Transition Metal‐Promoted Reactions in Aqueous Media and Biological Settings

This is the peer reviewed version of the following article: P. Destito, C. Vidal, F. López, J. L. Mascareñas, Chem. Eur. J. 2021, 27, 4789, which has been published in final form at https://doi.org/10.1002/chem.202003927. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived VersionsDuring the last decade, there has been a tremendous interest for developing non‐natural biocompatible transformations in biologically relevant media. Among the different encountered strategies, the use of transition metal complexes offers unique possibilities due to their high transformative power. However, translating the potential of metal catalysts to biological settings, including living cells or small‐animal models such as mice or zebrafish, poses numerous challenges associated to their biocompatibility, and their stability and reactivity in crowded aqueous environments. Herein, we describe the most relevant advances in this direction, with a particular emphasis on the systems’ structure, their mode of action and the mechanistic bases of each transformation. Thus, the key challenges from an organometallic perspective might be more easily identifiedWe would like to acknowledge financial support from Spanish grants (SAF2016‐76689‐R, CTQ2017‐84767‐P and ORFEO‐CINQA network CTQ2016‐81797‐REDC), the Consellería de Cultura, Educación e Ordenación Universitaria (2015‐CP082, ED431C‐2017/19 and Centro Singular de Investigación de Galicia accreditation 2019–2022, ED431G 2019/03), the European Union (European Regional Development Fund‐ERDF corresponding to the multiannual financial framework 2014–2020), and the European Research Council (Advanced Grant No. 340055). D.F.F. thanks Xunta de Galicia for his postdoctoral fellowship (ED481B‐2019‐005)S

Intracellular deprotection reactions mediated by palladium complexes equipped with designed phosphine ligands

Discrete palladium(II) complexes featuring purposely designed phosphine ligands can promote depropargylation and deallylation reactions in cell lysates. These complexes perform better than other palladium sources, which apparently are rapidly deactivated in such hostile complex media. This good balance between reactivity and stability allows the use of these discrete phosphine palladium complexes in living mammalian cells, whereby they can mediate similar transformations. The presence of a phosphine ligand in the coordination sphere of palladium also provides for the introduction of targeting groups, such as hydrophobic phosphonium moieties, which facilitate the accumulation of the complexes in mitochondria

Bioorthogonal Azide–Thioalkyne Cycloaddition Catalyzed by Photoactivatable Ruthenium(II) Complexes

Tailored ruthenium sandwich complexes bearing photoresponsive arene ligands can efficiently promote azide–thioalkyne cycloaddition (RuAtAC) when irradiated with UV light. The reactions can be performed in a bioorthogonal manner in aqueous mixtures containing biological components. The strategy can also be applied for the selective modification of biopolymers, such as DNA or peptides. Importantly, this ruthenium-based technology and the standard copper-catalyzed azide–alkyne cycloaddition (CuAAC) proved to be compatible and mutually orthogonalThis research received financial support from the Spanish MINECO (SAF2016-76689-R, CTQ2017-84767-P and PID2019-106184GB-I00, and a FPU predoctoral Fellowship to AGG), the Xunta de Galicia (ED431C 2017/19, 2015-CP082, Centro Singular de Investigación de Galicia accreditation 2019–2022, ED431G 2019/03), the ERDF, and the ERC (Adv. Grant No. 340055). The Orfeo-Cinqa network (CTQ2016-81797-REDC) is also acknowledgedS

Plasmonic-assisted thermocyclizations in living cells using metal−organic framework based nanoreactors

We describe a microporous plasmonic nanoreactor to carry out designed near-infrared (NIR)-driven photothermal cyclizations inside living cells. As a proof of concept, we chose an intramolecular cyclization that is based on the nucleophilic attack of a pyridine onto an electrophilic carbon, a process that requires high activation energies and is typically achieved in bulk solution by heating at ∼90 °C. The core–shell nanoreactor (NR) has been designed to include a gold nanostar core, which is embedded within a metal–organic framework (MOF) based on a polymer-stabilized zeolitic imidazole framework-8 (ZIF-8). Once accumulated inside living cells, the MOF-based cloak of NRs allows an efficient diffusion of reactants into the plasmonic chamber, where they undergo the transformation upon near-IR illumination. The photothermal-driven reaction enables the intracellular generation of cyclic fluorescent products that can be tracked using fluorescence microscopy. The strategy may find different type of applications, such as for the spatio-temporal activation of prodrugsThe authors thank the financial support of the MCIN/AEI (PID2020-119206RB-I00, PID2019-108624RB-I00, CTQ2017-84767-P, RYC-2017-23457, RYC-2019-028238-I, RTI2018-093813-J-I00), the Xunta de Galicia (ED431F 2017/02, 2021-CP054, ED431C-2021/25, Centro Singular de Investigación de Galicia Accreditation 2019−2022, and ED431G 2019/03), the European Union (European Regional Development Fund − ERDF; H2020-MSCA-IF grant agreement no. 749667; H2020-MSCA-ITN grant agreement no. 860942; H2020-FET-Open grant agreement No. 899612; and INTERREG V-A Spain−Portugal, project 0624_2IQBIONEURO_6_E), and the European Research Council (starting grant no. 950421, advanced grant no. 340055). The support of the orfeo-cinqa network (CTQ2016-81797-REDC) is also kindly acknowledgedS

Core-Shell Palladium/MOF Platforms as Diffusion-Controlled Nanoreactors in Living Cells and Tissue Models

Translating the potential of transition metal catalysis to biological and living environments promises to have a profound impact in chemical biology and biomedicine. A major challenge in the field is the creation of metal-based catalysts that remain active over time. Here, we demonstrate that embedding a reactive metallic core within a microporous metal-organic framework-based cloak preserves the catalytic site from passivation and deactivation, while allowing a suitable diffusion of the reactants. Specifically, we report the fabrication of nanoreactors composed of a palladium nanocube core and a nanometric imidazolate framework, which behave as robust, long-lasting nanoreactors capable of removing propargylic groups from phenol-derived pro-fluorophores in biological milieu and inside living cells. These heterogeneous catalysts can be reused within the same cells, promoting the chemical transformation of recurrent batches of reactants. We also report the assembly of tissue-like 3D spheroids containing the nanoreactors and demonstrate that they can perform the reactions in a repeated mannerThe authors thank the financial support of the MINECO ( CTQ2017-89588-R , SAF2016-76689-R , CTQ2017-84767-P , RYC-2014-16962 , and RYC-2017-23457 ), the Xunta de Galicia ( ED431F 2017/02 , 2015-CP082 , ED431C 2017/19 , and Centro singular de investigación de Galicia accreditation 2019-2022, ED431G 2019/03 ), the European Union (European Regional Development Fund [ERDF]; H2020-MSCA-IF-2016 grant agreement no. 749667 ; and INTERREG V-A Spain-Portugal [POCTEP] 2014-2020, project 0624_2IQBIONEURO_6_E ), and the European Research Council (advanced grant no. 340055 ). Support of the orfeo-cinqa network ( CTQ2016-81797-REDC ) is also kindly acknowledgedS

Structure-guided engineering of a receptor-agonist pair for inducible activation of the ABA adaptive response to drought

Strategies to activate abscisic acid (ABA) receptors and boost ABA signaling by small molecules that act as ABA receptor agonists are promising biotechnological tools to enhance plant drought tolerance. Protein structures of crop ABA receptors might require modifications to improve recognition of chemical ligands, which in turn can be optimized by structural information. Through structure-based targeted design, we have combined chemical and genetic approaches to generate an ABA receptor agonist molecule (iSB09) and engineer a CsPYL1 ABA receptor, named CsPYL15m, which efficiently binds iSB09. This optimized receptor-agonist pair leads to activation of ABA signaling and marked drought tolerance. No constitutive activation of ABA signaling and hence growth penalty was observed in transformed Arabidopsis thaliana plants. Therefore, conditional and efficient activation of ABA signaling was achieved through a chemical-genetic orthogonal approach based on iterative cycles of ligand and receptor optimization driven by the structure of ternary receptor-ligand-phosphatase complexes

Disease-specific and general health-related quality of life in newly diagnosed prostate cancer patients: The Pros-IT CNR study

Background: The National Research Council (CNR) prostate cancer monitoring project in Italy (Pros-IT CNR) is an observational, prospective, ongoing, multicentre study aiming to monitor a sample of Italian males diagnosed as new cases of prostate cancer. The present study aims to present data on the quality of life at time prostate cancer is diagnosed. Methods: One thousand seven hundred five patients were enrolled. Quality of life is evaluated at the time cancer was diagnosed and at subsequent assessments via the Italian version of the University of California Los Angeles-Prostate Cancer Index (UCLA-PCI) and the Short Form Health Survey (SF-12). Results: At diagnosis, lower scores on the physical component of the SF-12 were associated to older ages, obesity and the presence of 3+ moderate/severe comorbidities. Lower scores on the mental component were associated to younger ages, the presence of 3+ moderate/severe comorbidities and a T-score higher than one. Urinary and bowel functions according to UCLA-PCI were generally good. Almost 5% of the sample reported using at least one safety pad daily to control urinary loss; less than 3% reported moderate/severe problems attributable to bowel functions, and sexual function was a moderate/severe problem for 26.7%. Diabetes, 3+ moderate/severe comorbidities, T2 or T3-T4 categories and a Gleason score of eight or more were significantly associated with lower sexual function scores at diagnosis. Conclusions: Data collected by the Pros-IT CNR study have clarified the baseline status of newly diagnosed prostate cancer patients. A comprehensive assessment of quality of life will allow to objectively evaluate outcomes of different profile of care