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A β-cyclodextrin labeled with seven naphthoyloxy chromophores was studied by steady-state and time-resolved fluorescence spectroscopy in order to get information on the dynamics of energy hopping between chromophores. The steady-state fluorescence anisotropy was recorded as a function of excitation wavelength in a mixture of methanol and ethanol at 110 K (rigid glass). The fluorescence anisotropy decay was obtained under the same conditions by the multifrequency phase-modulation technique upon excitation at 290 nm. The data were analyzed and interpreted on the basis of a theoretical model involving a unique rate constant for energy hopping between nearest neighbors. In particular, this model predicts a long-time leveling-off of the emission anisotropy at 1/7th of the fundamental anisotropy, which is confirmed by both steady-state and time-resolved data and thus indicates that there is no preferred mutual orientation between the chromophores. As regards the rate of energy hopping, an average value of 2 × 109 s-1 can be deduced from the comparison between the theoretical and experimental decays. This value is shown to be consistent with a dipole-dipole mechanism of energy transfer. © 1996 American Chemical Society.

S N Ar reactions were remarkably accelerated using a pretargeting and activating unit based on dynamic covalent chemistry (DCvC). A Cys attack at the C-F bond on the aromatic ring of salicylaldehyde derivatives was only observed upon iminium formation with a neighboring Lys residue of model small peptides. Such self-activation was ascribed to the stronger electron-withdrawing capability of the iminium bond with respect to that of the parent aldehyde that stabilized the transition state of the reaction, together with the higher preorganization of the reactive groups in the cationic aldiminium species. This approach was further applied for the functionalization of two antibodies. In both cases, the presence of the aldehyde group in close proximity to the reactive C-F bond resulted in a noteworthy increase in bioconjugation yields, with excellent chemo-selectivity. Whereas the modification of an IgG1 antibody led to stochastic product distributions, microenvironment selectivity was noted when employing IgG4, in line with the lower number of Lys residues in the hinge region of the latter. Additionally, the postfunctionalization of the modified antibodies was attained through the dynamic covalent exchange of the tethered iminium derivative with hydrazides, representing an unprecedented "tag and modify" selective bioconjugation strategy based on DCvC.

Molecular recognition and detection of small bioactive molecules, like neurotransmitters, remain a challenge for chemists, whereas nature found an elegant solution in form of protein receptors. Here, we introduce a concept of a dynamic artificial receptor that synergically combines molecular recognition with dynamic imine bond formation inside a lipid nanoreactor, inducing a fluorescence response. The designed supramolecular system combines a lipophilic recognition ligand derived from a boronic acid, a fluorescent aldehyde based on push-pull styryl pyridine and a phenol-based catalyst. The recognition ligand specifically captures dopamine inside lipid nanodroplets and thus triggers imine bond formation with the aldehyde, producing the emission color change. The rational design of the fluorescent aldehyde, the catalyst and the recognition ligand allows dramatic acceleration of the imine bond formation required for rapid sensing of dopamine. The nanoprobe enables dopamine detection with micromolar sensitivity and singe-nanoprobe imaging of dopamine gradients through its robust two-color ratiometric response. It displays remarkable selectivity without interference of competing biogenic primary amines and biological media: blood serum, plasma, urine and cell lysate. The proposed concept of a dynamic artificial receptor offers a solution to the long-standing problem of molecular recognition and sensing of small molecules in complex biological media., (© 2025 Wiley‐VCH GmbH.)

The hypoxic microenvironment is crucial for tumour cell growth and invasiveness. Tumour tissue results from adaptation to reduced oxygen availability. Hypoxia first activates pro-angiogenic signals for alleviation. Pathologic, tumour angiogenesis maintains hypoxia, impairing treatment outcomes. Vessel normalisation requires physioxia. Oxygen delivery by red blood cell (RBC) carrying haemoglobin (Hb) is enhanced by myo-inositol trispyrophosphate (ITPP), an effector of oxygen transport by RBCs. Altering glycolytic activity, it lowers intracellular pH and increases oxygen release from Hb. 31 P NMR tracking of 2,3-diphosphoglycerate (2,3-DPG), allosteric effector of Hb and non-penetrating anion in RBCs, reports on erythrocytes internal environment. 31 P resonances of 2,3-DPG are pH-sensitive, their positions indicate the oxygenation state of RBCs and interactions with effectors such as ITPP. Here we show in vitro and in vivo, that modifying Hb activity through band-3 anion transporter, ITPP enhances oxygen release and controls RBC internal pH. Its blood availability validates applicability of ITPP-based strategies., (© 2025 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Developing visible-light-driven fluorescent photoswitches in the solid state remains an enormous challenge in smart materials. Such photoswitches are obtained from salicylaldimines through excited-state intramolecular proton transfer (ESIPT) and subsequent cis-trans isomerization strategies. By incorporating a bulky naphthalimide fluorophore into a Schiff base, three photoswitches achieve dual-mode changes (both in color and fluorescence) in the solid state. In particular, the optimal one generates triple fluorescence changing from green, to yellow and finally to orange upon visible-light irradiation. This switching process is fully reversible and can be repeated at least 10 times without obvious attenuation, suggesting its good photo-fatigue resistance. Mechanism studies reveal that the naphthalimide group not only enables the tuning of multicolor with an additional emission, but also induces a folded structure, reducing molecular stacking and facilitating ESIPT and cis-trans isomerization. As such, photopatterning, ternary encoding and transient information recording and erasing are successfully developed. The present study provides a reliable strategy for visible-light-driven fluorescent photoswitches, showing implications for advanced information encryption materials., (© 2024 Wiley-VCH GmbH.)

We disclose the features of a category of reversible nucleophilic aromatic substitutions in view of their significance and generality in dynamic aromatic chemistry. Exchange of sulfur components surrounding arenes and heteroarenes may occur at 25 °C, in a process that one may call a "sulfur dance". These S N Ar systems present their own features, apart from common reversible reactions utilized in dynamic covalent chemistry (DCC). By varying conditions, covalent dynamics may operate to provide libraries of thiaarenes with some selectivity, or conversion of a hexa(thio)benzene asterisk into another one. The reversible nature of S N Ar is confirmed by three methods: a convergence of the products distribution in reversible S N Ar systems, a related product redistribution between two per(thio)benzenes by using a thiolate promoter, and from kinetic/thermodynamic data. A four-component dynamic covalent system further illustrates the thermodynamically-driven formation of a thiacalix[2]arene[2]pyrimidine by sulfur component exchanges. This work stimulates the implementation of reversible S N Ar in aromatic chemistry and in DCC., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Sea urchin eggs are covered with layers of extracellular matrix, namely, the vitelline layer (VL) and jelly coat (JC). It has been shown that sea urchin eggs' JC components serve as chemoattractants or ligands for the receptor on the fertilizing sperm to promote the acrosome reaction. Moreover, the egg's VL provides receptors for conspecific sperm to bind, and, to date, at least two sperm receptors have been identified on the surface of sea urchin eggs. Interestingly, however, according to our previous work, denuded sea urchin eggs devoid of the JC and VL do not fail to become fertilized by sperm. Instead, they are bound and penetratedby multiple sperm, raising the possibility that an alternative pathway independent of the VL-residing sperm receptor may be at work. In this research, we studied the roles of the JC and VL using intact and denuded eggs and the synthetic polyamine BPA-C8. BPA-C8 is known to bind to the negatively charged macromolecular complexes in the cells, such as the JC, VL, and the plasma membrane of echinoderm eggs, as well as to the actin filaments in fibroblasts. Our results showed that, when added to seawater, BPA-C8 significantly repressed the Ca 2+ wave in the intact P. lividus eggs at fertilization. In eggs deprived of the VL and JC, BPA-C8 binds to the plasma membrane and increases fibrous structures connecting microvilli, thereby allowing the denuded eggs to revert towards monospermy at fertilization. However, the reduced Ca 2+ signal in denuded eggs was nullified compared to the intact eggs because removing the JC and VL already decreased the Ca 2+ wave. BPA-C8 does not cross the VL and the cell membrane of unfertilized sea urchin eggs to diffuse into the cytoplasm at variance with the fibroblasts. Indeed, the jasplakinolide-induced polymerization of subplasmalemmal actin filaments was inhibited in the eggs microinjected with BPA-C8, but not in the ones bath-incubated with the same dose of BPA-C8.

Imination reactions in water represent a challenge not only because of the high propensity of imines to be hydrolysed but also as a result of the competing hydrate formation through H 2 O addition to the aldehyde. In the present work we report a successful approach that allows for favouring imitation reactions while silencing hydrate formation. Such remarkable reactivity and selectivity can be attained by fine-tuning the electronic and steric structural features of the ortho -substituents of the carbonyl groups. It resulted from studying the structure-reactivity relationships in a series of condensation reactions between different amines and aldehydes, comparing the results to the ones obtained in the presence of the biologically-relevant pyridoxal phosphate (PLP). The key role of negatively-charged and sterically-crowding units ( i.e. , sulfonate groups) in disfavouring hydrate formation was corroborated by DFT and steric-hindrance calculations. Furthermore, the best-performing aldehyde leads to higher imine yields, selectivity and stability than those of PLP itself, allowing for the inhibition of a PLP-dependent enzyme (transaminase) through dynamic aldimine exchange. These results will increase the applicability of imine-based dynamic covalent chemistry (DCvC) under physiological conditions and will pave the way for the design of new carbonyl derivatives that might be used in the dynamic modification of biomolecules., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Dynamic noncovalent and covalent chemistries have enabled the constitutional modulation of chemical entities within chemical dynamic systems. The switching between order and disorder, i.e., self-sorted and unsorted states of constitutional dynamic libraries, remains challenging. Herein, we study the adaptive behaviors of a dynamic library of imine macrocycles generated from dialdehydes and diamines, seeking ways to exert control over sorting and unsorting processes. The distribution of constituents in the present library of dynamic macrocycles is modulated in response to internal and external effectors (e.g., time, metal cations, and chemical fuels), resulting in the transient amplification of self-sorted constituents in out-of-equilibrium states. The present study showcases higher complexity in systems subject to multiple adaptation through the dynamic interconversion between singularity/order and diversity/disorder.

The mechanisms through which environmental conditions affect the expression of interconnected species is a key step to comprehending the principles underlying complex chemical processes. In Nature, chemical modifications triggered by the environment have a major impact on the structure and function of biomolecules and regulate different reaction pathways. Yet, minimalistic artificial systems implementing related adaptation behaviours remain barely explored. The hydrolysis of amino acid methyl esters to their corresponding amino acids leads to a drastic change in p K a ( ca. 7 and 9, respectively) that protonates the free amino group at physiological conditions. Dynamic covalent libraries (DCvLs) based on amino acid methyl esters and aldehydes respond to such hydrolysis and lead to constitutional adaptation. Each of the libraries studied experiences a DCvL conversion allowing for constituent selection due to the silencing of the zwitterionic amino acids towards imine formation. The selective action of different enzymes on the DCvLs results in states with simplified constitutional distributions and transient chirality. When additional components ( i.e. , scavengers) that are not affected by hydrolysis are introduced into the dynamic libraries, the amino acid methyl ester hydrolysis induces the up-regulation of the constituents made of these scavenging components. In these systems, the constituent distribution is resolved from a scrambled mixture of imines to a state characterized by the predominance of a single aldimine. Remarkably, although the final libraries display higher "simplexity", the different transient states present an increased complexity that allows for the emergence of organized structures [micelle formation] and distributions [up-regulation of two antagonistic constituents]. This reactive site inhibition by a remote chemical modification resembles the scenario found in some enzymes for the regulation of their activity through proximal post-translational modifications., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Understanding the behavior of complex chemical reaction networks and how environmental conditions can modulate their organization as well as the associated outcomes may take advantage of the design of related artificial systems. Microenvironments with defined boundaries are of particular interest for their unique properties and prebiotic significance. Dynamic covalent libraries (DCvLs) and their underlying constitutional dynamic networks (CDNs) have been shown to be appropriate for studying adaptation to several processes, including compartmentalization. However, microcompartments (e.g., micelles) provide specific environments for the selective protection from interfering reactions such as hydrolysis and an enhanced chemical promiscuity due to the interface, governing different processes of network modulation. Different interactions between the micelles and the library constituents lead to dynamic sensing, resulting in different expressions of the network through pattern generation. The constituents integrated into the micelles are protected from hydrolysis and hence preferentially expressed in the network composition at the cost of constitutionally linked members. In the present work, micellar integration was observed for two processes: internal uptake based on hydrophobic forces and interfacial localization relying on attractive electrostatic interactions. The latter drives a complex triple adaptation of the network with feedback on the shape of the self-assembled entity. Our results demonstrate how microcompartments can enforce the expression of constituents of CDNs by reducing the hydrolysis of uptaken members, unravelling processes that govern the response of reactions networks. Such studies open the way toward using DCvLs and CDNs to understand the emergence of complexity within reaction networks by their interactions with microenvironments.

ConspectusSince its inception in the early 1990s, the field of supramolecular polymers (SPs) has grown into an interdisciplinary field of chemistry. It expanded from the self-assembly of molecular building blocks based on H-bonding into the realm of complex dynamic material, encompassing both supramolecular noncovalent and molecular covalent regimes. It has paved the path for a more diverse field of research into a new class of polymeric materials, coined dynamic polymers or dynamers. Dynamers are bringing a paradigm shift not only in material science research but also in a broad field of applications from self-healing materials to biocompatible polymeric materials. The present Account presents the evolution of supramolecular polymer chemistry from simple linear polymeric chains to complex dynamic polymers imparting novel functional properties, such as component exchange and self-healing. We explore how SPs led to materials of increasing complexity, starting from simple main-chain polymers to the formation of more complex columnar SPs and lateral SPs. The field has experienced three partially overlapping periods. The main goal was first the generation of polymeric entities from various molecular components connected through noncovalent interactions, especially complementary hydrogen bonding recognition patterns as well as stacked columnar SPs. Thereafter, attention was directed in parallel to the exploration of the properties of SPs and their applications as novel materials. In a third period, the dynamic properties of supramolecular polymers were explored, taking advantage of the lability of noncovalent interactions to perform component rearrangement and exchange. We illustrate how the field of SPs has emerged as a multidisciplinary field of chemistry, biology, and materials science with selected examples from the literature. The SPs, specifically dynamic owing to their inherent reversibility, also pave the path to easier sorting and recycling, as desired in the plastics industry.One of the biggest challenges that the plastics industry is facing today is the end-of-life fate of plastics. Plastics that cannot be recycled end up in landfills or are improperly disposed of in rivers and oceans, polluting and damaging the environmental balance irreversibly. Dynamic polymeric materials presenting inherent dynamicity could pave the way for addressing this long-standing challenge of nonrecyclability of plastics. Dynamers formed via noncovalent interactions or reversible covalent bonds can be broken into components that could be easily recycled and reused. Therefore, dynamers could play a pivotal role toward closing the loop for the plastics industry and provide a solution to an elusive circular economy with plastics being an integral part.

In cancer patients, immune cells are often functionally compromised due to the immunosuppressive features of the tumor microenvironment (TME) which contribute to the failures in cancer therapies. Clinical and experimental evidence indicates that developing tumors adapt to the immunological environment and create a local microenvironment that impairs immune function by inducing immune tolerance and invasion. In this context, microenvironmental hypoxia, which is an established hallmark of solid tumors, significantly contributes to tumor aggressiveness and therapy resistance through the induction of tumor plasticity/heterogeneity and, more importantly, through the differentiation and expansion of immune-suppressive stromal cells. We and others have provided evidence indicating that hypoxia also drives genomic instability in cancer cells and interferes with DNA damage response and repair suggesting that hypoxia could be a potential driver of tumor mutational burden. Here, we reviewed the current knowledge on how hypoxic stress in the TME impacts tumor angiogenesis, heterogeneity, plasticity, and immune resistance, with a special interest in tumor immunogenicity and hypoxia targeting. An integrated understanding of the complexity of the effect of hypoxia on the immune and microenvironmental components could lead to the identification of better adapted and more effective combinational strategies in cancer immunotherapy. Clearly, the discovery and validation of therapeutic targets derived from the hypoxic tumor microenvironment is of major importance and the identification of critical hypoxia-associated pathways could generate targets that are undeniably attractive for combined cancer immunotherapy approaches., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest or any competing interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The forthcoming generation of materials, including artificial muscles, recyclable and healable systems, photochromic heterogeneous catalysts, or tailorable supercapacitors, relies on the fundamental concept of rapid switching between two or more discrete forms in the solid state. Herein, we report a breakthrough in the "speed limit" of photochromic molecules on the example of sterically-demanding spiropyran derivatives through their integration within solvent-free confined space, allowing for engineering of the photoresponsive moiety environment and tailoring their photoisomerization rates. The presented conceptual approach realized through construction of the spiropyran environment results in ~1000 times switching enhancement even in the solid state compared to its behavior in solution, setting a record in the field of photochromic compounds. Moreover, integration of two distinct photochromic moieties in the same framework provided access to a dynamic range of rates as well as complementary switching in the material's optical profile, uncovering a previously inaccessible pathway for interstate rapid photoisomerization., (© 2023. The Author(s).)

This work reports the effect of Pd(II) as chemical effector on an acylhydrazone-based dynamic covalent library (DCL) in biphasic systems (water/chloroform). The constituents of the DCL are self-built and distributed in the two phases, two of them are lipophilic enough to play the role of a carrier agent that may transfer Pd(II) from the aqueous phase to the organic phase. Upon addition of Pd(II), the DCL of components exhibits a strong amplification of the constituent that is the most adapted to stabilize Pd(II) in chloroform as well as its agonist in water. This evolution is driven by the combination of the interaction of the DCL with Pd(II) and the presence of the two phases. This study paves the way to a novel approach for liquid/liquid extraction and metal recovery by means of adaptive extractant species generated in situ by a DCL., (© 2023 Wiley-VCH GmbH.)

Imine formation under physiological conditions represents a challenging reaction due to the strong propensity of aldimines to be hydrolyzed. Herein we disclose the remarkable effect of supramolecular multivalency on increasing imine stability. A family of reactive aldehydes was synthesized bearing supramolecularly-active sites within their structure. The imine formation activity for such aldehydes was evaluated and compared with model aldehydes. The reaction of the best-performing species - containing two carboxylate groups-with a set of amines showed a significant decrease in imine yields as the degree of supramolecular multivalency between sidechains decreased. The reversible conjugation of amino acid derivatives and small peptides was also assayed, with excellent selectivities for the imine formation at the Nα position even in substrates containing competing sites. Preliminary results on protein bioconjugation revealed that a model enzyme could be dynamically inhibited upon reaction with the aldehyde, with its native activity being recovered by displacing the imine bonds with a suitable chemical effector ( i.e. , acylhydrazide)., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Investigating the self-assembly and self-sorting behaviour of dynamic covalent organic architectures makes possible the parallel generation of multiple discrete products in a single one pot procedure. We here report the self-assembly of covalent organic macrocycles and macrobicyclic cages from dialdehyde and polyamine components via multiple [2 + 2] and [3 + 2] polyimine condensations. Furthermore, component self-sorting processes have been monitored within the dynamic covalent libraries formed by these macrocycles and macrobicyclic cages. The progressive assembly of the final structures involves intermediates which undergo component selection and self-correction to generate the final thermodynamic constituents. The homo-self-sorting observed seems to involve entropic factors, as the homoleptic species present a higher symmetry than the competing heteroleptic ones. This study not only emphasizes the importance of an adequate design of the components of complex self-sorting systems, but also verifies the conjecture that systems of higher complexity may generate simpler outputs through the operation of competitive self-sorting., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

In starfish, the addition of the hormone 1-methyladenine (1-MA) to immature oocytes (germinal vesicle, GV-stage) arrested at the prophase of the first meiotic division induces meiosis resumption (maturation), which makes the mature eggs able to respond to the sperm with a normal fertilization response. The optimal fertilizability achieved during the maturation process results from the exquisite structural reorganization of the actin cytoskeleton in the cortex and cytoplasm induced by the maturing hormone. In this report, we have investigated the influence of acidic and alkaline seawater on the structure of the cortical F-actin network of immature oocytes of the starfish ( Astropecten aranciacus ) and its dynamic changes upon insemination. The results have shown that the altered seawater pH strongly affected the sperm-induced Ca 2+ response and the polyspermy rate. When immature starfish oocytes were stimulated with 1-MA in acidic or alkaline seawater, the maturation process displayed a strong dependency on pH in terms of the dynamic structural changes of the cortical F-actin. The resulting alteration of the actin cytoskeleton, in turn, affected the pattern of Ca 2+ signals at fertilization and sperm penetration.

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, and it is a disease of dismal prognosis. While immunotherapy has revolutionized the treatment of various solid tumors, it has achieved little success in PDAC. Hypoxia within the stroma-rich tumor microenvironment is associated with resistance to therapies and promotes angiogenesis, giving rise to a chaotic and leaky vasculature that is inefficient at shuttling oxygen and nutrients. Hypoxia and its downstream effectors have been implicated in immune resistance and could be contributing to the lack of response to immunotherapy experienced by patients with PDAC. Paradoxically, increasing evidence has shown hypoxia to augment genomic instability and mutagenesis in cancer, suggesting that hypoxic tumor cells could have increased production of neoantigens that can potentially enable their clearance by cytotoxic immune cells. Strategies aimed at relieving this condition have been on the rise, and one such approach opts for normalizing the tumor vasculature to reverse hypoxia and its downstream support of tumor pathogenesis. An important consideration for the successful implementation of such strategies in the clinic is that not all PDACs are equally hypoxic, therefore hypoxia-detection approaches should be integrated to enable optimal patient selection for achieving improved patient outcomes.

We report the implementation of coordination complexes containing two types of cationic moieties, i. e. pyridinium and ammonium quaternary salt, as potential inhibitors of human cholinesterase enzymes. Utilization of ligands containing NNO-coordination site and binding zinc metal ion allowed mono- and tetra-nuclear complexes to be obtained with corner and grid structural type, respectively, thus affecting the overall charge of the compounds (from +1 to +8). We were able to examine for the first time the multivalency effect of metallosupramolecular species on their inhibitory abilities towards acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Importantly, resolution of the crystal structures of the obtained enzyme-substrate complexes provided a better understanding of the inhibition process at the molecular level., (© 2022 Wiley-VCH GmbH.)

Dynamic combinatorial libraries (DCLs) display adaptive behavior, enabled by the reversible generation of their molecular constituents from building blocks, in response to external effectors, e.g., protein receptors. So far, chemoinformatics has not yet been used for the design of DCLs-which comprise a radically different set of challenges compared to classical library design. Here, we propose a chemoinformatic model for theoretically assessing the composition of DCLs in the presence and the absence of an effector. An imine-based DCL in interaction with the effector human carbonic anhydrase II (CA II) served as a case study. Support vector regression models for the imine formation constants and imine-CA II binding were derived from, respectively, a set of 276 imines synthesized and experimentally studied in this work and 4350 inhibitors of CA II from ChEMBL. These models predict constants for all DCL constituents, to feed software assessing equilibrium concentrations. They are publicly available on the dedicated website. Models rationally selected two amines and two aldehydes predicted to yield stable imines with high affinity for CA II and provided a virtual illustration on how effector affinity regulates DCL members., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

A series of complexes of Na, K, NH 4 , and H 3 O with [bpy.bpy.bpy]cryptand, [2.2.2]cryptand, and spherical cryptand were investigated via DFT and ab initio methods. We found that by coating Rydberg molecules with the "organic skin" one could further decrease their ionization potential energy, reaching the values of ∼1.5 eV and a new low record of 1.3 eV. The neutral cryptand complexes in this sense possess a weakly bounded electron and may be considered as very strong reducing agents. Moreover, the presence of an organic cage increases the thermodynamic stability of Rydberg molecules making them stable toward the proton detachment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tkachenko, Rublev, Boldyrev and Lehn.)

Aerosol lung gene therapy using non-viral delivery systems represents a credible therapeutic strategy for chronic respiratory diseases, such as cystic fibrosis (CF). Progress in CF clinical setting using the lipidic formulation GL67A has demonstrated the relevance of such a strategy while emphasizing the need for more potent gene transfer agents. In recent years, many novel non-viral gene delivery vehicles were proposed as potential alternatives to GL67 cationic lipid. However, they were usually evaluated using procedures difficult or even impossible to implement in clinical practice. In this study, a clinically-relevant administration protocol via aerosol in murine lungs was used to conduct a comparative study with GL67A. Diverse lipidic compounds were used to prepare a series of formulations inspired by the composition of GL67A. While some of these formulations were ineffective at transfecting murine lungs, others demonstrated modest-to-very-efficient activities and a series of structure-activity relationships were unveiled. Lipidic aminoglycoside derivative-based formulations were found to be at least as efficient as GL67A following aerosol delivery of a luciferase-encoding plasmid DNA. A single aerosol treatment with one such formulation was found to mediate long-term lung transgene expression, exceeding half the animal's lifetime. This study clearly supports the potential of aminoglycoside-based cationic lipids as potent GL67-alternative scaffolds for further enhanced aerosol non-viral lung gene therapy for diseases such as CF.

The vitelline layer (VL) of a sea urchin egg is an intricate meshwork of glycoproteins that intimately ensheathes the plasma membrane. During fertilization, the VL plays important roles. Firstly, the receptors for sperm reside on the VL. Secondly, following cortical granule exocytosis, the VL is elevated and transformed into the fertilization envelope (FE), owing to the assembly and crosslinking of the extruded materials. As these two crucial stages involve the VL, its alteration was expected to affect the fertilization process. In the present study, we addressed this question by mildly treating the eggs with a reducing agent, dithiothreitol (DTT). A brief pretreatment with DTT resulted in partial disruption of the VL, as judged by electron microscopy and by a novel fluorescent polyamine probe that selectively labelled the VL. The DTT-pretreated eggs did not elevate the FE but were mostly monospermic at fertilization. These eggs also manifested certain anomalies at fertilization: (i) compromised Ca 2+ signaling, (ii) blocked translocation of cortical actin filaments, and (iii) impaired cleavage. Some of these phenotypic changes were reversed by restoring the DTT-exposed eggs in normal seawater prior to fertilization. Our findings suggest that the FE is not the decisive factor preventing polyspermy and that the integrity of the VL is nonetheless crucial to the egg's fertilization response.

A triple dynamic complex system has been designed, implementing a dynamic covalent process coupled to two supramolecular self-assembly steps. To this end, two dynamic covalent libraries (DCLs), DCL-1 and DCL-2 , have been established on the basis of dynamic covalent C═C/C═N organo-metathesis between two Knoevenagel derivatives and two imines. Each DCL contains a barbituric acid-based Knoevenagel constituent that may undergo a sequential double self-organization process involving first the formation of hydrogen-bonded hexameric supramolecular macrocycles that subsequently undergo stacking to generate a supramolecular polymer SP yielding a viscous gel state. Both DCLs display selective self-organization-driven amplification of the constituent that leads to the SP. Dissociation of the SP on heating causes reversible randomization of the constituent distributions of the DCLs as a function of temperature. Furthermore, diverse distribution patterns of DCL-2 were induced by modulation of temperature and solvent composition. The present dynamic systems display remarkable self-organization-driven constitutional adaption and tunable composition by coupling between dynamic covalent component selection and two-stage supramolecular organization. In more general terms, they reveal dynamic adaptation by component selection in low Reynolds number conditions of living systems where frictional effects dominate inertial behavior.

Hypoxia is prominent in solid tumors and a recognized driver of malignancy. Thus far, targeting tumor hypoxia has remained unsuccessful. Myo-inositol trispyrophosphate (ITPP) is a re-oxygenating compound without apparent toxicity. In preclinical models, ITPP potentiates the efficacy of subsequent chemotherapy through vascular normalization. Here, we report the results of an unrandomized, open-labeled, 3 + 3 dose-escalation phase Ib study (NCT02528526) including 28 patients with advanced primary hepatopancreatobiliary malignancies and liver metastases of colorectal cancer receiving nine 8h-infusions of ITPP over three weeks across eight dose levels (1'866-14'500 mg/m 2 /dose), followed by standard chemotherapy. Primary objectives are assessment of the safety and tolerability and establishment of the maximum tolerated dose, while secondary objectives include assessment of pharmacokinetics, antitumor activity via radiological evaluation and assessment of circulatory tumor-specific and angiogenic markers. The maximum tolerated dose is 12,390 mg/m 2 , and ITPP treatment results in 32 treatment-related toxicities (mostly hypercalcemia) that require little or no intervention. 52% of patients have morphological disease stabilization under ITPP monotherapy. Following subsequent chemotherapy, 10% show partial responses while 60% have stable disease. Decreases in angiogenic markers are noted in ∼60% of patients after ITPP and tend to correlate with responses and survival after chemotherapy.

Optimizing C=N bond formation and C/N component exchange has major significance in Dynamic Covalent Chemistry (DCC). Imine and hydrazone generation from their aldehyde, amine and hydrazine components showed large accelerations in presence of AgOTf or Zn(OTf) 2 , up to 10 4 for the Zn(II)-(p-anisidine)imine complex. Zn(OTf) 2 and auxiliary p-anisidine together accelerated 630 times the formation of the Zn(II)-hydrazone complex, revealing a strong synergistic effect, traced to very fast initial formation of the reactive Zn(II)-imine complex presenting a C=N bond metallo-activated towards reaction with the hydrazine component. Reactions involving more entities showed kinetically faster and thermodynamically simpler outputs due to dynamic competition within a mixture of higher complexity. Catalytic amounts of metal salts and auxiliary amine gave similar marked rate accelerations and turnover, indicating true catalysis. The synergistic effect achieved by combining metallo- and organo-catalysis points to a powerful co-catalysis strategy of bond-formation in DCC through interconnected chemical transformations., (© 2021 Wiley-VCH GmbH.)

A S 6 -symmetric triarylamine-based macrocycle (i.e., hexaaza[1 6 ]paracyclophane), decorated with six lateral amide functions, is synthesized by a convergent and modular strategy. This macrocycle is shown to undergo supramolecular polymerization in o -dichlorobenzene, and its nanotubular structure is elucidated by a combination of spectroscopy and microscopy techniques, together with X-ray scattering and molecular modeling. Upon sequential oxidation, a spectroelectrochemical analysis of the supramolecular polymer suggests an extended electronic delocalization of charge carriers both within the macrocycles (through bond) and between the macrocycles along the stacking direction (through space).

The understanding and the application of reversible covalent reactions and coordination chemistry together with the proper design of the molecular frameworks, allow to achieve not only well-defined output architectures but also different grades of complex behavior. In this work, the dynamic nature of the helical systems offers an additional level of complexity by combining self-sorting on two levels: 1) the build-up of the ligand strand constituents from their components through dynamic covalent chemistry; 2) the assembly of the helicates from the ligands and the metal cations through dynamic metallo-supramolecular chemistry. The information encoded in the ligands constituent molecule was read differently (and accurately at the same time) by metal cations that varied in the coordination algorithms. It enabled the selective formation of a specific type of helicates from a wide library of helicates formed by the possible combination of subcomponents. Ligands containing dynamic tridentate and/or bidentate binding motifs in the same strand were studied to explore the helicates self-assembly with appropriate metal cations., (© 2020 Wiley-VCH GmbH.)

In contrast to the classical method where a single molecule is designed to extract metal cations under specific conditions, dynamic covalent chemistry provides an approach based on the implementation of an adaptive dynamic covalent library for inducing the generation of the extractant species. This approach has been applied to the liquid-liquid extraction of copper(ii) nitrate based on a dynamic library of acylhydrazones constituents that self-build and distribute through the interface of a biphasic system. The addition of copper(ii) cations to this library triggers a modification of its composition and the up-regulation of the ligand molecules driven by coordination to the metal cations. Among these, one species has proven to be sufficiently lipophilic to play the role of carrier agent and its formation by component exchange enables the partial extraction of the copper(ii). The study of different pathways to generate the dynamic covalent library demonstrates the complete reversibility and the adaptability of the system. The detailed analytical investigation of the system provides a means to assess the mechanism of the dynamic extraction process., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Dynamic covalent component self-sorting processes have been investigated for constituents of different cyclic orders , macrocycles and macrobicyclic cages based on multiple reversible imine formation. The progressive assembly of the final structures from dialdehyde and polyamine components involved the generation of kinetic products and mixtures of intermediates which underwent component selection and self-correction to generate the final thermodynamic constituents. Importantly, constitutional dynamic networks (CDNs) of macrocycles and macrobicyclic cages were set up either from separately prepared constituents or by in situ assembly from their components. Over time, these CDNs underwent conversion from a kinetically trapped out-of-equilibrium distribution of constituents to the thermodynamically self-sorted one through component exchange in different dimensional orders.

Three imine-based metal complexes, having no overlap in terms of their compositions, have been simultaneously generated from the self-sorting of a constitutional dynamic library (CDL) containing three amines, three aldehydes, and three metal salts. The hierarchical ordering of the stability of the three metal complexes assembled and the leveraging of the antagonistic and agonistic relationships existing between the constituents within the constitutional dynamic network corresponding to the CDL were pivotal in achieving the sorting. Examination of the process by NMR spectroscopy showed that the self-sorting of the Fe II and Zn II complexes depended on an interplay between the thermodynamic driving forces and a kinetic trap involved in their assembly. These results also exemplify the concept of "simplexity"-the fact that the output of a self-assembling system may be simplified by increasing its initial compositional complexity-as the two complexes could self-sort only in the presence of the third pair of organic components, those of the Cu I complex., (© 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

Two constitutional dynamic libraries (CDLs)-each containing two amines, two dialdehydes, and two metal salts-have been found to self-sort, generating two pairs of imine-based metallosupramolecular architectures (sharing no component) each with a [2 × 2] grid-like complex and a linear double helicate. These CDLs provided unique examples of a three-level self-sorting process, as only two imine-based ligand constituents, two metal complexes, and two architectures were selected during their assembly out of all the possible combinations of their initial components. The metallosupramolecular architectures assembled were characterized by NMR, mass spectroscopy, and X-ray crystallography.

A major hurdle in the development of complex constitutional dynamic networks (CDNs) is the lack of strategies to simultaneously control the output of two (or more) interconnected dynamic processes over several species, namely reversible covalent imine bond formation and dynamic metal-ligand coordination. We have studied in detail the self-sorting process of 11 constitutional dynamic libraries containing two different amines, aldehydes and metal salts into two imine-based metal complexes, having no overlap in terms of their compositions. This study allowed us to determine the factors influencing the fidelity of this process (concentration, electronic and steric parameters of the organic components, and nature of the metal cations). In all 11 systems, the outcome of the process was primarily determined by the ability of the octahedral metal ion to select its pair of components from the initial pool of components, with the composition of the weaker tetrahedral complex being imposed by the components rejected by the octahedral metal ions. Different octahedral metal ions required different levels of precision in the "assembling instructions" provided by the organic components of the CDN to guide it towards a sorted output. The concentration of the reaction mixture, and the electronic and steric properties of the initial components of the library were all found to influence the lifetime of unwanted metastable intermediates formed during the assembling of the two complexes., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The distribution of the constituents of a constitutional dynamic library (CDL) may undergo time-dependent changes as a function of the kinetics of the processes generating the CDL from its components. Thus, the constitutional dynamic network (CDN) representing the connections between the constituents changes from a kinetic distribution to the thermodynamic one as a function of time. We investigated the behavior of dynamic covalent libraries (DCLs) of four constituents generated by reversible formation of C═N bonds between four components, 2 aldehydes and 2 amino compounds, both in absence and in the presence of metal cations. The associated [2 × 2] networks underwent time-dependent changes from the initial kinetic distribution to the final thermodynamic one, involving an orthogonal switch from one diagonal to the other diagonal of the square [2 × 2] network leading to a very large change in distribution. The DCL constituents could be switched from kinetic products (imines) to thermodynamic products (oximes or acylhydrazones) based on the reactivities of the components and the thermodynamic stabilities of the constituents without addition of any external effector, solely on the basis of the intrinsic properties of the self-contained system. Such processes were achieved for purely organic DCLs/CDNs as well as for inorganic ones containing two metal cations, the latter changing from the silver(I) complex of an imine (kinetic product) to the zinc(II) complex of a hydrazone (thermodynamic product). The results bear relationship to out-of-equilibrium systems concerning kinetic behavior in adaptive chemistry.

The immense discriminative capacity of the human olfactory chemosensory systems relies on the generation of a combinatorial signal in response to the interaction of a particular odorant molecule with many different olfactory receptors. In this work, we report the generation of distributional signals by the action of particular effectors, here metal cations, on dynamic covalent libraries (DCLs) of receptor molecules, here ligands for metal cations. Different effectors are discriminated by the formation of different constitutional distributions, which result from the adaptation of the DCL to the action of a particular cation effector through the selection and exchange of components. Compartmentalization by operation in a system of immiscible solvents (here water and chloroform) results in a 3D constitutional dynamic network (CDN), effecting distributional signal and information transfer between two domains, through the interface from the "writing" input phase (the IN-phase) and the "reading" output phase (the OUT-phase). Here, it is not the selectivity of a specific recognition process between a particular DCL member and a given effector that is key to the information processing, but the change in the distribution of the components and constituents, a dynamic pattern or fingerprint , induced in one phase in response to interaction with a given effector binding and transmitted to the other phase by component and constituent exchange across the phase boundary. Finally, the pattern recognition techniques such as hierarchical cluster analysis (HCA) and principal component analysis (PCA) were successfully applied to analyze the output generated by the action of different effectors on the higher order [5 × 5] DCL. Discrimination between different effectors was characterized by specific domains. Such data processing also opens the way toward extension to much larger DCLs.

Objective: To establish a return on investment (ROI) for a pharmacist position on a hospital-based palliative care (PC) team. Background: Utilizing a pharmacist to provide PC services is often overlooked as a solution to physician shortages. Integration of a pharmacist into PC teams yields a favorable ROI. Methods: A 16-month retrospective review comparing PC patients at two hospitals with consultative PC teams. The PC teams at the two facilities had identical full-time equivalent team members, except for a PC pharmacist at Facility 1. The PC pharmacist's ROI was calculated based on cost savings created by utilizing the PC pharmacist as a physician extender and costs attributable to preventable adverse drug events (pADEs) identified by the PC pharmacist. Results: An annual ROI of 1.2 to 2.9 million dollars was calculated, $125,760 from physician time saved and $1.1-2.8 million dollars from pADEs. A statistically significant difference in rates of pADEs was realized between the PC pharmacist and non-PC pharmacists at Facility 1 as well as between pharmacists at Facility 1 (PC pharmacist and non-PC pharmacists) and pharmacists at Facility 2 (non-PC pharmacists). Conclusion: A PC pharmacist's unique qualifications and perspective contribute to the value of care provided to PC patients. A favorable ROI that exceeds a pharmacist's annual salary was demonstrated in this analysis.

Self-assembling macrobicyclic cryptand-type organic cages display remarkable self-sorting behavior with efficient component selection. Making use of the dynamic covalent chemistry approach, eight different cages were synthesized by condensation of tris(2-aminopropyl)amine with structurally different dialdehydes. A series of self-sorting experiments were first carried out on simple dynamic covalent libraries. They reveal the influence of different structural features of the aldehyde components on the condensation with two triamine capping units. Subsequently, self-sorting experiments were performed on more complex systems involving several dialdehyde building blocks. Altogether, the results obtained describe the effect of the presence of a heteroatom, of electrostatic interactions, of delocalization and of the flexibility/stiffness of the propensity of a component to undergo formation of a macrobicyclic cage. In the presence of a catalytic amount of acid, the macrobicyclic structure undergoes dynamic component exchange.

We report a study of the behavior of four dynamic covalent libraries (DCLs) based on acylhydrazones a A b B and of the corresponding square constitutional dynamic networks (CDNs) NA-ND under the effect of three agents, namely, metal cations, base + metal cations and light irradiation; in particular, the successful switching of the CDN NB between two orthogonal distributions results, respectively, from metallo-selection and photo-selection. The four DCLs undergo triple adaptation when subjected to the three agents with the generation of specific CDN distributions characteristic of each of the four DCLs. The ternary outputs displayed by the DCLs present three states (-1, 0 and 1) related to three different constitutional distributions expressed in response to the triple inputs applied. This latter process amounts to the storage of molecular information in dynamic distributions rather than in selective interactions between complementary entities undergoing molecular recognition.

The information encoded in the base sequences of nucleic acids is used to construct [3 × 2] or [3 × 3] constitutional dynamic networks (CDNs) composed of six or nine constituents, respectively. In the presence of appropriate triggers, the adaptive and hierarchical reconfiguration of the CDNs is demonstrated. The reconfiguration of the CDNs, which involves the triggered stabilization and upregulation of a specific constituent is accompanied by the upregulation of the constituents that do not share component connectivities with the trigger-stabilized constituent, and by the concomitant downregulation of the constituents sharing component connectivities with the trigger-stabilized constituent. Using a set of different triggers, a series of reconfigured networks-in-networks are demonstrated. The operation and reconfiguration of the CDNs are based on the following motives: (i) Each of the constituents in the [3 × 2] or [3 × 3] CDNs is composed of a supramolecular structure consisting of two duplex-bridged double-loop quasi-circle units. The hybridization of a single-stranded trigger with the double-loop domain stabilizes the respective constituent, and this results in the reconfiguration of the CDNs. (ii) To each of the constituents is conjugated a Mg 2+ -ion-dependent DNAzyme that cleaves a sequence-specific fluorophore/quencher substrate. The time-dependent fluorescence changes upon the cleavage of the different substrates by the reporter DNAzymes, and the use of appropriate calibration curves, provide means to quantitatively evaluate the contents of all constituents in the different CDNs. The triggered transitions of the parent [3 × 2] or [3 × 3] CDNs into three different CDNs using three different triggers, respectively, are exemplified. In addition, the transitions of the parent [3 × 2] or [3 × 3] CDNs using sequential triggers are demonstrated. Adaptive equilibrated reconfiguration of the CDNs subjected to triggers is demonstrated, and hierarchical adaptive dynamic transitions of the CDNs, subjected to two sequential triggering signals are highlighted. In addition, emerging catalytic functions driven by the adaptive and hierarchical transitions across different equilibrated states of the [3 × 3] CDNs are demonstrated.