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A number of artificial cation ionophores (or transporters) have been developed for basic research and biomedical applications. However, their mechanisms of action and the putative correlations between changes in intracellular cation concentrations and induced cell death remain poorly understood. Here we show that three hemispherand-strapped calix[4]pyrrole based ion pair receptors act as efficient Na+/K+ exchangers in the presence of Cl- in liposomal models, and promote Na+ influx and K+ efflux (Na+/K+ exchange) in cancer cells to induce apoptosis. Mechanistic studies reveal that these cation exchangers induce endoplasmic reticulum (ER) stress in cancer cells by perturbing intracellular cation homeostasis, promote generation of reactive oxygen species, and eventually enhance mitochondria-mediated apoptosis. However, they neither induce osmotic stress nor affect autophagy. The present study provides support for the notion that synthetic receptors which perturb cellular cation homeostasis may provide a new approach to generating agents with potentially useful apoptotic activity.

Acute kidney injury (AKI) is common after cardiac surgery and is difficult to predict. N-terminal pro-B-type natriuretic peptide (NT-proBNP) is highly predictive for perioperative cardiovascular complications and may also predict renal injury. We therefore tested the hypothesis that preoperative NT-proBNP concentration is associated with renal injury after major cardiac surgery.We included 35 337 patients who had cardiac surgery and measurements of preoperative NT-proBNP and postoperative creatinine. The primary outcome was Kidney Disease: Improving Global Outcomes Stages 1-3 AKI. We also separately considered severe AKI, including Stage 2, Stage 3, and new-onset dialysis.Postoperative AKI occurred in 11 999 (34.0%) patients. Stage 2 AKI occurred in 1200 (3.4%) patients, Stage 3 AKI in 474 (1.3%) patients, and new-onset dialysis was required in 241 (0.7%) patients. The NT-proBNP concentrations (considered continuously or in quartiles) were significantly correlated with any-stage AKI and severe AKI (all adjusted P0.01). Including NT-proBNP significantly improved AKI prediction (net reclassification improvement: 0.24 [0.22-0.27]; P0.001) beyond basic models derived from other baseline factors in the overall population. Reclassification was especially improved for higher grades of renal injury: 0.30 (0.25-0.36) for Stage 2, 0.46 (0.37-0.55) for Stage 3, and 0.47 (0.35-0.60) for dialysis.Increased preoperative NT-proBNP concentrations were associated with postoperative AKI in patients having cardiac surgery. Including NT-proBNP substantially improves AKI predictions based on other preoperative factors.

Background Erythrocyte transfusions are independently associated with acute kidney injury. Kidney injury may be consequent to the progressive hematologic changes that develop during storage. This study therefore tested the hypothesis that prolonged erythrocyte storage increases posttransfusion acute kidney injury. Methods The Informing Fresh versus Old Red Cell Management (INFORM) trial randomized 31,497 patients to receive either the freshest or oldest available matching erythrocyte units and showed comparable mortality with both. This a priori substudy compared the incidence of posttransfusion acute kidney injury in the randomized groups. Acute kidney injury was defined by the creatinine component of the Kidney Disease: Improving Global Outcomes criteria. Results The 14,461 patients included in this substudy received 40,077 erythrocyte units. For patients who received more than one unit, the mean age of the blood units was used as the exposure. The median of the mean age of blood units transfused per patient was 11 days [interquartile range, 8, 15] in the freshest available blood group and 23 days [interquartile range, 17, 30] in the oldest available blood group. In the primary analysis, posttransfusion acute kidney injury was observed in 688 of 4,777 (14.4%) patients given the freshest available blood and 1,487 of 9,684 (15.4%) patients given the oldest available blood, with an estimated relative risk (95% CI) of 0.94 (0.86 to 1.02; P = 0.132). The secondary analysis treated blood age as a continuous variable (defined as duration of storage in days), with an estimated relative risk (95% CI) of 1.00 (0.96 to 1.04; P = 0.978) for a 10-day increase in the mean age of erythrocyte units. Conclusions In a population of patients without severely impaired baseline renal function receiving fewer than 10 erythrocyte units, duration of blood storage had no effect on the incidence of posttransfusion acute kidney injury. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

A pair of meso-unsubstituted expanded carbaporphyrins containing two carbazole moieties were prepared in high isolated yields (82 and 76 %, respectively). The two macrocycles, namely 3 and 4, differ with respect to their substitution at the carbazole N-atoms i. e. by H and i-Bu, respectively. As prepared in their free-base forms, macrocycles 3 and 4 adopt figure-of-eight conformations and are best characterized as 40 π-electron, non-aromatic species possessing a decaphyrin(1.1.0.0.0.1.1.0.0.0) skeleton. Protonation of 3 with either trifluoroacetic acid (TFA) or perchloric acid (HClO4 ) produces a parallelogram-shaped structure. A similar structure is produced when N-functionalized system 4 is treated with TFA. In contrast, protonation of 4 with HClO4 leads it to adopt a twisted Mobius strip-like structure in the solid state, thus allowing access to three distinct conformational states as a function of the conditions.

Photodynamic therapy (PDT) is a therapeutic modality that uses light to treat malignant or benign diseases. A photosensitizer, light, and oxygen are the three main components needed to generate a cytotoxic effect. Pyrrole-based photosensitizers have been widely used for PDT. Many of the photosensitizers within this class are macrocyclic. This is particularly true for systems that have received regulatory approval or been the subject of clinical trials. However, in recent years, a number of boron dipyrromethanes (BODIPY) have been studied as photosensitizers. Herein, we review examples of some of the most relevant pyrrole-based photosensitizers.

A long-standing question in porphyrin chemistry is why pyrrole monomers selectively form tetrapyrrolic macrocycles, whereas the corresponding tripyrrolic macrocycles are never observed. Calix[3]pyrrole, a tripyrrolic porphyrinogen-like macrocycle bearing three sp(3)-carbon linkages, is a missing link molecule that might hold the key to this enigma; however, it has remained elusive. Here we report the synthesis and strain-induced transformations of calix[3]pyrrole and its furan analogue, calix[3]furan. These macrocycles are readily accessed from cyclic oligoketones. Crystallographic and theoretical analyses reveal that these three-subunit systems possess the largest strain energy among known calix[n]-type macrocycles. The ring-strain triggers transformation of calix[3]pyrrole into first calix[6]pyrrole and then calix[4]pyrrole under porphyrin cyclization conditions. The present results help explain the absence of naturally occurring three-pyrrole macrocycles and the fact that they are not observed as products or intermediate during classic porphyrin syntheses.

Background Mechanical ventilation injures lungs, but there are currently no reliable methods for detecting early injury. We therefore evaluated whether exhaled pentanal, a lipid peroxidation product, might be a useful breath biomarker for stretch-induced lung injury in rats. Methods A total of 150 male Sprague-Dawley rats were investigated in 2 substudies. The first randomly assigned 75 rats to 7 hours of mechanical ventilation at tidal volumes of 6, 8, 12, 16, and 20 mL·kg-1. The second included 75 rats. A reference group was ventilated at a tidal volume of 6 mL·kg-1 for 10 hours 4 interventional groups were ventilated at a tidal volume of 6 mL·kg-1 for 1 hour, and then for 0.5, 1, 2, or 3 hours at a tidal volume of 16 mL.kg-1 before returning to a tidal volume of 6 mL·kg-1 for additional 6 hours. Exhaled pentanal was monitored by multicapillary column-ion mobility spectrometry. The first substudy included cytokine and leukocyte measurements in blood and bronchoalveolar fluid, histological assessment of the proportion of alveolar space, and measurements of myeloperoxidase activity in lung tissue. The second substudy included measurements of pentanal in arterial blood plasma, cytokine and leukocyte concentrations in bronchoalveolar fluid, and cleaved caspase 3 in lung tissue. Results Exhaled pentanal concentrations increased by only 0.5 ppb·h-1 (95% confidence interval [CI], 0.3-0.6) when rats were ventilated at 6 mL·kg-1. In contrast, exhaled pentanal concentrations increased substantially and roughly linearly at higher tidal volumes, up to 3.1 ppb·h-1 (95% CI, 2.3-3.8) at tidal volumes of 20 mL·kg-1. Exhaled pentanal increased at average rates between 1.0 ppb·h-1 (95% CI, 0.3-1.7) and 2.5 ppb·h-1 (95% CI, 1.4-3.6) after the onset of 16 mL·kg-1 tidal volumes and decreased rapidly by a median of 2 ppb (interquartile range [IQR], 0.9-3.2), corresponding to a 38% (IQR, 31-43) reduction when tidal volume returned to 6 mL·kg-1. Tidal volume, inspiratory pressure, and mechanical power were positively associated with pentanal exhalation. Exhaled and plasma pentanal were uncorrelated. Alveolar space decreased and inflammatory markers in bronchoalveolar lavage fluid increased in animals ventilated at high tidal volumes. Short, intermittent ventilation at high tidal volumes for up to 3 hours increased neither inflammatory markers in bronchoalveolar fluid nor the proportion of cleaved caspase 3 in lung tissue. Conclusions Exhaled pentanal is a potential biomarker for early detection of ventilator-induced lung injury in rats.

We report here the synthesis and structural characterization of a novel expanded Schiff base oligopyrrolic macrocycle TxLH ([Formula: see text] compound 2) along with its smaller congener hemi-TxLH ([Formula: see text] compound 1). The solid-state structure of TxLH is reminiscent of the shape of a Texas Longhorn[Formula: see text]. It thus defines a new architectural form for porphyrin analogues. The present study thus underscores the potential of using functionalized oligopyrroles as readily accessible molecular building blocks for the construction of structurally non-trivial molecules.

Tumor hypoxia is correlated with increased resistance to chemotherapy and poor overall prognoses across a number of cancer types. We present here a cancer cell-selective and hypoxia-responsive probe (fol-BODIPY) designed on the basis of density functional theory (DFT)-optimized quantum chemical calculations. The fol-BODIPY probe was found to provide a rapid fluorescence "off-on" response to hypoxia relative to controls, which lack the folate or nitro-benzyl moieties. In vitro confocal microscopy and flow cytometry analyses, as well as in vivo near-infrared optical imaging of CT26 solid tumor-bearing mice, provided support for the contention that fol-BODIPY is more readily accepted by folate receptor-positive CT26 cancer cells and provides a superior fluorescence "off-on" signal under hypoxic conditions than the controls. Based on the findings of this study, we propose that fol-BODIPY may serve as a tumor-targeting, hypoxia-activatable probe that allows for direct cancer monitoring both in vitro and in vivo.

The subtilase cytotoxin (SubAB) is secreted by certain Shiga toxin-producing Escherichia coli (STEC) strains and is composed of the enzymatically active subunit SubA and the pentameric binding/transport subunit SubB. We previously demonstrated that SubA (10 µg/ml), in the absence of SubB, binds and intoxicates the human cervix cancer-derived epithelial cell line HeLa. However, the cellular and molecular mechanisms underlying the cytotoxic activity of SubA in the absence of SubB remained unclear. In the present study, the cytotoxic effects mediated by SubA alone were investigated in more detail in HeLa cells and the human colon cancer cell line HCT116. We found that in the absence of SubB, SubA (10 µg/ml) is internalized into the endoplasmic reticulum (ER), where it cleaves the chaperone GRP78, an already known substrate for SubA after its canonical uptake into cells via SubB. The autonomous cellular uptake of SubA and subsequent cleavage of GRP78 in cells is prevented by treatment of cells with 10 µM brefeldin A, which inhibits the transport of protein toxins into the ER. In addition, by analyzing the SubA mutant SubAΔC344, we identified the C-terminal SEEL motif as an ER-targeting signal. Conclusively, our results strongly suggest that SubA alone shares the same intracellular transport route and cytotoxic activity as the SubAB holotoxin. Supplementary Information The online version contains supplementary material available at 10.1007/s00204-020-02965-2.

Water compatible supramolecular polymers (WCSPs) combine aqueous compatibility with the reversibility and environmental responsiveness of supramolecular polymers. WCSPs have seen application across a number of fields, including stimuli-responsive materials, healable materials, and drug delivery, and are attracting increasing attention from the design, synthesis, and materials perspectives. In this review, we summarize the chemistry of WCSPs from 2016 to mid-2021. For the sake of discussion, we divide WCSPs into five categories based on the core supramolecular approaches at play, namely hydrogen-bonding arrays, electrostatic interactions, large π-conjugated subunits, host-guest interactions, and peptide-based systems, respectively. We discuss both synthesis and polymer structure, as well as the underlying design expectations. The goal of this overview is to deepen our understanding of the strategies that have been exploited to prepare WCSPs, as well as their properties and uses. Thus, a section devoted to potential applications is included in this review.

We report here strategic functionalization of the FDA approved chelator deferasirox (1) in an effort to produce organelle-targeting iron chelators with enhanced activity against A549 lung cancer cells. Derivative 8 was found to have improved antiproliferative activity relative to 1. Fluorescent cell imaging revealed that compound 8 preferentially localises within the lysosome.

The synthesis of the pyridazine-bridged expanded rosarin 1 and a reduced precursor, semi-rosarinogen 2, is reported. A single crystal X-ray diffraction analysis of 1 and theoretical calculations show that both 1 and 2 have distorted structures. Expanded rosarin 1 and its precursor 2 can differentiate various thiols in organic solvents by means of species-specific colour changes and reaction times.

Photoacoustic imaging (PAI) relies on the use of contrast agents with high molar absorptivity in the NIR-I/NIR-II region. Expanded porphyrins, synthetic analogues of natural tetrapyrrolic pigments (e.g. heme and chlorophyll), constitute as potentially attractive platforms due to their NIR-II absorptivity and their ability to respond to stimuli. Here, we evaluate two expanded porphyrins, naphthorosarin (1) and octaphyrin (4), as stimuli responsive PA contrast agents for functional PAI. Both undergo proton-coupled electron transfer to produce species that absorb well in the NIR-II region. Octaphyrin (4) was successfully encapsulated into 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol) (DSPE-PEG2000) nanoparticles to afford OctaNPs. In combination with PAI, OctaNPs allowed changes in the acidic environment of the stomach to be visualized and cancerous versus healthy tissues to be discriminated., In this study, two expanded porphyrins, octaphyrin and naphthorosarin were evaluated as potential PA agents. The nanoparticle encapsulation of octaphyrin successfully enabled the visualization of acidic environments and the discrimination between cancerous and healthy tissues.

We report a chemiluminescent probe (CLPT1) that permits the paired detection of tyrosinase (Tyr) and biological thiols. Tyr only leads to a poor chemiluminescence response, a finding ascribed to the formation of a stable o-benzoquinone intermediate. The addition of glutathione (GSH), or ascorbate to the o-benzoquinone intermediate results in thiol conjugation or reduction to this intermediate, respectively. This produces a strong chemiluminescence response. Thiol co-dependence was demonstrated in live cells using the cell permeable analogue, CLPT3. The present chemiluminescence-based strategy allows the concurrent detection of tyrosinase activity and biological thiols.

Recent decades have witnessed the emergence of Au(i) bis-N-heterocyclic carbenes (NHCs) as potential anticancer agents. However, these systems exhibit little interaction with serum proteins (e.g., human serum albumin), which presumably impacts their pharmacokinetic profile and tumor exposure. Anticancer drugs bound to human serum albumin (HSA) often benefit from significant advantages, including longer circulatory half-lives, tumor targeted delivery, and easier administration relative to the drug alone. In this work, we present Au(i) bis-NHCs complexes, 7 and 9, capable of binding to HSA. Complex 7 contains a reactive maleimide moiety for covalent protein conjugation, whereas its congener 9 contains a naphthalimide fluorophore for non-covalent binding. A similar drug motif was used in both cases. Complexes 7 and 9 were prepared from a carboxylic acid functionalized Au(i) bis-NHC (complex 2) using a newly developed post-synthetic amide functionalization protocol that allows coupling to both aliphatic and aromatic amines. Analytical, and in vitro techniques were used to confirm protein binding, as well as cellular uptake and antiproliferative activity in A549 human lung cancer cells. The present findings highlight a hitherto unexplored approach to modifying Au(i) bis-NHC drug candidates for protein ligation and serve to showcase the relative benefits of covalent and non-covalent HSA binding.

Distillation-free separations of haloalkane isomers represents a persistent challenge for the chemical industry. Several classic molecular sorbents show high selectivity in the context of such separations; however, most suffer from limited tunability or poor stability. Herein, we report the results of a comparative study involving three trianglamine and trianglimine macrocycles as supramolecular adsorbents for the selective separation of halobutane isomers. Methylene-bridged trianglamine, TA, was found to capture preferentially 1-chlorobutane (1-CBU) from a mixture of 1-CBU and 2-chlorobutane (2-CBU) with a purity of 98.1%. It also separates 1-bromobutane (1-BBU) from a mixture of 1-BBU and 2-bromobutane (2-BBU) with a purity of 96.4%. The observed selectivity is ascribed to the thermodynamic stability of the TA-based host–guest complexes. Based on single crystal X-ray diffraction analyses, a [3]pseudorotaxane structure (2TA⊃1-CBU) is formed between TA and 1-CBU that is characterized by an increased level of noncovalent interactions compared to the corresponding [2]pseudorotaxane structure seen for TA⊃2-CBU. We believe that molecular sorbents that rely on specific molecular recognition events, such as the triangular pores detailed here, will prove useful as next generation sorbents in energy-efficient separations., The methylene-bridged trianglamine (TA) can selectively capture 1-chlorobutane from a mixture of 1-chlorobutane and 2-chlorobutane due to the greater thermodynamic stability of the TA-based host–guest complex formed with 1-chlorobutane.

Crystalline supramolecular architectures mediated by cations, anions, ion pairs or neutral guest species are well established. However, the robust crystallization of a well-designed receptor mediated by labile anionic solvate clusters remains unexplored. Herein, we describe the synthesis and crystalline behaviors of a trimacrocyclic hexasubstituted benzene 2 in the presence of guanidium halide salts and chloroform. Halide hexasolvate clusters, viz. [Cl(CHCl3)6]−, [Br(CHCl3)6]−, and [I(CHCl3)6]−, were found to be critical to the crystallization process, as suggested by the single-crystal structures, X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), scanning electron microscopy with energy dispersive spectroscopy (SEM-EDS), and NMR spectroscopy. This study demonstrates the hitherto unexpected role that labile ionic solvate clusters can play in stabilizing supramolecular architectures., We report the synthesis and robust crystallization of a trimacrocyclic hexasubstituted benzene and guanidium mediated by unprecedented labile halide hexasolvate clusters, viz. [Cl(CHCl3)6]−, [Br(CHCl3)6]−, [I(CHCl3)6]−, and [Br(CHBr3)6]−.

A doubly N-confused phlorin and phlorinone analogue were synthesized from a β,β'-linked dipyrromethane precursor and characterized by means of NMR and UV-Vis spectroscopies, X-ray crystallography, and electrochemistry. Solvents have a considerable impact on the optical absorption of the doubly N-confused phlorin so that it can differentiate simple alcohols such as methanol and ethanol.

Fosfomycin is an antibiotic with a broad spectrum of activity against many multidrug-resistant bacterial strains. It is mainly excreted unchanged by the kidneys, and its half-life therefore depends on kidney function which varies considerably among individuals, and within individuals over time. Proper fosfomycin dosing thus depends on assaying blood concentration of the drug. We developed and validated a simple, sensitive and specific chromatography assay, which was coupled to electrospray ionization mass spectrometry for determination of fosfomycin. Separation of fosfomycin was based on the method of the hydrophilic interaction liquid chromatography; specifically, plasma and dialysate samples were acidified and the protein precipitated with acetonitrile. The calibration curves showed excellent coefficients of determination (R2 > 0.999) over the relevant concentration range of 25–700 μg/mL. Intraday precision was 1.1–1.2% and accuracy was −5.9% to 0.9% for quality control samples. Interday precision was 2.9–3.4% and accuracy was −3.7% to 5.5%. Extraction recovery was ≥87% and matrix effects ranged from 2.2% to 4.3%. After laboratory validation, the method was successfully applied to clinical samples.

Immunogenic cell death (ICD) is a way of reengaging the tumor-specific immune system. ICD can be induced by treatment with chemotherapeutics. However, only a limited number of drugs and other treatment modalities have been shown to elicit the biomarker responses characteristic of ICD and to provide an anticancer benefit in vivo. Here, we report a rationally designed redox-active Au(I) bis-N-heterocyclic carbene that induces ICD both in vitro and in vivo. This work benefits from a synthetic pathway that allows for the facile preparation of asymmetric redox-active Au(I) bis-N-heterocyclic carbenes.

A hexacationic cage 36+ was synthesized via hydrazone condensation in aqueous acid. Cage 36+ bears three biscationic arms, each of which contains four relatively acidic protons, including one NH and three CH protons. These hydrogen bond donors, as well as its intrinsic cationic nature, enable cage 36+ to encapsulate two anions concurrently within its cavity. The axial asymmetrical nature of the biscationic arms allow the cage to recognize two different anions in a selective manner, to encompass bound heteroanion dimers, such as Cl-·NO3- and Cl-·Br-. Single crystal X-ray diffraction analyses reveal that in the solid state the two anions are constrained in ultraclose proximity within the cage; e.g., the Cl-···Cl- and Cl-···Br- distances are 3.2 and 2.9 A, respectively, which are shorter than the sum of their van der Waals radii. Evidence consistent with the sequential binding of two identical or disparate anions in CD3CN is also presented.

Access to clean drinking water is a recognized societal need that touches on the health and livelihood of millions of people worldwide. This is providing an incentive to develop new water-treatment technologies. Traditional technologies, while widespread, are usually inefficient at removing organic pollutants from sewage or so-called grey water. Macrocycle-containing covalent polymer networks have begun to attract attention in the context of water treatment owing to the inherent stability provided by the polymer backbones and their ability to capture micropollutant guests as the result of tunable macrocycle-based host-guest interactions. In this Minireview, we summarize recent advances (from 2016 to mid-2020) involving the removal of organic micropollutants from water using macrocycle-containing covalent polymer networks. An overview of future challenges within this subfield is also provided.

Transition metal catalyzed cross-electrophile coupling of alkyl electrophiles has evolved into a privileged strategy that permits the facile construction of valuable C(sp3)-C bonds. Numerous elegant Ni-catalyzed coupling methods, for example, arylation, allylation, acylation, and vinylation of primary and secondary alkyl halides have been developed. This prior work has provided important mechanistic insights into the selectivity and reactivity of the coupling partners, which are largely dictated by both the catalysts and the reactants. In spite of the advances made to date, a number of challenging issues remain, including (1) achieving stereoselective syntheses of C-C bonds that rely primarily on functionalized or activated alkyl precursors, (2) diversifying the electrophiles, and (3) gaining insights into the underlying reaction mechanisms.In this Account, we summarize a number of Ni- and Fe-catalyzed reductive C-C bond forming methods developed in our laboratory, which have allowed us to couple activated, sterically hindered tertiary alkyl and C(sp3)-O bond electrophiles and to access methylated and trifluoromethylated products, esters, C-glycosides, and quaternary carbon centers. We will begin with a brief discussion of Ni-catalyzed chemoselective construction of unactivated alkyl-alkyl bonds, with focus on the effects of ligands and reductants, along with leaving group-directed reactivities of alkyl halides, and the role they play in promoting the reductive coupling of activated electrophiles, including methyl, trifluoromethyl, and glycosyl electrophiles, and chloroformates. Matching the reactivities of these electrophiles with suitable coupling partners is considered essential for success; this is something that can be tuned by means of appropriate Ni catalysts. Second, we will detail how tuning the steric and electronic effects of nickel catalysts with labile pyridine-type ligands and additives (primarily MgCl2) permits effective creation of arylated all-carbon quaternary centers through the coupling of aryl halides with sterically encumbered tertiary alkyl halides. In contrast, the use of bulkier bipyridine and terpyridine ligands permits the incorporation of relative small-sized acyl and allyl groups into acylated and allylated all-carbon quaternary centers. Finally, we will show how the knowledge gained with halide electrophiles enabled us to develop methods that permit the coupling of tertiary alkyl oxalates with allyl, aryl, and vinyl electrophiles, wherein Barton C-O bond radical fragmentation is mediated by Zn and MgCl2 and promoted by Ni catalysts. The same protocol is applicable to the arylation of secondary alkyl oxalates derived from α-hydroxyl carbonyl substrates, which involves the formation of relatively stable α-carbonyl carbon centered radicals. Thus, this Account not only summarizes synthetic methods that allow formation of valuable C-C bonds using challenging electrophiles but also provides insight into the relationship between the structure and reactivity of the substrates and catalysts, as well as the effects of additives.

p53 is the most frequently mutated, well-studied tumor-suppressor gene, yet the molecular basis of the switch from p53-induced cell-cycle arrest to apoptosis remains poorly understood. Using a combination of transcriptomics and functional genomics, we unexpectedly identified a nodal role for the caspase-8 paralog and only human pseudo-caspase, FLIP(L), in regulating this switch. Moreover, we identify FLIP(L) as a direct p53 transcriptional target gene that is rapidly up-regulated in response to Nutlin-3A, an MDM2 inhibitor that potently activates p53. Genetically or pharmacologically inhibiting expression of FLIP(L) using siRNA or entinostat (a clinically relevant class-I HDAC inhibitor) efficiently promoted apoptosis in colorectal cancer cells in response to Nutlin-3A, which otherwise predominantly induced cell-cycle arrest. Enhanced apoptosis was also observed when entinostat was combined with clinically relevant, p53-activating chemotherapy in vitro, and this translated into enhanced in vivo efficacy. Mechanistically, FLIP(L) inhibited p53-induced apoptosis by blocking activation of caspase-8 by the TRAIL-R2/DR5 death receptor; notably, this activation was not dependent on receptor engagement by its ligand, TRAIL. In the absence of caspase-8, another of its paralogs, caspase-10 (also transcriptionally up-regulated by p53), induced apoptosis in Nutlin-3A-treated, FLIP(L)-depleted cells, albeit to a lesser extent than in caspase-8-proficient cells. FLIP(L) depletion also modulated transcription of canonical p53 target genes, suppressing p53-induced expression of the cell-cycle regulator p21 and enhancing p53-induced up-regulation of proapoptotic PUMA. Thus, even in the absence of caspase-8/10, FLIP(L) silencing promoted p53-induced apoptosis by enhancing PUMA expression. Thus, we report unexpected, therapeutically relevant roles for FLIP(L) in determining cell fate following p53 activation.

Summary Drawing inspiration from nature today remains a time-honored means of discovering the therapies of tomorrow. Porphyrins, the so-called “pigments of life” have played a key role in this effort due to their diverse and unique properties. They have seen use in a number of medically relevant applications, including the development of so-called drug conjugates wherein functionalization with other entities is used to improve efficacy while minimizing dose limiting side effects. In this Perspective, we highlight opportunities associated with newer, completely synthetic analogs of porphyrins, commonly referred to as porphyrinoids, as the basis for preparing drug conjugates. Many of the resulting systems show improved medicinal or site-localizing properties. As befits a Perspective of this type, our efforts to develop cancer-targeting, platinum-containing conjugates based on texaphyrins (a class of so-called “expanded porphyrins”) will receive particular emphasis; however, the promise inherent in this readily generalizable approach will also be illustrated briefly using two other common porphyrin analogs, namely the corroles (a “contracted porphyrin”) and porphycene (an “isomeric porphyrin”).

Tumor recurrence as a result of therapy-induced nuclear DNA lesions is a major issue in cancer treatment. Currently, only a few examples of potentially non-genotoxic drugs have been reported. Mitochondrial re-localization of ciprofloxacin, one of the most commonly prescribed synthetic antibiotics, is reported here as a new approach. Conjugating ciprofloxacin to a triphenyl phosphonium group (giving lead Mt-CFX), is used to enhance the concentration of ciprofloxacin in the mitochondria of cancer cells. The localization of Mt-CFX to the mitochondria induces oxidative damage to proteins, mtDNA, and lipids. A large bias in favor of mtDNA damage over nDNA was seen with Mt-CFX, contrary to classic cancer chemotherapeutics. Mt-CFX was found to reduce cancer growth in a xenograft mouse model and proved to be well tolerated. Mitochondrial relocalization of antibiotics could emerge as a useful approach to generating anticancer leads that promote cell death via the selective induction of mitochondrially-mediated oxidative damage. ispartof: CHEM vol:6 issue:6 pages:1408-1419 ispartof: location:United States status: published

Covalent polymers connected by non-covalent interactions constitute a fascinating set of materials known as supramolecular polymer networks (SPNs). A key feature of SPNs is that the underlying covalent polymers endow the resulting self-assembled materials with features, such as structural and mechanical integrity, good processability, recyclability, stimuli-responsiveness, self-healing, and shape memory, that are not recapitulated in the case of classic covalent polymer systems. The unique nature of SPNs derives from the controlled marriage of traditional covalent polymers and macrocycle-based host-guest interactions. As a consequence, supramolecular polymeric networks have played important roles in a number of diverse fields, including polymer science, supramolecular chemistry, materials science, biomedical materials, and information storage technology. In this Review, we summarize advances made in the area of functional SPNs, with a focus on original literature reports appearing in the past five years. The treatment is organized according to the key macrocycle-based host-guest interactions used to produce various SPNs. The role of the underlying polymer backbones is also discussed.

Oxidative stress is one of the hallmarks of ischemic stroke. Catalase-based (CAT) biomimetic complexes are emerging as promising therapeutic candidates that are expected to act as neuroprotectants for ischemic stroke by decreasing the damaging effects from H2O2. Unfortunately, these molecules result in the unwanted production of the harmful hydroxyl radical, HO•. Here, we report a series of salen-based tri-manganese (Mn(III)) metallocryptands (1-3) that function as catalase biomimetics. These cage-like molecules contain a unique "active site" with three Mn centers in close proximity, an arrangement designed to facilitate metal cooperativity for the effective dismutation of H2O2 with minimal HO• production. In fact, significantly greater oxygen production is seen for 1-3 as compared to the monomeric Mn(Salen) complex, 1c. The most promising system, 1, was studied in further detail and found to confer a greater therapeutic benefit both in vitro and in vivo than the monomeric control system, 1c, as evident from inter alia studies involving a rat model of ischemic stroke damage and supporting histological analyses. We thus believe that metallocryptand 1 and its analogues represent a new and seemingly promising strategy for treating oxidative stress related disorders.

Background Perioperative acute kidney injury is common. However, it is unclear whether this merely represents a transient increase in creatinine or has prognostic value. Therefore, the long-term clinical importance of mild postoperative acute kidney injury remains unclear. This study assessed whether adults who do and do not experience mild kidney injury after noncardiac surgery are at similar risk for long-term renal injury. Methods This study is a retrospective cohort analysis of adults having noncardiac surgery at the Cleveland Clinic who had preoperative, postoperative, and long-term (1 to 2 yr after surgery) plasma creatinine measurements. The exposure (postoperative kidney injury) and outcome (long-term renal injury) were defined and staged according to the Kidney Disease: Improving Global Outcomes (KDIGO) initiative criteria. The primary analysis was for lack of association between postoperative kidney injury (stage I vs. no injury) and long-term renal injury. Results Among 15,621 patients analyzed, 3% had postoperative stage I kidney injury. Long-term renal outcomes were not similar in patients with and without postoperative stage I injury. Specifically, about 26% of patients with stage I postoperative kidney injury still had mild injury 1 to 2 yr later, and 11% had even more severe injury. A full third (37%) of patients with stage I kidney injury therefore had renal injury 1 to 2 yr after surgery. Patients with postoperative stage I injury had an estimated 2.4 times higher odds of having long-term renal dysfunction (KDIGO stage I, II, or III) compared with patients without postoperative kidney injury (odds ratio [95% CI] of 2.4 [2.0 to 3.0]) after adjustment for potential confounding factors. Conclusions In adults recovering from noncardiac surgery, even small postoperative increases in plasma creatinine, corresponding to stage I kidney injury, are associated with renal dysfunction 1 to 2 yr after surgery. Even mild postoperative renal injury should therefore be considered a clinically important perioperative outcome. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

TRAIL-R2 (DR5) is a clinically-relevant therapeutic target and a key target for immune effector cells. Herein, we identify a novel interaction between TRAIL-R2 and the Skp1-Cullin-1-F-box (SCF) Cullin-Ring E3 Ubiquitin Ligase complex containing Skp2 (SCFSkp2). We find that SCFSkp2 can interact with both TRAIL-R2’s pre-ligand association complex (PLAC) and ligand-activated death-inducing signalling complex (DISC). Moreover, Cullin-1 interacts with TRAIL-R2 in its active NEDDylated form. Inhibiting Cullin-1’s DISC recruitment using the NEDDylation inhibitor MLN4924 (Pevonedistat) or siRNA increased apoptosis induction in response to TRAIL. This correlated with enhanced levels of the caspase-8 regulator FLIP at the TRAIL-R2 DISC, particularly the long splice form, FLIP(L). We subsequently found that FLIP(L) (but not FLIP(S), caspase-8, nor the other core DISC component FADD) interacts with Cullin-1 and Skp2. Importantly, this interaction is enhanced when FLIP(L) is in its DISC-associated, C-terminally truncated p43-form. Prevention of FLIP(L) processing to its p43-form stabilises the protein, suggesting that by enhancing its interaction with SCFSkp2, cleavage to the p43-form is a critical step in FLIP(L) turnover. In support of this, we found that silencing any of the components of the SCFSkp2 complex inhibits FLIP ubiquitination, while overexpressing Cullin-1/Skp2 enhances its ubiquitination in a NEDDylation-dependent manner. DISC recruitment of TRAF2, previously identified as an E3 ligase for caspase-8 at the DISC, was also enhanced when Cullin-1’s recruitment was inhibited, although its interaction with Cullin-1 was found to be mediated indirectly via FLIP(L). Notably, the interaction of p43-FLIP(L) with Cullin-1 disrupts its ability to interact with FADD, caspase-8 and TRAF2. Collectively, our results suggest that processing of FLIP(L) to p43-FLIP(L) at the TRAIL-R2 DISC enhances its interaction with co-localised SCFSkp2, leading to disruption of p43-FLIP(L)’s interactions with other DISC components and promoting its ubiquitination and degradation, thereby modulating TRAIL-R2-mediated apoptosis.

For the past three decades, the coordination-driven self-assembly of three-dimensional structures has undergone rapid progress; however, parallel efforts to create large discrete two-dimensional architectures—as opposed to polymers—have met with limited success. The synthesis of metallo-supramolecular systems with well-defined shapes and sizes in the range of 10–100 nm remains challenging. Here we report the construction of a series of giant supramolecular hexagonal grids, with diameters on the order of 20 nm and molecular weights greater than 65 kDa, through a combination of intra- and intermolecular metal-mediated self-assembly steps. The hexagonal intermediates and the resulting self-assembled grid architectures were imaged at submolecular resolution by scanning tunnelling microscopy. Characterization (including by scanning tunnelling spectroscopy) enabled the unambiguous atomic-scale determination of fourteen hexagonal grid isomers. Metal-mediated self-assembly in solution typically leads to small two- and three-dimensional architectures on scales smaller than 10 nm, but now a series of large, discrete, two-dimensional supramolecular hexagonal grids have been prepared through a combination of intra- and intermolecular coordination interactions. These 20-nm-wide grids have been imaged at submolecular resolution using scanning tunnelling microscopy.

Calix[4]pyrrole (C4P)-based systems have been extensively explored as binding agents for anions and ion pairs. However, their capacity to act as molecular containers for neutral species remains underexplored. We report here the molecular recognition of pyrazine N,N′-dioxide (PZDO) using a series of aryl extended C4Ps including three α,α-diaryl substituted C4Ps (receptors 1–3), an α,β-diaryl substituted C4P (receptor 4) and an α,α,α,α-tetraaryl substituted C4P (receptor 5). Single crystal structural analyses of the 2 : 1 host–guest complexes between receptors 1–3 and PZDO revealed that the C4P subunits exist in an unusual partial cone conformation and that the PZDO guest is held within electron-rich cavities formed by the lower rims of the individual C4P macrocycle. In contrast, receptor 5 was seen to adopt the cone conformation in the solid state, allowing one PZDO molecule to be accommodated inside the upper-rim cavity. Evidence for guest-directed self-assembly is also seen in the solid state. Evidence for C4P–PZDO interactions in CD3CN/CD3OD solution came from 1H NMR spectroscopic titrations. Electrostatic potential maps created by means of density functional theory calculations were constructed. Density functional theory calculations were also performed to analyse the energetics of various limiting binding modes. On the basis of these studies, it is inferred that interactions between the ‘two-wall’ C4P derivatives (i.e. receptors 1–4) and PZDO involve a complex binding mode that differs from what has been seen in previous host–guest complexes formed between C4Ps and N-oxides. The present study thus paves the way for the further design of C4P-based receptors with novel recognition features., The molecular recognition of pyrazine N,N′-dioxide by aryl extended 'two-walled' calix[4]pyrrole-based receptors is seen to stabilise two different binding modes in the solid state.

Diagnostics and therapeutics are generally separate entities in medicine. Theranostics, agents that provide for both modalities, are being developed. However, they often require complex syntheses so as to incorporate within one molecular structure both diagnostic and therapeutic elements. Moreover, their use is often complicated by the disparate dosage requirements for diagnosis and therapy. Herein, we report that closely related porphyrinoid regioisomers produced from the same 1,3-dipolar cycloaddition reaction give rise to products that as their corresponding ytterbium(III) complexes may be split and used for the separate biological functions that are required for theranostics. Specifically, the cis isomer is luminescent and suitable for NIR imaging, while the trans isomer produces singlet oxygen with a good quantum yield and is thus attractive for use in photodynamic therapy (PDT). Both in vitro and in vivo experiments provide support for the complementary biological functions of the two regioisomers. The present study reveals how ostensibly related regioisomers may be used to switch between diagnosis and therapy. More broadly, it serves to highlight a new approach to creating paired sets of molecules that may be used in combination as effective theranostics.

Possessing structural homology with their active enzyme counterparts but lacking catalytic activity, pseudoenzymes have been identified for all major enzyme groups. Caspases are a family of cysteine‐dependent aspartate‐directed proteases that play essential roles in regulating cell death and inflammation. Here, we discuss the only human pseudo‐caspase, FLIP(L), a paralog of the apoptosis‐initiating caspases, caspase‐8 and caspase‐10. FLIP(L) has been shown to play a key role in regulating the processing and activity of caspase‐8, thereby modulating apoptotic signaling mediated by death receptors (such as TRAIL‐R1/R2), TNF receptor‐1 (TNFR1), and Toll‐like receptors. In this review, these canonical roles of FLIP(L) are discussed. Additionally, a range of nonclassical pseudoenzyme roles are described, in which FLIP(L) functions independently of caspase‐8. These nonclassical pseudoenzyme functions enable FLIP(L) to play key roles in the regulation of a wide range of biological processes beyond its canonical roles as a modulator of cell death., FLIP(L) is to date the only true pseudo‐caspase identified in the human proteome. As a classical pseudoenzyme, it functions as a regulator of its active homologs, the apoptosis‐initiating caspases, caspase‐8 and caspase‐10. Additionally, FLIP(L) functions independently of these caspases. These nonclassical pseudoenzyme functions enable FLIP(L) to play key roles in the regulation of a wide range of biological processes beyond its canonical roles as a modulator of cell death.

We report here a water-soluble metal cation sensor system based on the as-prepared or reduced form of an expanded porphyrin, texaphyrin. Upon metal complexation, a change in the redox state of the ligand occurs that is accompanied by a color change from red to green. Although long employed for synthesis in organic media, we have now found that this complexation-driven redox behavior may be used to achieve the naked eye detectable colorimetric sensing of several number of less-common metal ions in aqueous media. Exposure to In(III), Hg(II), Cd(II), Mn(II), Bi(III), Co(II), and Pb(II) cations leads to a colorimetric response within 10 min. This process is selective for Hg(II) under conditions of competitive analysis. Furthermore, among the subset of response-producing cations, In(III) proved unique in giving rise to a ratiometric change in the ligand-based fluorescence features, including an overall increase in intensity. The cation selectivity observed in aqueous media stands in contrast to what is seen in organic solvents, where a wide range of texaphyrin metal complexes may be prepared. The formation of metal cation complexes under the present aqueous conditions was confirmed by reversed phase high-performance liquid chromatography, ultra-violet-visible absorption and fluorescence spectroscopies, and high-resolution mass spectrometry.

Calix[4]pyrroles 1 and 2, diametrically strapped with a phenanthroline via ester and amide linkages, respectively, have been synthesized as anion receptors. It was revealed by 1H NMR spectroscopic analysis that receptors 1 and 2 possessing both hydrogen bonding donors and acceptors were able to bind the bicarbonate anion (as its tetraethylammonium (TEA+) or sodium salt) in CDCl3, as well as in 15% aqueous DMSO with high affinity and selectivity over other anions. The amide-based receptor 2 contains additional potential hydrogen bonding donors relative to its ester-based congener 1. Nevertheless, in CDCl3 receptor 1 was found to display a higher affinity for all test anions than receptor 2. In contrast, in 15% aqueous DMSO solution the affinities of receptor 2 for anions, in particular chloride, bicarbonate, and dihydrogen phosphate, were enhanced, whereas those of receptor 1 were reduced dramatically with no appreciable interaction being seen in the case of most test anions considered in this study. These reversals in selectivity and affinities underscore the importance of solvent in regulating the recognition features of seemingly similiar anion binding agents.

β,β'-Phenylene bridged hexaphyrin[1.0.1.0.1.0] (naphthorosarin), an expanded porphyrin possessing C3v-symmetry, has been shown to possess unique electronic features. We now report a bimetallic Rh(i)-complex of naphthorosarin retaining 24 π-antiaromatic characteristics. The two Rh(i) cations reside on opposite sides of the macrocyclic π-system and are separated at a distance consistent with a possible Rh(i)-Rh(i) metallic bond interaction.

A new set of PVA hydrogels were formed using the boronate ester fluorescent probe, PF1 and the novel boronate fluorescent probe PT1 as the covalent crosslinkers. Treatment with aqueous H2O2 allowed triggered release of the fluorescent dye accompanied by complete dissolution of the hydrogel

Classic prodrug strategies rely on covalent modification of active drugs to provide systems with superior pharmacokinetic properties than the parent drug and facilitate administration. Supramolecular chemistry is providing a new approach to developing prodrug-like systems, wherein the characteristics of a drug are modified in a beneficial manner by creating host-guest complexes that then permit the stimulus-induced release of the active species in a controlled manner. These complexes are termed "supramolecular prodrugs". In this review, we outline the concept of supramolecular drugs via host-guest chemistry and detail progress made in the area. This summary is designed to highlight the many advantages of supramolecular prodrugs, including ease-of-preparation, molecular-level protection, sensitive response to bio-stimuli, traceless release, and adaptability to different drugs. Limitations of the approach and opportunities for future growth are also detailed.

Supramolecular chemistry is a central topic in modern chemistry. It touches on many traditional disciplines, such as organic chemistry, inorganic chemistry, physical chemistry, materials chemistry, environmental chemistry, and biological chemistry. Supramolecular hosts, inter alia macrocyclic hosts, play critical roles in supramolecular chemistry. Calix[4]pyrroles, non-aromatic tetrapyrrolic macrocycles defined by sp3 hybridized meso bridges, have proved to be versatile receptors for neutral species, anions, and cations, as well as ion pairs. Compared to the parent system, octamethylcalix[4]pyrrole and its derivatives bearing simple appended functionalities, strapped calix[4]pyrroles typically display enhanced binding affinities and selectivities. In this review, we summarize advances in the design and synthesis of strapped calix[4]pyrroles, as well as their broad utility in molecular recognition, supramolecular extraction, separation technology, ion transport, and as agents capable of inhibiting cancer cell proliferation. Future challenges within this sub-field are also discussed.

Host-guest complex solid state molecular motion is a critical but underexplored phenomenon. In principle, it can be used to control molecular machines that function in the solid state. Here we describe a solid state system that operates on the basis of complexation between an all-hydrocarbon macrocycle, D4d-CDMB-8, and perylene. Molecular motion in this solid state machine is induced by exposure to organic solvents or grinding and gives rise to different co-crystalline, mixed crystalline, or amorphous forms. Distinct time-dependent emissive responses are seen for different organic solvents as their respective vapours or when the solid forms are subject to grinding. This temporal feature allows the present D4d-CDMB-8⊃perylene-based system to be used as a time-dependent, colour-based 4th dimension response element in pattern-based information codes. This work highlights how dynamic control over solid-state host-guest molecular motion may be used to induce a tuneable temporal response and provide materials with information storage capability., Host-guest solid state molecular motion is a critical but underexplored phenomenon which can be used to control molecular machines that function in the solid state. Here, the authors describe a solid state machine that shows solvent vapour- and mechanically-induced molecular motion that allows access to different crystalline and amorphous forms.

Presented here is the synthesis of three new Schiff-base cryptands, 4–6. Dynamic covalent imine bond formation via the condensation of a dialdehyde (7 or 8) with two different tris-amines allowed for the preparation of 4–6 in 84%, 80% and 83% yield, respectively. These systems were characterized by NMR spectroscopy, mass spectra, and, in the case of 5, single crystal X-ray diffraction analysis. These cages act as selective CO[Formula: see text] gas adsorbing materials in the solid state.

An efficient nickel(ii)-catalyzed transfer dehydrogenation oxidation of alcohols is reported that relies on cyclohexanone as the formal oxidant and does not require the use of an external base. The synthetic utility of this protocol is demonstrated via the facile oxidation of structurally complicated natural products.