Delving into the Variability of Supramolecular Affinity: Self-Ion Pairing as a Central Player in Aqueous Host-Guest Chemistry.

The determination of binding constants is a key matter in evaluating the strength of host-guest interactions. However, the profound impact of self-ion pairing on this parameter is often underrated in aqueous solution, leading in some cases to a misinterpretation of the true potential of supramolecular assemblies. In the present study, we aim to shed further light on this critical factor by exploring the concentration-dependent behavior of a multicharged pillararene in water. Our observations reveal an extraordinary 1-million-fold variability in the affinity of this macrocycle toward a given anion, showcasing the highly dynamic character of electrostatic interactions. We argue that these findings bring to the forefront the inherent determinism that underlies the estimation of affinity constants, a factor profoundly shaped by both the sensitivity of the instrumental technique in use and the intricacies of the experimental design itself. In terms of applications, these results may provide the opportunity to optimize the operational concentrations of multicharged hosts in different scenarios, aiming to achieve their maximum efficiency based on the intended application. Unlocking the potential of this hidden variability may pave the way for the creation of novel molecular materials with advanced functionalities.

Stereoselective Synthesis of Bisfuranoxide (Aurochrome, Auroxanthin) and Monofuranoxide (Equinenone 5',8'-Epoxide) Carotenoids by Double Horner-Wadsworth-Emmons Reaction.

The stereoselective synthesis of C40-all-trans-carotenoids with the formal hexahydrobenzofuran skeletons aurochrome, auroxanthin, and equinenone-5',8'-epoxide is reported. The synthesis is based on a one-pot or stepwise double Horner-Wadsworth-Emmons (HWE) reaction of a terminal enantiopure C15-5,6-epoxycyclohexadienylphosphonate and a central C10-trienedial. The ring expansion of the epoxycyclohexadienylphosphonate, generated by a Stille cross-coupling reaction, to the hexahydrobenzofuran skeleton was promoted by the reaction conditions of the HWE reaction prior to double-bond formation.

Palladium-Catalyzed Aminocyclization-Coupling Cascades: Preparation of Dehydrotryptophan Derivatives and Computational Study.

Dehydrotryptophan derivatives have been prepared by palladium-catalyzed aminocyclization-Heck-type coupling cascades starting from o-alkynylaniline derivatives and methyl α-aminoacrylate. Aryl, alkyl (primary, secondary, and tertiary), and alkenyl substituents have been introduced at the indole C-2 position. Further variations at the indole benzene ring, as well as the C-2-unsubstituted case, have all been demonstrated. In the case of C-2 aryl substitution, the preparation of the o-alkynylaniline substrate by Sonogashira coupling and the subsequent cyclization-coupling cascade have been performed in a one-pot protocol with a single catalyst. DFT calculations have revealed significant differences in the reaction profiles of these reactions relative to those involving methyl acrylate or methacrylate, and between the reactions of the free anilines and their corresponding carbamates. Those calculations suggest that the nature of the alkene and of the acid HX released in the HX/alkene exchange step that precedes C-C bond formation could be responsible for the experimentally observed differences in reaction efficiencies.

Pyrene-Containing ortho-Oligo(phenylene)ethynylene Foldamer as a Ratiometric Probe Based on Circularly Polarized Luminescence.

In this manuscript, we report the first synthesis of an organic monomolecular emitter, which behaves as a circularly polarized luminescence (CPL)-based ratiometric probe. The enantiopure helical ortho-oligo(phenylene)ethynylene ( o-OPE) core has been prepared by a new and efficient macrocyclization reaction. The combination of such o-OPE helical skeleton and a pyrene couple leads to two different CPL emission features in a single structure whose ratio linearly responds to silver(I) concentration.

9-cis-13,14-Dihydroretinoic Acid Is an Endogenous Retinoid Acting as RXR Ligand in Mice.

The retinoid X receptors (RXRs) are ligand-activated transcription factors which heterodimerize with a number of nuclear hormone receptors, thereby controlling a variety of (patho)-physiological processes. Although synthetic RXR ligands are developed for the treatment of various diseases, endogenous ligand(s) for these receptors have not been conclusively identified. We show here that mice lacking cellular retinol binding protein (Rbp1-/-) display memory deficits reflecting compromised RXR signaling. Using HPLC-MS and chemical synthesis we identified in Rbp1-/- mice reduced levels of 9-cis-13,14-dihydroretinoic acid (9CDHRA), which acts as an RXR ligand since it binds and transactivates RXR in various assays. 9CDHRA rescues the Rbp1-/- phenotype similarly to a synthetic RXR ligand and displays similar transcriptional activity in cultured human dendritic cells. High endogenous levels of 9CDHRA in mice indicate physiological relevance of these data and that 9CDHRA acts as an endogenous RXR ligand.

A Biomimetic Escape Strategy for Cytoplasm Invasion by Synthetic Particles.

The translocation of nanomaterials or complex delivery systems into the cytosol is a major challenge in nanobiotechnology. After receptor-mediated endocytosis, most nanomaterials are sequestered and undergo degradation, therapy inactivation, or exocytosis. Herein we explore a novel surface particle coating made of adsorbed carbon nanotubes that provides coated materials with new properties that reproduce the viral cell-invasive mechanisms, namely, receptor-mediated endocytosis, endolysosomal escape, and cytosolic particle release preserving cell viability. This novel biomimetic coating design will enable the intracytoplasmic delivery of many different functional materials endowed with therapeutic, magnetic, optical, or catalytic functionalities, thus opening the door to a wide array of chemical and physical processes within the cytosolic or nuclear domains, and supporting new developments in the biotechnological, pharmaceutical, and biomedical industries.

Enhancing the Exploitation of Functional Nanomaterials through Spatial Confinement: The Case of Inorganic Submicrometer Capsules.

Hollow inorganic nanostructures have attracted much interest in the last few years due to their many applications in different areas of science and technology. In this Feature Article, we overview part of our current work concerning the collective use of plasmonic and magnetic nanoparticles located in voided nanostructures and explore the more specific operational issues that should be taken into account in the design of inorganic nanocapsules. Along these lines, we focus our attention on the applications of silica-based submicrometer capsules aiming to stress the importance of creating nanocavities in order to further exploit the great potential of these functional nanomaterials. Additionally, we will examine some of the recent research on this topic and try to establish a perspective for future developments in this area.

Synthesis of labile all-trans-7,8,7',8'-bis-acetylenic carotenoids by bi-directional Horner-Wadsworth-Emmons condensation.

A new stereoselective synthesis of the C40-bis-acetylenic carotenoids all-trans-(3R,3'R)-alloxanthin and all-trans-3,4,7,8,3',4',7',8'-octadehydro-ß,ß-carotene, both compounds featuring a stereochemically labile C7-C10 enyne, based on a bi-directional Horner-Wadsworth-Emmons (HWE) reaction of a C15-phosphonate and a central C10-dialdehyde, is reported. The triene unit of the latter fragment was synthesized using the acyclic metathesis/dimerization reaction.

Nanoreactors for simultaneous remote thermal activation and optical monitoring of chemical reactions.

We report herein the design of plasmonic hollow nanoreactors capable of concentrating light at the nanometer scale for the simultaneous performance and optical monitoring of thermally activated reactions. These reactors feature the encapsulation of plasmonic nanoparticles on the inner walls of a mesoporous silica capsule. A Diels-Alder cycloaddition reaction was carried out in the inner cavities of these nanoreactors to evidence their efficacy. Thus, it is demonstrated that reactions can be accomplished in a confined volume without alteration of the temperature of the bulk solvent while allowing real-time monitoring of the reaction progress.

SH3-mediated targeting of Wrch1/RhoU by multiple adaptor proteins.

Wrch1/RhoU is an atypical member of the Rho family. A major structural difference is the extended N-terminus of Wrch1 (nWrch1) containing three putative SH3 domain-binding motifs whose specificities are unknown. To define the impact of this extended region on coupling Wrch1 to cellular signaling, we analyzed in this study nWrch1 interaction with Src homology 3 (SH3) domains of different adaptor proteins. Using sedimentation and isothermal titration calorimetric (ITC) measurements, we identified isolated SH3 domains of growth factor receptor-bound protein 2 (Grb2), noncatalytic region of tyrosine kinase adaptor protein 1 (Nck1), c-Src, chicken tumor virus no. 10 (CT 10) regulator kinase 1 (Crk1), and p120 as low-affinity Wrch1-binding partners. Interestingly, under cell-based conditions, nWrch1 bound tightly to endogenous Grb2 and Nck, but not to Crk, c-Src, or p120. Consistent with this, a very tight nWrch1 interaction with full-length Grb2 and Nck1 was confirmed in vitro by ITC measurements indicating that high avidity of the adaptor proteins can compensate for the low affinity of their SH3 domains. Peptide analysis revealed that the central PxxP motif of nWrch1, which employs a minimal consensus sequence of eight amino acids with an essential arginine next to the PxxP motif, is responsible for these interactions. Thus, novel functional insights from this study suggest that multiple upstream signals may converge on Wrch1 directly through its SH3 domain-binding properties.

Total synthesis of enantiopure pyrrhoxanthin: alternative methods for the stereoselective preparation of 4-alkylidenebutenolides.

A new stereocontrolled total synthesis of the configurationally labile C37 -norcarotenoid pyrrhoxanthin in enantiopure form has been completed. A highly stereoselective Horner-Wadsworth-Emmons (HWE) condensation of a C17-allylphosphonate and a C20-aldehyde was used as the last conjunctive step. Both a Sonogashira reaction to form the C17-phosphonate and the final HWE condensation proved to be compatible with the sensitive C7-C10 enyne E configuration. Regioselective (5-exo-dig) silver-promoted lactonization reactions of three alternative pent-2-en-4-ynoic acid precursors with increased complexity, including a fully functionalized C20-fragment, were explored for the preparation of the γ-alkylidenebutenolide fragment. This survey extends the existing methodologies for the preparation of oxygen-containing carotenoids (xanthophylls) and streamlines the synthesis of additional members of the C37-norcarotenoid butenolide family of natural products.

Hollow-shelled nanoreactors endowed with high catalytic activity.

Hollow-shelled nanoreactors have emerged as efficient structures to maximize the potential of nanoparticles in the field of catalysis. In this Concept article, we underline the importance of both the morphology of the active nanoparticles as well as the composition and porosity of the shell for the catalytic performance of the overall nanocomposite. Different configurations are discussed, with a focus on preparative methods and applications in organic synthesis. Perspectives on future designs that may offer new opportunities to improve the selectivity of the catalyzed transformations and add additional features are also addressed, in order to illustrate the potential of these unique nanostructures.

Polymeric premicelles as efficient lipophilic nanocarriers: extending drug uptake to the submicellar regime.

A multitechnique investigation on the self-assembly behavior of a biocompatible polymer in the high dilution regime is reported herein. The obtained results unambiguously reveal the existence of premicellar structures that may further extend the efficiency of traditional polymeric micelles as drug-delivery vehicles. Such an expansion in the excipient capacity arises from (i) the increased drug retention of submicellar assemblies due to their higher resistance to dilution and therefore to their improved circulation time and (ii) the superior carrier permeability of these premicellar aggregates as a result of their smaller size, which makes these drug vehicles more effectively targeted to the tumors through the so-called enhanced permeability and retention effect. The uptake ability of the polymeric premicelles described in this work has been tested through the use of Nile Red as drug model given its intermediate lipophilicity (log P ≈ 3-5) similar to that of potent chemotherapy agents and its microenvironment-sensitive fluorescence properties relevant for localization purposes. Thus, it has been found that an efficient drug encapsulation can be achieved under conditions well below the normally required critical micelle concentration. These results may constitute a promising strategy in order to develop new and more efficient polymeric formulations in drug delivery technology.

Unraveling Structure-Performance Relationships in Porphyrin-Sensitized TiO2 Photocatalysts.

Over the years, porphyrins have arisen as exceptional photosensitizers given their ability to act as chlorophyll-mimicking dyes, thus, transferring energy from the light-collecting areas to the reaction centers, as it happens in natural photosynthesis. For this reason, porphyrin-sensitized TiO2-based nanocomposites have been widely exploited in the field of photovoltaics and photocatalysis in order to overcome the well-known limitations of these semiconductors. However, even though both areas of application share some common working principles, the development of solar cells has led the way in what is referred to the continuous improvement of these architectures, particularly regarding the molecular design of these photosynthetic pigments. Yet, those innovations have not been efficiently translated to the field of dye-sensitized photocatalysis. This review aims at filling this gap by performing an in-depth exploration of the most recent advances in the understanding of the role played by the different structural motifs of porphyrins as sensitizers in light-driven TiO2-mediated catalysis. With this goal in mind, the chemical transformations, as well as the reaction conditions under which these dyes must operate, are taken in consideration. The conclusions drawn from this comprehensive analysis offer valuable hints for the implementation of novel porphyrin-TiO2 composites, which may pave the way toward the fabrication of more efficient photocatalysts.

Mechanistic and sterochemical insights on the Pt-catalyzed rearrangement of oxiranylpropargylic esters to cyclopentenones.

A mechanism for the rearrangement of oxiranylpropargylic esters to cyclopentenones catalyzed by PtCl(2) is proposed based on DFT calculations (M06/6-31++G(d,p)). Although the basic steps are coincidental with those proposed by Sarpong et al., who characterized a 2H-pyran as intermediate, calculations have revealed other intricate details of this complex rearrangement. The 2H-pyran is proposed to result from the ring-opening of a bicyclic oxonium ion that follows the nucleophilic capture by the epoxide of a platinum carbene generated by an initial Pt-mediated 1,2-propargylic rearrangement. The key steps in the evolution of this system are the electrocyclic ring-opening of the 2H-pyran to a α-methoxycarbonyl dienone and an iso-Nazarov ring closure. Prior to those, changes in hapticity and in the conformation of the dienone are required in order to produce the helical conformation needed to generate a single diastereomer of the cyclopentenone product obtained experimentally. The metal is needed well beyond the first step of the mechanism, and both electrocyclic reactions are favored by coordination to the metal when compared to their uncomplexed counterparts. Moreover, we have experimentally demonstrated that the rearrangement is stereoconvergent, a feature that is traced back to the initial configuration of the epoxide, which determines the somewhat counterthermodynamic placement of the metal syn to the methyl group of the stereogenic center in the 2H-pyran intermediate. Finally, starting from enantiopure oxiranylpropargylic ester 13, a racemate of cyclopentenone (R*,S*)-16 was obtained. Thus, the sequence does not proceed with memory of chirality, and the absolute stereochemical information is already lost at the stage of the 2H-pyran 14.

SERS optical accumulators as unified nanoplatforms for tear sampling and sensing in soft contact lenses.

Tear analysis has become an invaluable asset in clinical research in order to identify and quantify novel biomarkers for a wide array of conditions. The present work is intended to take this area of study one step further by implementing an innovative sensing platform through which exploration of low-molecular-weight compounds is conducted outperforming traditional analytical technologies. With this aim, carefully engineered plasmonic nanoassemblies have been synergistically combined with molecular-sieving materials giving rise to size-selective samplers with SERS detection capabilities. These architectures have been then integrated onto hydrogel-based contact lenses and tested in simulated tear fluids in order to evidence their operational features. Through this approach, a prolonged analyte accumulation can be realized, thus providing a competitive advantage in those scenarios where concentration of biomarkers is typically low or minimum sample volumes are not met. Additionally, quenching of metabolic flux and analyte extraction protocols can be circumvented, hence preventing the intrinsic physical and chemical interferences stemming from these procedures. The obtained results render these sensing platforms as promising medical devices, and constitute a great opportunity in order to expand the clinical toolkit in tear analysis.

Vitamin A5/X controls stress-adaptation and prevents depressive-like behaviors in a mouse model of chronic stress.

9-cis-13,14-dihydroretinoic acid (9CDHRA), acts as an endogenous ligand of the retinoid X receptors (RXRs), and is an active form of a suggested new vitamin, vitamin A5/X. Nutritional-relevance of this pathway as well as its detailed role in vertebrate physiology, remain largely unknown. Since recent GWAS data and experimental studies associated RXR-mediated signaling with depression, we explored here the relevance of RXR and vitamin A5/X-mediated signaling in the control of stress adaptation and depressive-like behaviors in mice. We found that compromised availability of 9CDHRA in Rbp1-/- mice was associated with increased despair in the forced swim and anhedonia in the sucrose preference test. 9CDHRA similarly to synthetic RXR agonist, BMS649, normalized despair behaviors in Rbp1-/- but not Rxrγ-/- mice, supporting involvement of RXR signaling in anti-despair activity of these ligands. Importantly, similarly to BMS649, the 9CDHRA and its nutritional-precursor, 9-cis-13,14-dihydroretinol (vitamin A5/X alcohol), prevented development of depressive-like behaviors in mice exposed to chronic social defeat stress, revealing the beneficial role of RXRs and its endogenous ligand in stress adaptation process. These data point to the need for relevant nutritional, biochemical and pharmacological studies of this signaling pathway in human, both in physiological conditions and in pathologies of stress-related disorders.

Structural coupling of 11-cis-7-methyl-retinal and amino acids at the ligand binding pocket of rhodopsin.

It was previously shown that opsin can be regenerated with the newly synthesized 11-cis-7-methyl-retinal forming an artificial visual pigment. We now extend this study to include mutants at positions close to the retinal to further dissect the interactions of native and artificial chromophores with opsin. Several mutants at M207, W265 and Y268 have been obtained and regenerated with 11-cis-retinal and the 7-methyl analog. M207 is the site of the point mutation M207R associated with the retinal degenerative disease retinitis pigmentosa. All the studied mutants regenerated with 11-cis-retinal except for M207C which proved to be completely misfolded. The naturally occurring M207R mutant formed a pigment with an unprotonated Schiff base linkage, altered photobleaching and low MetarhodopsinII stability. Mutants regenerated with the 7-methyl analog showed altered photobleaching reflecting a structural perturbation in the vicinity of M207. The newly obtained mutants at M207 also showed reduced levels of transducin activation with M207R showing essentially no transducin activation. Our results highlight the tight coupling of the vicinity of C7 of retinal and M207 and support the involvement of this amino acid residue in the conformational changes associated with rhodopsin photoactivation.

Selective, potent PPARgamma agonists with cyclopentenone core structure.

A series of analogues of the PPARgamma ligand 15-deoxy-Delta(12,14)-PGJ(2) have been synthesized by functionalization of a 5-alkyl-4-hydroxycyclopentenone core structure obtained by Piancatelli rearrangement of precursor furylcarbinol. Transient transactivation assays indicate that analogues 18 and 20 are selective nanomolar agonists of PPARgamma. This subtype selectivity is lost in derivatives (23, 24) with an alkynyl (oct-1-yn) chain at the C3 position, although the cyclopentenone derivative with cis relative configuration (23) showed greater affinity for PPARalpha.