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The application of biocatalysis has become essential in both academic and industrial domains for the asymmetric synthesis of chiral amines, and it serves as an alternative tool to transition-metal catalysis and complements traditional chemical methods. It relies on the swift expansion of available processes, primarily as a result of advanced tools for enzyme discovery, combined with high-throughput laboratory evolution techniques for optimizing biocatalysts. This concept paper explores the utilization of non-conventional media such as ether-type solvents, deep eutectic solvents, and micellar catalysis to enhance biocatalytic reactions for chiral amine synthesis. Each section focuses on the unique properties of these media, including their ability to stabilize enzymes, alter substrate solubility, and modulate enzyme selectivity. The paper aims to provide insights into how these innovative media can overcome traditional limitations, offering new avenues for sustainable and efficient chiral amine production through biocatalytic processes.
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Aminas , Biocatálisis , Solventes , Aminas/química , Estereoisomerismo , Solventes/química , Micelas , SolubilidadRESUMEN
Wittig reaction between substituted phosphonium salts and (hetero)aromatic and alkyl carbonyl compounds in Deep Eutectic Solvents has been developed under a scalable and friendly protocol. Highly efficient reactions were successfully run with a wide range of bases including organic (DBU, LiTMP, t-BuOK) and inorganic (NaOH, K2CO3) ones in ChCl/Gly 1 : 2 (mol/mol) as solvent under mild conditions, at room temperature and under air. The proposed protocol was applied to a wide range of substrates, including (hetero)aromatic aldehydes with substituents as halogens (I, Br, Cl), EDG (alkoxy, methyl), EWG (NO2, CF3) or reactive groups as CN, esters, and ketones. Vinylic, alkynyl and cycloalkyl, alicyclic and α,ß-unsaturated aldehydes can also be used. Highly electrophilic ketones gave good yields. The diastereoselectivity of the reaction is in complete agreement with the E/Z ratio predictable under traditional conditions. We demonstrated that the protocol is scalable to 2â g (5â mmol) of phosphonium salt, furthermore the proposed workup protocol allows to remove TPPO without need of additional chromatographic purification.
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The first enantioselective reduction of 2-substituted cyclic imines to the corresponding amines (pyrrolidines, piperidines, and azepines) by imine reductases (IREDs) in non-conventional solvents is reported. The best results were obtained in a glycerol/phosphate buffer 1 : 1 mixture, in which heterocyclic amines were produced with full conversions (>99 %), moderate to good yields (22-84 %) and excellent S-enantioselectivities (up to >99 % ee). Remarkably, the process can be performed at a 100â mM substrate loading, which, for the model compound, means a concentration of 14.5â g L-1 . A fed-batch protocol was also developed for a convenient scale-up transformation, and one millimole of substrate 1 a was readily converted into 120â mg of enantiopure amine (S)-2 a with a remarkable 80 % overall yield. This aspect strongly contributes to making the process potentially attractive for large-scale applications in terms of economic and environmental sustainability for a good number of substrates used to produce enantiopure cyclic amines of high pharmaceutical interest.
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Iminas , Oxidorreductasas , Iminas/química , Solventes , Estereoisomerismo , Aminas/químicaRESUMEN
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.
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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.
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Terapia por Captura de Neutrón de Boro , Mesotelioma Maligno , Mesotelioma , Nanopartículas , Humanos , Terapia por Captura de Neutrón de Boro/métodos , Medicina de Precisión , Glicoles , Histidina , Mesotelioma/diagnóstico por imagen , Mesotelioma/radioterapia , Concentración de Iones de HidrógenoRESUMEN
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.
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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.
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Terapia por Captura de Neutrón de Boro , Medicina de Precisión , Biotina , Biotinilación , Terapia por Captura de Neutrón de Boro/métodos , Células HeLa , Humanos , Imagen por Resonancia Magnética/métodosRESUMEN
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.
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This paper discusses the design and prototype implementation of a software solution facilitating the interaction of third-party developers with a legacy monitoring and control system in the airfield environment. By following the Internet of Things (IoT) approach and adopting open standards and paradigms such as REpresentational State Transfer (REST) and Advanced Message Queuing Protocol (AMQP) for message dispatching, the work aims at paving the way towards a more open world in the airfield industrial sector. The paper also presents performance results achieved by extending legacy components to support IoT standards. Quantitative results not only demonstrate the feasibility of the proposed solution, but also its suitability in terms of prompt message dispatching and increased fault tolerance.
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Curcumin is currently being investigated for its capacity to treat many types of cancer and to prevent the neuron damage that is observed in Alzheimer's disease (AD). However, its clinical use is limited by its low stability and solubility in aqueous solutions. In this study, we propose a completely new class of boronated monocarbonyl analogues of Curcumin (BMAC, 6a-c), in which a carbonyl group replaces the Curcumin ß-diketone functionality, and an ortho-carborane, an icosahedral boron cluster, substitutes one of the two phenolic rings. BMAC antitumor activity against MCF7 and OVCAR-3 cell lines was assessed in vitro and compared to that of Curcumin and the corresponding MAC derivative. BMAC 6a-c showed efficiencies that are comparable to that of MAC and superior to that of Curcumin in both the cell lines. Moreover, the inhibition of the formation of ß-amyloid aggregates by BMAC 6a-c was evaluated and it was shown that compound 6c, which contains two OH moieties, has a better efficiency than Curcumin. The presence of a second -OH group can enhance the compound's binding efficacy with ß-amyloid aggregates. For the future, the presence of at least one carborane group means that the BMAC antitumor effect can be coupled with Boron Neutron Capture Therapy.
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Péptidos beta-Amiloides/efectos de los fármacos , Antineoplásicos/farmacología , Compuestos de Boro/química , Compuestos de Boro/farmacología , Curcumina/química , Curcumina/farmacología , Diseño de Fármacos , Compuestos de Boro/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , HumanosRESUMEN
An unprecedented efficient palladium(0)-catalyzed reaction of vinyl oxiranes with N-tosylhydrazones, affording "skipped" allylic alcohols in total regioselectivity and stereoselectivity, with excellent functional-group compatibility, is reported. In this Tsuji-Trost-like allylation, we propose the use of N-tosylhydrazones as a synthetic equivalent of α-styryl anions. More than 20 new products are described, including naturally occurring derivatives. A catalytic system involving an iodide (I-) source is necessary to sustain the catalytic cycle.
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Polycyclic molecules featuring all-carbon quaternary bridgehead centers were synthesized through domino cyclizations between N-tosylhydrazones and boronic acids. Variations of the general cascade have been applied for the preparation of 3-quinuclidinones and related alkaloid-like scaffolds through transannular heterocyclizations. Moreover, the employment of 3-cyanopropyl and 4-cyanobutylboronic acids and α,ß-unsaturated N-tosylhydrazones led to spirocycles through unprecedented formal [n+1] cyclizations, including the stereoselective spirocyclization of the Hajos-Parrish ketone. The common feature of all the new reactions described is the creation of an all-carbon quaternary center by formation of two Csp3 -C bonds on the hydrazonic carbon atom. DFT-based calculations suggested the occurrence of cascade processes, which involve a diazo compound carboborylation followed by a 1,3-borotropic rearrangement on an intermediate allylboronic acid and a novel bora-aza-ene cyclization.
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Palladium(0)-catalysed hydro-alkylation or -alkenylation of alkoxyallenes with N-tosylhydrazones gives direct access to conjugated and skipped 1-alkoxydienes with high efficiency and excellent functional-group compatibility. The reaction is proposed to involve the inâ situ-formed t-butanol as proton source in the key step of the allylpalladium(II) species generation. Moreover, lithium iodide or iodobenzene are employed as an unprecedented iodide (I- ) reservoir to sustain the catalytic cycle.
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As part of our ongoing work on the synthesis of a new class of plant hormones named Strigolactones (SLs) and their analogues, we became interested in tracing bioactive molecules with red emitting BODIPY fluorophores in order to unravel signaling and distribution of SLs in plants. In this paper we report on an unprecedented Heck functionalization of azadipyrromethenes (aza-DIPY) which allows for the introduction of suitable functional groups to convert aza-BODIPY in bioconjugate complexes useful for untangling biological processes.
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Compuestos Aza/farmacocinética , Compuestos de Boro/farmacocinética , Colorantes Fluorescentes/farmacocinética , Arabidopsis/química , Compuestos Aza/química , Compuestos de Boro/química , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/química , Estructura Molecular , Procesos Fotoquímicos , Raíces de Plantas/química , Espectroscopía Infrarroja Corta , Distribución TisularRESUMEN
Strigolactones (SLs) are new plant hormones with various developmental functions. They are also soil signaling chemicals that are required for establishing beneficial mycorrhizal plant/fungus symbiosis. In addition, SLs play an essential role in inducing seed germination in root-parasitic weeds, which are one of the seven most serious biological threats to food security. There are around 20 natural SLs that are produced by plants in very low quantities. Therefore, most of the knowledge on SL signal transduction and associated molecular events is based on the application of synthetic analogues. Stereochemistry plays a crucial role in the structure-activity relationship of SLs, as compounds with an unnatural D-ring configuration may induce biological effects that are unrelated to SLs. We have synthesized a series of strigolactone analogues, whose absolute configuration has been elucidated and related with their biological activity, thus confirming the high specificity of the response. Analogues bearing the R-configured butenolide moiety showed enhanced biological activity, which highlights the importance of this stereochemical motif.