Enantiopure Double ortho-Oligophenylethynylene-Based Helical Structures with Circularly Polarized Luminescence Activity

We thank the Ministerio de Economia y Competitividad (CTQ2017-85454-C2-1-P and CTQ2017-85454-C2-2-P), Ministerio de Ciencia e Innovacion (PID2020-113059GB-C21 and PID2020-113059GB-C22) and Junta de Andalucia (P20.00162) (Spain) for funding and P.R. and A. O. G. also for FPU contracts. Funding for open access charge is acknowledged to Universidad de Granada / CBUA.We also thank Big&Open Data Innovation Laboratory (BODaI-Lab), University of Brescia, granted by Fondazione Cariplo and Regione Lombardia, for access to resources of Computing Center CINECA (Bologna), Italy. Support from the Italian MIUR (Grant No. 2017A4XRCA) is also acknowledged.In this paper, we describe the optical and chiroptical properties of an enantiopure multipodal ortho-oligophenylethynylene (S,S,S,S)-1 presenting four chiral sulfoxide groups at the extremes. The presence of these groups together with alkynes allows the coordination with carbophilic Ag(I), and/or oxophilic Zn(II) cations, yielding double helical structures in an enantiopure way. In this sense, different behaviors in absorption, fluorescence, ECD and CPL spectra have been found depending on the stoichiometry and nature of the metal. We have observed that Zn(II) coordination favors an intensity increase of the electronic circular dichroism (ECD) spectra of compound (S,S,S,S)-1 yielding an M-helicity in the ortho-oligophenylene ethynylene (o-OPE) backbone. On the other hand, ECD spectra of final Ag(I) complex shows two different bands with an opposite sign to the free ligand, thus giving the P-helical isomer. In addition, circularly polarized luminescence (CPL) exhibit an enhanced intensity and negative sign in both complexes. Computational studies were also carried out, supporting the experimental results.Spanish Government CTQ2017-85454-C2-1-P CTQ2017-85454-C2-2-PInstituto de Salud Carlos III Spanish Government European Commission PID2020-113059GB-C21 PID2020-113059GB-C22Junta de Andalucia European Commission P20.00162University of Brescia / CBUAFondazione CariploMinistry of Education, Universities and Research (MIUR) 2017A4XRCARegione Lombardi

Chiral Single-Molecule Potentiometers Based on Stapled ortho- Oligo(phenylene)ethynylenes

We report on the chemical design of chiral molecular junctions with stress-dependent conductance, whose helicity is maintained during the stretching of a single molecule junction due to the stapling of both ends of the inner helix. In the reported compounds, different conductive pathways are observed, with clearly different conductance values and plateau-length distributions, attributed to different conformations of the helical structures. The large chiro-optical responses and the potential use of these molecules as unimolecular spin filters have been theoretically proved using state-of-the-art Density Functional Theory (DFT) calculations, including a fully ab-initio estimation of the CISS-originating spin polarization which is done, for the first time, for a realistic molecular system

Exploring Potentialities and Limitations of Stapled o- Oligo(PhenyleneEthynylene)s (o-OPEs) as Efficient Circularly Polarized Luminescence Emitters

In this paper we have studied the chiroptical properties of a family of o-OPE derivatives with different steric hindrance. Experimental results show high dissymmetry factors (gabs and glum up to 1.1x10-2) and very similar ECD and CPL for all the derivatives, that makes this basic o-OPE scaffold a robust pure organic emitter. VCD spectra are used to characterize conformational properties in solution. DFT and TD-DFT calculations support experimental results also proving that ECD and CPL are almost exclusively linked to helical moiety and not to size or conformation of substituents. As chiroptical properties of these emitters are independent of substituents, this OPE scaffold can be used as basic skeleton for the design of sensing probes with high CPL efficiencies.We thank MICINN (CTQ2014-53598-R) and Junta de Andalucía (FQM1484) for financial support. Computing Center CINECA Via Magnanelli 6/3 40033 – Casalecchio di Reno (Bologna) Italy and Regione Lombardia for the LISA Grant No. “ChiPhyto: HPL13POZE1” is acknowledged for access to computational facilities. P. Reiné thanks MICINN for a FPU fellowship

Cell Survival Enabled by Leakage of a Labile Metabolic Intermediate

Many metabolites are generated in one step of a biochemical pathway and consumed in a subsequent step. Such metabolic intermediates are often reactive molecules which, if allowed to freely diffuse in the intracellular milieu, could lead to undesirable side reactions and even become toxic to the cell. Therefore, metabolic intermediates are often protected as protein-bound species and directly transferred between enzyme active sites in multi-functional enzymes, multi-enzyme complexes, and metabolons. Sequestration of reactive metabolic intermediates thus contributes to metabolic efficiency. It is not known, however, whether this evolutionary adaptation can be relaxed in response to challenges to organismal survival. Here, we report evolutionary repair experiments on Escherichia coli cells in which an enzyme crucial for the biosynthesis of proline has been deleted. The deletion makes cells unable to grow in a culture medium lacking proline. Remarkably, however, cell growth is efficiently restored by many single mutations (12 at least) in the gene of glutamine synthetase. The mutations cause the leakage to the intracellular milieu of a highly reactive phosphorylated intermediate common to the biosynthetic pathways of glutamine and proline. This intermediate is generally assumed to exist only as a protein-bound species. Nevertheless, its diffusion upon mutation-induced leakage enables a new route to proline biosynthesis. Our results support that leakage of sequestered metabolic intermediates can readily occur and contribute to organismal adaptation in some scenarios. Enhanced availability of reactive molecules may enable the generation of new biochemical pathways and the potential of mutation-induced leakage in metabolic engineering is noted.This work was supported by Human Frontier Science Program Grant RGP0041/2017 (J.M.S.R. and B.S.), Spanish Ministry of Science and Innovation FEDER Funds Grants RTI2018-097142-B-100 and PID2021-124534OB-100 (J.M.S.R.), National Aeronautics and Space Administration (NASA) Grant 80NSSC18K1277 (B.S.) Grant RYC2021-031155-I (E.M.C.) from Spanish Ministry of Science and Innovation and NextGenerationEU/PRTR and Grant E-BIO-464-UGR-20 (E.M.C.) from FEDER Funds and Consejería de Economía, Conocimiento, Empresas y Universidad de la Junta de Andalucia. E.A.L. was a recipient of a postdoctoral fellowship from the regional Andalusian Government (2020_DOC_00541). We thank the “Centro de Supercomputacion” (ALHAMBRA-CSIRC) of the University of Granada for providing computational resources and Dr Valeria A. Risso for useful discussions, comments on the manuscript and help with the evolutionary and structural analyses of the rescuing mutations.Peer reviewe

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

Background A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. Methods This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Findings Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. Interpretation ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials

Design and synthesis of organic ligands for developing new palladium, platinum and silver complexes with new optic and electronic properties

El primer bloque se centra en las propiedades quirópticas de moléculas orgánicas simples (simple organic molecules, SOM) y más específicamente las que poseen luminiscencia circularmente polarizada (circularly polarized luminescence, CPL). En la introducción se realiza un repaso bibliográfico de moléculas y materiales activos en CPL hasta la fecha y por qué han despertado el interés de la comunidad científica en los últimos años. Este bloque cuenta con tres capítulos, el primero se basa en la síntesis y evaluación de propiedades quirópticas de foldámeros basados en un esqueleto de orto-oligofeniletinilenos (o-OPE) que presentan grupos sulfóxido como inductores quirales y el efecto de la coordinación de diferentes metales con tales propiedades. El capítulo 2 se dedica a la síntesis y propiedades quirópticas de o-OPE grapados. Mediante esta metodología se consiguen estructuras más estables y con mayores respuestas de CPL que en el capítulo anterior. Para ello se diseña un esqueleto de o-OPE sobre el que se evalúan sus propiedades tanto en derivados con diferente impedimento estérico, como en otros cromóforos como los pirenos que permiten construir una sonda ratiométrica. También se considera la influencia del aumento del número de vueltas de la hélice, obteniéndose compuestos con respuesta de CPL muy superiores a la media. Por último el capítulo 3 se centra en la combinación de CPL y absorción de doble fotón (two photon absorption, TPA). La síntesis de moléculas con diferentes propiedades combinadas es una estrategia interesante para el desarrollo de nuevos materiales. En este caso la síntesis de una molécula sencilla basada en un ciclohexano quiral y perilendiimidas (PDI) permite la obtención de un compuesto que presenta las propiedades de CPL y TPA combinadas. El segundo bloque, de menor extensión, trata sobre las propiedades electrónicas de cables moleculares. Con el objetivo de medir la conductancia unimolecular de estos compuestos durante este capítulo se hace uso fundamentalmente del microscopio de efecto túnel (STM). En la introducción se discuten los distintos elementos de un circuito electrónico y la relación entre estructura química y conductancia, así como las aplicaciones más destacables de este tipo de dispositivos. Este bloque se compone de un solo capítulo que aborda las propiedades electrónicas de un conjunto de complejos metálicos de paladio que presentan enlaces N-M-C (nitrógeno-metal-carbono). El objetivo de este capítulo consiste en esclarecer las propiedades electrónicas en cables moleculares que presentan enlaces de distinta naturaleza que no han sido estudiados de forma sistemática hasta la fecha. Finalmente se incluyen unos anexos en los que se incorpora una lista de publicaciones donde se exponen los resultados obtenidos durante todo el periodo predoctoral y un listado de las referencias usadas para las figuras no originales del texto.First part is related with chiroptical properties of simple organic molecules (SOMs), especially molecules with circularly polarized luminescence (CPL). The introduction consists of an overview about active CPL molecules and materials and their relevance in nowadays researches. This initial part is divided in three chapters; first one is based on synthesis and chiroptical properties evaluation of orto-oligophenylethynylenes (o-OPE) foldamers with sulfoxide as chiral inductor and the effect of metal coordination in these properties. Chapter 2 is related with synthesis and chiroptical characterization of stapled o-OPEs which are more stable and CPL active than previous structures. A main o-OPE scaffold is designed in order to evaluate the chiroptical properties in derivatives with steric effect groups or chromophores like pyrene that allows to build a ratiometric probe. In addition, longer helix structures which lead to higher CPL signals are considered. Last, chapter 3 focuses on combined CPL and two photon absorption (TPA). Synthesis of molecules with different combined properties is an interesting approach for the development of new materials. A new simple molecule based on a chiral cyclohexane and perylendiimides (PDI) is synthesized in order to obtain a combined CPL and TPA compound. Second part addresses the electronic properties in molecular wires. Scanning tunneling microscope (STM) is mainly used in this part with the aim of measure the unimolecular conductance of the compounds. The introduction discusses about different aspects of the electronic circuit and the relationship between chemical structure and property, also most important applications of these devices are commented. The main objective of this part with just one chapter is measuring electronic properties of nitrogen-metal-carbon bonds in palladium complexes to shed light about the behaviour of conductance in this kind of structures. Finally, there are some annexes with a list of publications made during the predoctoral period and a list of permissions for every figure used in this thesis.Tesis Univ. Granada.Ministerio de Educación y Ciencia y la Consejería de Innovación, Ciencia y Empresa de la Junta de Andalucía. Grupo de investigación “Materiales Orgánicos Funcionales” (FQM-367

Extended enantiopure ortho-phenylene ethylene (o-OPE)-based helical systems as scaffolds for supramolecular architectures: a study of chiroptical response and its connection to the CISS effect

We thank the Ministerio de Economia y Competitividad (CTQ2017-85454-C2-1-P), Ministerio de Ciencia en Innovacion (PID2020-113059GB-C21) and Junta de Andalucia (P20_00162) (Spain) for funding and P. R. and A. O. G. also for FPU contracts. We also thank the UGR CSIRC for access to computational facilities. We also thank Big&Open Data Innovation Laboratory (BODaI-Lab), University of Brescia, granted by Fondazione Cariplo and Regione Lombardia, for access to resources of Computing Center CINECA (Bologna), Italy. Support from the Italian MIUR (grant N. 2017A4XRCA) is also acknowledged. VM acknowledges a Fellowship from Ikerbasque, the Basque Foundation for Science.A novel synthetic strategy based on a bifunctional stapled chiral nucleus from which segments of different lengths can be added to both ends of o-phenylene ethynylenes (o-OPEs) has been developed to obtain a new type of foldamer and a novel chiral Pd2L2 metallacycle. For the first time, an enantiopure fully conjugated helical foldamer having 14 phenyl rings and 13 alkynes is reported. The folded structure has four complete loops and is able to host three Ag(I) cations in their cavity with high binding constants. The complete photophysical and chiroptical (ECD, CPL and VCD) characterization of these foldamers has shown that these molecules show intense chiroptical responses with dissymmetry ratios in the range of 10−2. Theoretical modeling of these systems reveals the origin of these remarkable responses and points out a potential connection with the chiral induced spin selectivity (CISS) effect. The magnetic dipole moment is proposed as a key physical variable connecting the chiroptical properties and CISS-based spin filtering properties observed in chiral compounds.Ministerio de Economia y Competitividad (Spain) CTQ2017-85454-C2-1-PMinisterio de Ciencia en Innovacion (Spain) PID2020-113059GB-C21Junta de Andalucia European Commission P20_00162Ministry of Education, Universities and Research (MIUR) 2017A4XRCAIkerbasque, the Basque Foundation for Scienc

Simple Perylene Diimide Cyclohexane Derivative With Combined CPL and TPA Properties

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fchem. 2020.00306/full#supplementary-materialIn this work we describe the linear and non-linear (chiro)optical properties of an enantiopure bis-perylenediimide (PDI) cyclohexane derivative. This compound exhibits upconversion based on a two-photon absorption (TPA) process with a cross-section value of 70 GM together with emission of circularly polarized luminescence (CPL), showing a glum in the range of 10−3. This simple structure represents one of the scarce examples of purely organic compounds combining both TPA and CPL responses, together with large values of molar absorptivity and fluorescence quantum yield with emission in the 500–600 nm. Self-assembly induced by introduction of a poor solvent allows for a spectacular shift of the emission into the near-infrared (NIR, 650–750 nm) by formation of well-defined rotationally displaced dimers. Therefore, we are here presenting a versatile platform whose optical properties can be simply tuned by self-assembly or by functionalization of the electron-deficient aromatic core of PDIs.Ministerio de Ciencia, Innovacion y Universidades PG2018-101181-B-I00Spanish Government CTQ2017-85454-C2-1-PEuropean Research Council (ERC) ERC-2015-STG-677023MINECO RyC-2013-12943Spanish GovernmentPortuguese Foundation for Science and TechnologyPOCIEuropean Union (EU) PTDC/NAN-MAT/29317/2017 PTDC/QUI-QFI/29319/2017 UIDB/00100/202

2D self-assembly of o-OPE foldamers for chiroptical barcoding

We report on the preparation and characterization of two dimensional (2D) films of (S,S,P)-1 and (R,R,M)-1 ortho-oligophenylene ethylene (o-OPE) enantiomers presenting high values of circularly polarized luminescence (CPL). The amphiphilic character of these two molecules allows a precise 2D self-assembly at the air/water interface and an efficient transfer onto a glass solid support. The morphological and chiroptical characterization of the solid supports after the transfer of 1, 8, 16 and 32 Langmuir films of (S,S,P)-1 and (R,R,M)-1 has been carried out. The strong chiroptical values of these monomers allow reliable ECD measurements to be obtained after a single transfer, with ECD values increasing as the number of transferred films increases. The semi-liquid behavior of the monomers on the solid substrate allows CPL measurements free of photoselection artifacts that show values similar to those obtained in solution and independent of monomer concentration. All these properties have allowed us to develop the first simple organic molecule (SOM)-based chiroptical barcoding presenting positive and negative regions as a proof of concept.Spanish Ministry of Science and Innovation (AEI, Spain) PID2020-112744GB-I00 Ministry of Science and Innovation, Spain (MICINN) Spanish Government MCIN/AIEFSE "El FSE invierte en tu futuro" in SpainFEDER/Junta de Andalucia-Consejeria de Economia y Conocimiento/Proyecto PID2020-113059GB-C21/AEI PRE2021-097546 FPU16/02597 P20_0016