pH-Responsive Trihydroxylated Piperidines Rescue The Glucocerebrosidase Activity in Human Fibroblasts Bearing The Neuronopathic Gaucher-Related L444P/L444P Mutations in GBA1 Gene.

Engineering bioactive iminosugars with pH-responsive groups is an emerging approach to develop pharmacological chaperones (PCs) able to improve lysosomal trafficking and enzymatic activity rescue of mutated enzymes. The use of inexpensive l-malic acid allowed introduction of orthoester units into the lipophilic chain of an enantiomerically pure iminosugar affording only two diastereoisomers contrary to previous related studies. The iminosugar was prepared stereoselectively from the chiral pool (d-mannose) and chosen as the lead bioactive compound, to develop novel candidates for restoring the lysosomal enzyme glucocerebrosidase (GCase) activity. The stability of orthoester-appended iminosugars was studied by 1 H NMR spectroscopy both in neutral and acidic environments, and the loss of inhibitory activity with time in acid medium was demonstrated on cell lysates. Moreover, the ability to rescue GCase activity in the lysosomes as the result of a chaperoning effect was explored. A remarkable pharmacological chaperone activity was measured in fibroblasts hosting the homozygous L444P/L444P mutation, a cell line resistant to most PCs, besides the more commonly responding N370S mutation.

Light-Triggered Control of Glucocerebrosidase Inhibitors: Towards Photoswitchable Pharmacological Chaperones.

Piperidine-based photoswitchable derivatives have been developed as putative pharmacological chaperones for glucocerebrosidase (GCase), the defective enzyme in Gaucher disease (GD). The structure-activity study revealed that both the iminosugar and the light-sensitive azobenzene are essential features to exert inhibitory activity towards human GCase and a system with the correct inhibition trend (IC50 of the light-activated form lower than IC50 of the dark form) was identified. Kinetic analyses showed that all compounds are non-competitive inhibitors (mixed or pure) of GCase and the enzyme allosteric site involved in the interaction was identified by means of MD simulations. A moderate activity enhancement of mutant GCase assessed in GD patients' fibroblasts (ex vivo experiments) carrying the most common mutation was recorded. This promising observation paves the way for further studies to improve the benefit of the light-to-dark thermal conversion for chaperoning activity.

A Dihydroazulene-Based Photofluorochromic AIE System for Rewritable 4D Information Encryption.

Dynamic patterns based on luminescent materials play an essential role in the digital age. However, it is still challenging to develop highly emissive photofluorochromic materials with dynamic behaviors to store information with multiple characteristics. Here, we report a series of dihydroazulene-based compounds which show typical aggregation-induced emission (AIE) effect. Moreover, the photo-switching ability of the dihydroazulene units, undergoing light-induced ring-opening, enables photofluorochromic properties. The photofluorochromism also shows quantitively described responses to time and temperature via a reverse ring-closing process. Ultimately, a rewritable 4D information system, embedded with a quick response code, dot matrix with microstructures, color matrix of fluorescence, and time/temperature-dependent intensity change, is established with dynamic patterns. This work not only develops a dynamic AIE skeleton with photofluorochromic properties but also provides a new strategy for information encryption and cybernetics.

Photoswitchable inhibitors of human ß-glucocerebrosidase.

Light-switchable inhibitors of the enzyme ß-glucocerebrosidase (GCase) have been developed by anchoring a specific azasugar to a dihydroazulene or an azobenzene responsive moiety. Their inhibitory effect towards human GCase, before and after irradiation are reported, and the effect on thermal denaturation of recombinant GCase and cytotoxicity were studied on selected candidates.

ortho-Substituted 2-Phenyldihydroazulene Photoswitches: Enhancing the Lifetime of the Photoisomer by ortho-Aryl Interactions.

Photochromic molecules are systems that undergo a photoisomerization to high-energy isomers and are attractive for the storage of solar energy in a closed-energy cycle, for example, in molecular solar thermal energy storage systems. One challenge is to control the discharge time of the high-energy isomer. Here, we show that different substituents in the ortho position of a phenyl ring at C-2 of dihydroazulene (DHA-Ph) significantly increase the half-life of the metastable vinylheptafulvene (VHF-Ph) photoisomer; thus, the energy-releasing VHF-to-DHA back-reaction rises from minutes to days in comparison to the corresponding para- and meta-substituted systems. Systems with two photochromic DHA-Ph units connected by a diacetylene bridge either at the para, meta and ortho positions and corresponding to a linear or to a cross-conjugated pathway between the two photochromes are also presented. Here, the ortho substitution was found to compromise the switching properties. Thus, irradiation of ortho-bridged DHA-DHA resulted in degradation, probably due to the proximity of the different functional groups that can give rise to side-reactions.

Liquid-Based Multijunction Molecular Solar Thermal Energy Collection Device.

Photoswitchable molecules-based solar thermal energy storage system (MOST) can potentially be a route to store solar energy for future use. Herein, the use of a multijunction MOST device that combines various photoswitches with different onsets of absorption to push the efficiency limit on solar energy collection and storage is explored. With a parametric model calculation, it is shown that the efficiency limit of MOST concept can be improved from 13.0% to 18.2% with a double-junction system and to 20.5% with a triple-junction system containing ideal, red-shifted MOST candidates. As a proof-of-concept, the use of a three-layered MOST device is experimentally demonstrated. The device uses different photoswitches including a norbornadiene derivative, a dihydroazulene derivative, and an azobenzene derivative in liquid state with different MOSTproperties, to increase the energy capture and storage behavior. This conceptional device introduces a new way of thinking and designing optimal molecular candidates for MOST, as much improvement can be made by tailoring molecules to efficiently store solar energy at specific wavelengths.

Transient Symmetry Controls Photo Dynamics near Conical Intersections.

Excited-state chemistry lacks generalized symmetry rules. With many femtochemistry studies focused on individual cases, it is hard to build up the same level of chemical intuition for excited states as that for ground states. Here, we unravel the degrees of freedom involved in ultrafast internal conversion (IC) by mapping the vibrational coherence of the initial wavepacket and the dependence on molecular symmetry in various cyclic tertiary amines. Molecular symmetry plays an important role in the preservation of vibrational coherence in the transit from one electronic state to another. We show here that it is sufficient for the molecule to simply have the possibility of a more symmetric structure to achieve the preservation of vibrational coherence. It can be transient and still lead to preservation. This finding provides an additional angle on how symmetry influences electronic transitions and an additional piece to the puzzle of establishing symmetry-based selection rules for excited-state processes.

Dihydroazulene-Azobenzene-Dihydroazulene Triad Photoswitches.

Photoswitch triads comprising two dihydroazulene (DHA) units in conjugation with a central trans-azobenzene (AZB) unit were prepared in stepwise protocols starting from meta- and para-disubstituted azobenzenes. The para-connected triad had significantly altered optical properties and lacked the photoactivity of the separate photochromes. In contrast, for the meta-connected triad, all three photochromes could be photoisomerized to generate an isomer with two vinylheptafulvene (VHF) units and a cis-azobenzene unit. Ultrafast spectroscopy of the photoisomerizations revealed a fast DHA-to-VHF photoisomerization and a slower trans-to-cis AZB photoisomerization. This meta triad underwent thermal VHF-to-DHA back-conversion with a similar rate of all VHFs, independent of the identity of the neighboring units, and in parallel thermal cis-to-trans AZB conversion. The experimental observations were supported by computation (excitation spectra and orbital analysis of the transitions).

Multi-Photochromic Molecules Based on Dihydroazulene Units.

Multi-photochromic systems incorporating individually addressable switching units are attractive for development of advanced data storage devices. Here, we present the synthesis and properties of a selection of such molecular systems incorporating the dihydroazulene/vinylheptafulvene (DHA/VHF) photo-/thermoswitch. The influence of the linker (meta-phenylene vs. azulene-1,3-diyl vs. thiophene-2,5-diyl) separating two DHA units on the switching properties was investigated. An azulene-1,3-diyl spacer largely inhibited both the DHA-to-VHF photoisomerizations and the thermal VHF-to-DHA back-reactions; the latter occurred ten times slower than for the related compound with a meta-phenylene spacer. A DHA trimer containing three DHA units around a central benzene ring was found to undergo stepwise DHA-to-VHF photoisomerizations, whereas the thermal back-reactions occurred at similar rates for the three VHF entities. A meta-phenylene-bridged DHA dimer was subjected to further structural modifications at position C-1 of each DHA, having strong implications for the switching events, and synthetic steps for further functionalizations at position C-7 of each DHA were investigated. Finally, the molecular structure (from X-ray crystallographic analysis) between the meta-phenylene-bridged DHA dimer and CuI is presented.

Computational and Experimental Evidence of Two Competing Thermal Electrocyclization Pathways for Vinylheptafulvene.

The thermal electrocyclic ring-closure reaction of vinylheptafulvene (VHF) to form dihydroazulene (DHA) is elucidated herein by using DFT and 1 H NMR spectroscopy. Two different transition states were found computationally; one corresponds to a disrotatory pathway, which is allowed according to the Woodward-Hoffmann selection rules, whereas the other corresponds to a conrotatory pathway. The conrotatory pathway is found to be zwitterionic in the transition state, whereas the disrotatory transition state varies in zwitterionic character depending on solvent and substituents in the molecular framework. The conrotatory and disrotatory transition states are found to have similar energy and their relative stability varies with solvent polarity and functionalization at the C1 position. To support these findings, we chemically ring-opened diastereomerically pure 1-(benzothiazol-2-yl)-DHA to give the VHF form, then subsequently thermally reconverted the VHF to DHA in a range of solvents with various polarities. We found that, depending on solvent polarity, different ratios of anti- and syn-diastereoisomers of DHA were formed in a systematic manner, which supports the existence of two distinct thermal ring-closure pathways for VHF.

An effective trigger for energy release of vinylheptafulvene-based solar heat batteries.

Stoichiometric copper(i) tetrakis(acetonitrile) is found to activate the thermal ring-closure reaction of a series of high-energy vinylheptafulvene isomers to the corresponding low-energy and photoactive dihydroazulenes, allowing the release of energy upon request.

Aromaticity-Controlled Energy Storage Capacity of the Dihydroazulene-Vinylheptafulvene Photochromic System.

Photochemical conversion of molecules into high-energy isomers that, after a stimulus, return to the original isomer presents a closed-cycle of light-harvesting, energy storage, and release. One challenge is to achieve a sufficiently high energy storage capacity. Here, we present efforts to tune the dihydroazulene/vinylheptafulvene (DHA/VHF) couple through loss/gain of aromaticity. Two derivatives were prepared, one with aromatic stabilization of DHA and the second of VHF. The consequences for the switching properties were elucidated. For the first type, sigmatropic rearrangements of DHA occurred upon irradiation. Formation of a VHF complex could be induced by a Lewis acid, but addition of H2 O resulted in immediate regeneration of DHA. For the second type, the VHF was too stable to convert into DHA. Calculations support the results and provide new targets. We predict that by removing one of the two CN groups at C-1 of the aromatic DHA, the heat storage capacity will be further increased, as will the life-time of the VHF. Calculations also reveal that a CN group at the fulvene ring retards the back-reaction, and we show synthetically that it can be introduced regioselectively.

Solar Thermal Energy Storage in a Photochromic Macrocycle.

The conversion and efficient storage of solar energy is recognized to hold significant potential with regard to future energy solutions. Molecular solar thermal batteries based on photochromic systems exemplify one possible technology able to harness and apply this potential. Herein is described the synthesis of a macrocycle based on a dimer of the dihydroazulene/vinylheptafulvene (DHA/VHF) photo/thermal couple. By taking advantage of conformational strain, this DHA-DHA macrocycle presents an improved ability to absorb and store incident light energy in chemical bonds (VHF-VHF). A stepwise energy release over two sequential ring-closing reactions (VHF→DHA) combines the advantages of an initially fast discharge, hypothetically addressing immediate energy consumption needs, followed by a slow process for consistent, long-term use. This exemplifies another step forward in the molecular engineering and design of functional organic materials towards solar thermal energy storage and release.

Towards solar energy storage in the photochromic dihydroazulene-vinylheptafulvene system.

One key challenge in the field of exploitation of solar energy is to store the energy and make it available on demand. One possibility is to use photochromic molecules that undergo light-induced isomerization to metastable isomers. Here we present efforts to develop solar thermal energy storage systems based on the dihydroazulene (DHA)/vinylheptafulvene (VHF) photo/thermoswitch. New DHA derivatives with one electron-withdrawing cyano group at position 1 and one or two phenyl substituents in the five-membered ring were prepared by using different synthetic routes. In particular, a diastereoselective reductive removal of one cyano group from DHAs incorporating two cyano groups at position 1 turned out to be most effective. Quantum chemical calculations reveal that the structural modifications provide two benefits relative to DHAs with two cyano groups at position 1: 1) The DHA-VHF energy difference is increased (i.e., higher energy capacity of metastable VHF isomer); 2) the Gibbs free energy of activation is increased for the energy-releasing VHF to DHA back-reaction. In fact, experimentally, these new derivatives were so reluctant to undergo the back-reaction at room temperature that they practically behaved as DHA to VHF one-way switches. Although lifetimes of years are at first attractive, which offers the ultimate control of energy release, for a real device it must of course be possible to trigger the back-reaction, which calls for further iterations in the future.

On the bromination of the dihydroazulene/vinylheptafulvene photo-/thermoswitch.

BACKGROUND: The dihydroazulene (DHA)/vinylheptafulvene (VHF) system (with two cyano groups at C1) functions as a photo-/thermoswitch. Direct ionic bromination of DHA has previously furnished a regioselective route to a 7,8-dibromide, which by elimination was converted to a 7-bromo-substituted DHA. This compound has served as a central building block for functionalization of the DHA by palladium-catalyzed cross-coupling reactions. The current work explores another bromination protocol for achieving the isomeric 3-bromo-DHA and also explores the outcome of additional bromination of this compound as well as of the known 7-bromo-DHA. RESULTS: Radical bromination on two different VHFs by using N-bromosuccinimide/benzoyl peroxide and light, followed by a ring-closure reaction generated the corresponding 3-bromo-DHAs, as confirmed in one case by X-ray crystallography. According to a (1)H NMR spectroscopic study, the ring closure of the brominated VHF seemed to occur readily under the reaction conditions. A subsequent bromination-elimination protocol provided a 3,7-dibromo-DHA. In contrast, treating the known 7-bromo-DHA with bromine generated a very labile species that was converted to a new 3,7-dibromoazulene, i.e., the fully unsaturated species. Azulenes were also found to form from brominated compounds when left standing for a long time in the solid state. Kinetics measurements reveal that the 3-bromo substituent enhances the rate of the thermal conversion of the VHF to DHA, which is opposite to the effect exerted by a bromo substituent in the seven-membered ring. CONCLUSION: Two general procedures for functionalizing the DHA core with a bromo substituent (at positions 3 and 7, respectively) are now available with the DHA as starting material.

Pyrrolic tripodal receptors for carbohydrates. Role of functional groups and binding geometry on carbohydrate recognition.

The contribution from several H-bonding groups and the impact of geometric requirements on the binding ability of benzene-based tripodal receptors toward carbohydrates have been investigated by measuring the affinity of a set of structures toward octyl ß-D-glucopyranoside, selected as a representative monosaccharide. The results reported in the present study demonstrate that a judicious choice of correct geometry and appropriate functional groups is critical to achieve the complementary hydrogen bonding interactions required for an effective carbohydrate recognition.

Inhibition and dispersion of Pseudomonas aeruginosa biofilms by glycopeptide dendrimers targeting the fucose-specific lectin LecB.

The human pathogenic bacterium Pseudomonas aeruginosa produces a fucose-specific lectin, LecB, implicated in tissue attachment and the formation of biofilms. To investigate if LecB inhibition disrupts these processes, high-affinity ligands were obtained by screening two 15,536-member combinatorial libraries of multivalent fucosyl-peptide dendrimers. The most potent LecB-ligands identified were dendrimers FD2 (C-Fuc-LysProLeu)(4)(LysPheLysIle)(2)LysHisIleNH(2) (IC(50) = 0.14 microM by ELLA) and PA8 (OFuc-LysAlaAsp)(4)(LysSerGlyAla)(2)LysHisIleNH(2) (IC(50) = 0.11 microM by ELLA). Dendrimer FD2 led to complete inhibition of P. aeruginosa biofilm formation (IC(50) approximately 10 microM) and induced complete dispersion of established biofilms in the wild-type strain and in several clinical P. aeruginosa isolates. These experiments suggest that LecB inhibition by high-affinity multivalent ligands could represent a therapeutic approach against P. aeruginosa infections by inhibition of biofilm formation and dispersion of established biofilms.

A beta-mannoside-selective pyrrolic tripodal receptor.

Acetalic substituents strategically located in a pyrrolic tripodal structure provide a new synthetic receptor endowed with unprecedented affinity for mannosides and the highest selectivity for beta-mannose ever reported for synthetic H-bonding receptors. Binding properties have been determined by NMR, ITC, and ESI-MS techniques, while affinities have been univocally assessed by the BC50(0) parameter, a general descriptor of binding affinity.

A tricatecholic receptor for carbohydrate recognition: synthesis and binding studies.

A new tripodal receptor bearing three catechol subunits on a benzene platform has been synthesized in four steps from 1,3,5-triethylbenzene and pyrogallol. The binding ability of the tricatecholic receptor was investigated toward several monosaccharides in CDCl3, where multiple equilibria were detected, and compared to that of a previously reported trisureidic receptor of analogous structure. Association constants were measured by 1H NMR titrations, and the corresponding affinities were assessed through the BC50 parameter, a binding descriptor univocally defining the affinity of a host for a guest in multi-equilibrium systems. Results show that the tripodal catecholic receptor binds the octyl glycosides with affinities ranging from 0.87 to 5.2 mM and with a 6-fold selectivity factor for the alpha-mannoside over the beta-glucoside. Although the affinity for glycosides was not appreciably improved with respect to the ureidic receptor, a significant change in selectivity was obtained by the H-bonding group replacement.