts for the visible light promoted hydrosulfonylation of unactivated alkenes. For the first time, these salts, which are bench stable and easily preparable on a multi-gram scale, were employed as organocatalysts. Interestingly, a catalyst loading of only 1 mol% allowed sulfone products to be efficiently obtained from good-to-excellent yields with high functional-group tolerance and scalability up to 15 mmol of alkene. The mechanistic study, both experimental and computational, presented here, revealed an alternative mechanism for the formation of the key sulfonyl radical. Indeed, the photoactive species was proved not to be the diarylcarbenium salt itself, but two intermediates, a stable S-C adduct and an ion couple, that were formed after its interaction with sodium benzenesulfinate. Upon absorbing light, the ion couple could reach an excited state with a charge-transfer character which gave the fundamental sulfonyl radical. A PCET (proton-coupled electron transfer) closes the catalytic cycle reforming the diarylcarbenium salt.

A novel pH sensitive theranostic PLGA nanoparticle for boron neutron capture therapy in mesothelioma treatment.

This study aims to develop poly lactic-co-glycolic acid (PLGA) nanoparticles with an innovative imaging-guided approach based on Boron Neutron Capture Therapy for the treatment of mesothelioma. The herein-reported results demonstrate that PLGA nanoparticles incorporating oligo-histidine chains and the dual Gd/B theranostic agent AT101 can successfully be exploited to deliver a therapeutic dose of boron to mesothelioma cells, significantly higher than in healthy mesothelial cells as assessed by ICP-MS and MRI. The selective release is pH responsive taking advantage of the slightly acidic pH of the tumour extracellular environment and triggered by the protonation of imidazole groups of histidine. After irradiation with thermal neutrons, tumoral and healthy cells survival and clonogenic ability were evaluated. Obtained results appear very promising, providing patients affected by this rare disease with an improved therapeutic option, exploiting PLGA nanoparticles.

Photoinduced Chloroamination Cyclization Cascade with N-Chlorosuccinimide: From N-(Allenyl)sulfonylamides to 2-(1-Chlorovinyl)pyrrolidines.

Here, we present an intriguing photoinduced chloroamination cyclization of allenes bearing a tethered sulfonylamido group to afford 2-(1-chlorovinyl)pyrrolidines and related heterocycles in the presence of N-chlorosuccinimide (NCS) as the chlorine source. An in depth experimental and computational mechanistic study revealed the existence of multiple reaction pathways leading to a common nitrogen centered radical (NCR). This key NCR can be, in fact, originated from (a) the oxidation of the deprotonated allene by the photoexcited state of the Ru-catalyst and (b) the photodissociation of the in situ formed N-chloroallene. The NCR formation triggers an intramolecular cyclization to a highly reactive pyrrolidine vinyl radical, which upon chlorination delivers the final product. Thus, NCS plays a dual role, serving both as an activator of the sulfonamido functionality and as the chlorinating agent.

Biotinylation of a MRI/Gd BNCT theranostic agent to access a novel tumour-targeted delivery system.

A new biotin based BNCT (Boron Neutron Capture Therapy)-MRI theranostic is here reported (Gd-AL01) in order to exploit the high tumour specificity of biotin and the selectivity of BNCT in a synergistic manner. The key is the preparation of an intermediate where an o-carborane is linked to two amino groups orthogonally protected via the exploitation of two consecutive Mitsunobu reactions. The aim is its functionalisation in two different steps with biotin as the biological vector and Gd-DOTA as the MRI probe and GdNCT agent. Cell uptake was evaluated on HeLa tumour cells overexpressing biotin receptors. The internalised boron is proportional to the concentration of the theranostic agent incubated in the presence of cells. A maximum value of 77 ppm is reached and a well detectable signal intensity increase in the T1 weighted image of HeLa cells was observed, differently from clinically used GdHPDO3A, where no contrast is detected. These excellent results indicate that Gd-AL01 can be applied as a theranostic probe in BNCT studies.

Unconventional approaches for the introduction of sulfur-based functional groups.

Organosulfur compounds have a pivotal role in the functionalities of many natural products, pharmaceuticals and organic materials. For these reasons, the search for new methodologies for the formation of carbon-sulfur bonds has been the object of intensive work for organic chemists. However, the proposed strategies suffer from various drawbacks, such as volatility, toxicity, and instability of the sulfur sources or the use of VOC solvents. In this review, we summarise the recent protocols which have the goal of obtaining sulfones, thioethers, thiazines, thiazepines and sulfonamides in an unconventional and/or sustainable way. The use of starting materials less invasive and toxic with respect to the traditional reagents, alternative solvents such as water, ionic liquids or deep eutectic solvents, the exploitation of ultrasound and electrochemistry, increasing the efficiency of the process, are reported. Moreover, representative reaction mechanisms are also discussed.

Green Chemistry Meets Asymmetric Organocatalysis: A Critical Overview on Catalysts Synthesis.

Can green chemistry be the right reading key to let organocatalyst design take a step forward towards sustainable catalysis? What if the intriguing chemistry promoted by more engineered organocatalysts was carried on by using renewable and naturally occurring molecular scaffolds, or at least synthetic catalysts more respectful towards the principles of green chemistry? Within the frame of these questions, this Review will tackle the most commonly occurring organic chiral catalysts from the perspective of their synthesis rather than their employment in chemical methodologies or processes. A classification of the catalyst scaffolds based on their E factor will be provided, and the global E factor (EG factor) will be proposed as a new green chemistry metric to consider, also, the synthetic route to the catalyst within a given organocatalytic process.

Visible Light Mediated Photocatalytic N-Radical Cascade Reactivity of γ,δ-Unsaturated N-Arylsulfonylhydrazones: A General Approach to Structurally Diverse Tetrahydropyridazines.

Tetrahydropyridazines are of particular interest for their versatility as intermediates in organic synthesis and display pharmacological activity in several domains. Here, we describe the photocatalytic synthesis of different tetrahydropyridazines starting from γ,δ-unsaturated N-arylsulfonylhydrazones. Simple structural changes of substrates result into three different pathways beginning from a common N-hydrazonyl radical, which evolves through a domino carboamination/dearomatization, a HAT process, or a photoinduced radical Smiles rearrangement to afford diverse tetrahydropyridazines. All reactions are carried out in very mild conditions, and the quite inexpensive [Ru(bpy)3]Cl2 is used as the catalyst. Preliminary mechanism studies are presented, among them luminescence and electrochemical characterization of the involved species. Computational studies allow to rationalize the mechanism in accord with the experimental findings.

Caesium for Perovskite Solar Cells: An Overview.

Perovskite solar cells have the potential to revolutionize the world of photovoltaics, and their efficiency close to 23 % on a lab-scale recently certified this novel technology as the one with the most rapidly raising performance per year in the whole story of solar cells. With the aim of improving stability, reproducibility and spectral properties of the devices, in the last three years the scientific community strongly focused on Cs-doping for hybrid (typically, organolead) perovskites. In parallel, to further contrast hygroscopicity and reach thermal stability, research has also been carried out to achieve the development of all-inorganic perovskites based on caesium, the performances of which are rapidly increasing. The potential of caesium is further strengthened when it is used as a modifying agent of charge-carrier layers in solar cells, but also for the preparation of perovskites with peculiar optoelectronic properties for unconventional applications (e.g., in LEDs, photodetectors, sensors, etc.). This Review offers a 360-degree overview on how caesium can strongly tune the properties and performance of perovskites and relative perovskite-based devices.

Enamine/Dienamine and Brønsted Acid Catalysis: Elusive Intermediates, Reaction Mechanisms, and Stereoinduction Modes Based on in Situ NMR Spectroscopy and Computational Studies.

Over the years, the field of enantioselective organocatalysis has seen unparalleled growth in the development of novel synthetic applications with respect to mechanistic investigations. Reaction optimization appeared to be rather empirical than rational. This offset between synthetic development and mechanistic understanding was and is generally due to the difficulties in detecting reactive intermediates and the inability to experimentally evaluate transition states. Thus, the first key point for mechanistic studies is detecting elusive intermediates and characterizing them in terms of their structure, stability, formation pathways, and kinetic properties. The second key point is evaluating the importance of these intermediates and their properties in the transition state. In the past 7 years, our group has addressed the problems with detecting elusive intermediates in organocatalysis by means of NMR spectroscopy and eventually theoretical calculations. Two main activation modes were extensively investigated: secondary amine catalysis and, very recently, Brønsted acid catalysis. Using these examples, we discuss potential methods to stabilize intermediates via intermolecular interactions; to elucidate their structures, formation pathways and kinetics; to change the kinetics of the reactions; and to address their relevance in transition states. The elusive enamine in proline-catalyzed aldol reactions is used as an example of the stabilization of intermediates via inter- and intramolecular interactions; the determination of kinetics on its formation pathway is discussed. Classical structural characterization of intermediates is described using prolinol and prolinol ether enamines and dienamines. The Z/E dilemma for the second double bond of the dienamines shows how the kinetics of a reaction can be changed to allow for the detection of reaction intermediates. We recently started to investigate substrate-catalyst complexes in the field of Brønsted acid catalysis. These studies on imine/chiral phosphoric acid complexes show that an appropriate combination of highly developed NMR and theoretical methods can provide detailed insights into the complicated structures, exchange kinetics, and H-bonding properties of chiral ion pairs. Furthermore, the merging of these structural investigations and photoisomerization even allowed the active transition state combinations to be determined for the first time on the basis of experimental data only, which is the gold standard in mechanistic investigations and was previously thought to be exclusively the domain of theoretical calculations. Thus, this Account summarizes our recent mechanistic work in the field of organocatalysis and explains the potential methods for addressing the central questions in mechanistic studies: stabilization of intermediates, elucidation of structures and formation pathways, and addressing transition state combinations experimentally.

Decrypting Transition States by Light: Photoisomerization as a Mechanistic Tool in Brønsted Acid Catalysis.

Despite the wide applicability of enantioselective Brønsted acid catalysis, experimental insight into transition states is very rare, and most of the mechanistic knowledge is gained by theoretical calculations. Here, we present an alternative approach (decrypting transition state by light = DTS-hν), which enables the decryption of the transition states involved in chiral phosphoric acids catalyzed addition of nucleophiles to imines. Photoisomerization of double bonds is employed as a mechanistic tool. For this class of reactions four pathways (Type I Z, Type I E, Type II Z, Type II E) are possible, leading to different enantiomers depending on the imine configuration (E- or Z-imine) and on the nucleophilic attack site (top or bottom). We demonstrated that the imine double bond can be isomerized by light (365 nm LED) during the reaction leading to a characteristic fingerprint pattern of changes in reaction rate and enantioselectivity. This characteristic fingerprint pattern is directly correlated to the transition states involved in the transformation. Type I Z and Type II Z are demonstrated to be the competing pathways for the asymmetric transfer hydrogenation of ketimines, while in the nucleophilic addition of acetylacetone to N-Boc protected aldimines Type I E and Type II E are active. Accelerations on reaction rate up to 177% were observed for ketimines reduction. Our experimental findings are supported by quantum chemical calculations and noncovalent interaction analysis.

Kinetic resolution of oxazinones: rational exploration of chemical space through the design of experiments.

The organocatalytic kinetic resolution of 4-substituted oxazinones has been optimised (selectivity factor S up to 98, chiral oxazinone ee values up to 99.6 % (1 a-g) and product ee values up to 90 % (3 a-g)) in a rational way by applying the Design of Experiments (DoE) approach.

Enantioselective aza-Michael addition of imides by using an integrated strategy involving the synthesis of a family of multifunctional catalysts, usage of multiple catalysis, and rational design of experiment.

A challenging asymmetric reaction (aza-Michael addition of imides to enones) has been optimized through an integrated approach involving the synthesis of a family of organocatalysts, multiple catalysis (usage of additives), and finally with rational exploration of the chemical space by the application of the experiment design.

Non-asymmetric organocatalysis.

Asymmetric organocatalysis is now an established methodology for the preparation of chiral compounds. However, these are not the only valuable molecules which can be conveniently obtained. Organocatalytic reactions affording achiral compounds are gaining momentum, opening unexplored pathways in the synthesis of densely functionalized aromatic moieties, olefins and useful molecules such as natural substances.

Biomimetic organocatalytic asymmetric synthesis of 2-substituted piperidine-type alkaloids and their analogues.

Natural substances such as pelletierine and its analogues have been prepared in up to 97% ee and good yield by a protective-group-free, biomimetic approach. Usage of benzonitrile or acetonitrile as solvents effectively prevents product racemization.

Multicomponent asymmetric reactions mediated by proline lithium salt.

The multicomponent reaction between proline lithium salt, 2-cyclohexen-1-one and aliphatic aldehydes affords the 4-alkylidene-2-cyclohexen-1-ones, which are interesting fragrances, and bicyclic amino acids that bear four additional stereocenters, obtained as single stereoisomer.