Urea-Based [2]Rotaxanes as Effective Phase-Transfer Organocatalysts: Hydrogen-Bonding Cooperative Activation Enabled by the Mechanical Bond.

We finely designed a set of [2]rotaxanes with urea threads and tested them as hydrogen-bonding phase-transfer catalysts in two different nucleophilic substitutions requiring the activation of the reactant fluoride anion. The [2]rotaxane bearing a fluorinated macrocycle and a fluorine-containing urea thread displayed significantly enhanced catalytic activity in comparison with the combination of both noninterlocked components. This fact highlights the notably beneficial role of the mechanical bond, cooperatively activating the processes through hydrogen-bonding interactions.

Mechanically Planar-to-Point Chirality Transmission in [2]Rotaxanes.

Herein we describe an effective transmission of chirality, from mechanically planar chirality to point chirality, in hydrogen-bonded [2]rotaxanes. A highly selective mono-N-methylation of one (out of four) amide N atom at the macrocyclic counterpart of starting achiral rotaxanes generates mechanically planar chirality. Followed by chiral resolution, both enantiomers were subjected to a base-promoted intramolecular cyclization, where their interlocked threads were transformed into new lactam moieties. As a matter of fact, the mechanically planar chiral information was effectively transferred to the resulting stereocenters (covalent chirality) of the newly formed heterocycles. Upon removing the entwined macrocycle, the final lactams were obtained with high enantiopurity.

Modulating the shuttling motion of [2]rotaxanes built of p-xylylenediamine units through permethylation at the benzylic positions of the ring.

In this study, we show the effect of the gem-dimethyl substitution at the four benzylic carbons of the ring on the internal dynamics of two-station [2]rotaxanes. Such structural modification of the polyamide macrocycles promotes a drastic change of the internal dynamics as shown by variable-temperature (VT) 1H NMR experiments. We determined that the shuttling rates of the octamethylated macrocycle along a series of symmetrical threads were significantly faster compared to the non-substituted ring. This effect was particularly pronounced in the fumaramide-based system, in which the rate was 27 times faster than that of the model system.

Mechanically interlocked molecules in metal-organic frameworks.

Mechanically interlocked molecules (MIMs) have great potential in the development of molecular machinery due to their intercomponent dynamics. The incorporation of these molecules in a condensed phase makes it possible to take advantage of the control of the motion of the components at the macroscopic level. Metal-organic frameworks (MOFs) are postulated as ideal supports for intertwined molecules. This review covers the chemistry of the mechanical bond incorporated into metal-organic frameworks from the seminal studies to the latest published advances. We first describe some fundamental concepts of MIMs and MOFs. Next, we summarize the advances in the incorporation of rotaxanes and catenanes inside MOF matrices. Finally, we conclude by showing the study of the rotaxane dynamics in MOFs and the operation of some stimuli-responsive MIMs within MOFs. In addition to emphasising some selected examples, we offer a critical opinion on the state of the art of this research field, remarking the key points on which the future of these systems should be focused.

Cloning of an Albino Mutation of Arabidopsis thaliana Using Mapping-by-Sequencing.

We report the molecular characterization of an ethyl methanesulfonate (EMS)-induced mutation that causes albinism and lethality at the seedling stage in Arabidopsis thaliana. We identified the mutation using a mapping-by-sequencing approach that uses Fisher's exact tests to detect changes in allele frequencies among the seedlings of an F2 mapping population, which had been pooled according to their phenotypes (wild-type or mutant). After purifying genomic DNA from the plants of both pools, the two samples were sequenced using the Illumina HiSeq 2500 next-generation sequencing platform. The bioinformatic analysis allowed us to identify a point mutation that damages a conserved residue at the acceptor site of an intron of the At2g04030 gene, which encodes the chloroplast-localized AtHsp90.5 protein, a member of the HSP90 family of heat shock proteins. Our RNA-seq analysis demonstrates that the new allele alters the splicing of At2g04030 transcripts in multiple ways, leading to massive deregulation of genes encoding plastid-localized proteins. A search for protein-protein interactions using the yeast two-hybrid method allowed us to identify two members of the GrpE superfamily as potential interactors of AtHsp90.5, as has previously been reported for green algae.

Exploring the Chemistry of the Mechanical Bond: Synthesis of a [2]Rotaxane through Multicomponent Reactions.

The synthesis of a [2]rotaxane through three- or five-component coupling reactions has been adapted to an organic chemistry experiment for upper-division students. The experimental procedure addresses the search for the most favorable reaction conditions for the synthesis of the interlocked compound, which is obtained in a yield of up to 71%. Moreover, the interlocked nature of the rotaxane is proven by NMR spectroscopy. The content of the sessions has been designed on the basis of a proactive methodology whereby upper-division undergraduate students have a dynamic role. The laboratory experience not only introduces students to the chemistry of the mechanical bond but also reinforces their previous knowledge of basic organic laboratory procedures and their skills with structural elucidation techniques such as NMR and FT-IR spectroscopies. The experiment has been designed in such a customizable way that both experimental procedures and laboratory material can be adapted to a wide range of undergraduate course curricula.

Reactivity of Glutaconamides Within [2]Rotaxanes: Mechanical Bond Controlled Chemoselective Synthesis of Highly Reactive α-Ketoamides and their Light-Triggered Cyclization.

Glutaconamide-based [2]rotaxanes are efficiently oxidized to the respective interlocked α-ketoamides, whereas their non-interlocked threads afford hydroxycyclohexene tetraamides under similar reaction conditions. These results showcase the mechanically interlocking of highly reactive substrates as a powerful tool for controlling their chemical behavior. Inside the macrocycle and under irradiation with light, the α-ketoamide threads convert, in a divergent manner, into the corresponding interlocked hydroxy-ß-lactams or oxazolidinones by two modes of Norrish/Yang type-II intramolecular cyclizations, processes that are efficiently chemocontrolled by the mechanical bond.

Main Determinants Affecting the Antiproliferative Activity of Stilbenes and Their Gut Microbiota Metabolites in Colon Cancer Cells: A Structure-Activity Relationship Study.

trans-Resveratrol can be catabolized by the gut microbiota to dihydroresveratrol, 3,4'-dihydroxy-trans-stilbene, lunularin, and 4-hydroxydibenzyl. These metabolites can reach relevant concentrations in the colon. However, not all individuals metabolize RSV equally, as it depends on their RSV gut microbiota metabotype (i.e., lunularin producers vs. non-producers). However, how this microbial metabolism affects the cancer chemopreventive activity of stilbenes and their microbial metabolites is poorly known. We investigated the structure-antiproliferative activity relationship of dietary stilbenes, their gut microbial metabolites, and various analogs in human cancer (Caco-2 and HT-29) and non-tumorigenic (CCD18-Co) colon cells. The antiproliferative IC50 values of pterostilbene, oxy-resveratrol, piceatannol, resveratrol, dihydroresveratrol, lunularin, 3,4'-dihydroxy-trans-stilbene, pinosylvin, dihydropinosylvin, 4-hydroxy-trans-stilbene, 4-hydroxydibenzyl, 3-hydroxydibenzyl, and 4-trans-stilbenemethanol were calculated. IC50 values were correlated with 34 molecular characteristics by bi- and multivariate analysis. Little or no activity on CCD18-Co was observed, while Caco-2 was more sensitive than HT-29, which was explained by their different capacities to metabolize the compounds. Caco-2 IC50 values ranged from 11.4 ± 10.1 µM (4-hydroxy-trans-stilbene) to 73.9 ± 13.8 µM (dihydropinosylvin). In HT-29, the values ranged from 24.4 ± 11.3 µM (4-hydroxy-trans-stilbene) to 96.7 ± 6.7 µM (4-hydroxydibenzyl). At their IC50, most compounds induced apoptosis and arrested the cell cycle at the S phase, pterostilbene at G2/M, while 4-hydroxy-trans-stilbene and 3,4'-dihydroxy-trans-stilbene arrested at both phases. Higher Connolly values (larger size) hindered the antiproliferative activity, while a lower pKa1 enhanced the activity in Caco-2, and higher LogP values (more hydrophobicity) increased the activity in HT-29. Reducing the styrene double bond in stilbenes was the most critical feature in decreasing the antiproliferative activity. These results (i) suggest that gut microbiota metabolism determines the antiproliferative effects of dietary stilbenes. Therefore, RSV consumption might exert different effects in individuals depending on their gut microbiota metabotypes associated with RSV metabolism, and (ii) could help design customized drugs with a stilbenoid and (or) dibenzyl core against colorectal cancer.

Ring-to-Thread Chirality Transfer in [2]Rotaxanes for the Synthesis of Enantioenriched Lactams.

The synthesis of chiral mechanically interlocked molecules has attracted a lot of attention in the last few years, with applications in different fields, such as asymmetric catalysis or sensing. Herein we describe the synthesis of orientational mechanostereoisomers, which include a benzylic amide macrocycle with a stereogenic center, and nonsymmetric N-(arylmethyl)fumaramides as the axis. The base-promoted cyclization of the initial fumaramide thread allows enantioenriched value-added compounds, such as lactams of different ring sizes and amino acids, to be obtained. The chiral information is effectively transmitted across the mechanical bond from the encircling ring to the interlocked lactam. High levels of enantioselectivity and full control of the regioselectivity of the final cyclic compounds are attained.

Mechanically Interlocked Profragrances for the Controlled Release of Scents.

The synthesis of a series of interlocked profragrances and the study of the controlled release of the corresponding scents are reported. The structures of the profragrances are based on a [2]pseudorotaxane scaffold with a fumaramate thread derived from perfumery alcohols and a tetrabenzylamido ring. The delivery of the scents was accomplished by sequential thermal dethreading and further enzymatic hydrolysis. Alternatively, the dethreading can be achieved by increasing the polarity of the solvent or photochemical isomerization. The temperature of dethreading can be modulated by the steric demand of the ends of the thread, which allows the selection of different precursor structures depending on the desired rates of delivery. The inputs and outputs for the controlled release of the interlocked profragrances correspond to those of YES or AND logic gates.

Investigating the Impact of Usability on Energy Efficiency of Web-based Personal Health Records.

Usability plays an important role in eHealth applications for their widespread adoption. These software systems have been studied in depth in the literature from this perspective. However, the energy consumption of information systems in the eHealth domain lacks comprehensive research. In this paper, the relationship between the energy consumption of the main components of a PC and the usability evaluations of graphical user interfaces (GUI) were studied in client applications. For this purpose, personal health records (PHR) were used as a case study. A set of 4 web-based PHRs were evaluated with the performance of 20 common tasks in the aforementioned systems. The usability evaluations were carried out by 4 experts. A total of 8 heuristics particularly designed for electronic health record systems and based on the Nielsen usability heuristics were employed. The instantaneous energy values of the power supply and the monitor were collected with an energy consumption measuring equipment. As a result, the following significant correlations were found. In NoMoreClipboard between the Memory heuristic and the power supply (rs = 0.495, p = 0.044), and the Minimalist heuristic and the monitor (rs = - 0.513, p = 0.035). In PatientsLikeMe between the Minimalist heuristic and the power supply (rs = - 0.479, p = 0.083), as well as in the Error heuristic and the power supply (rs = - 0.638, p = 0.014). Finally, in Health Companion between the Match heuristic and the power supply (rs = - 0.481, p = 0.043), and the Error heuristic and the power supply again (rs = - 0.602, p = 0.008). Apart from that, the tasks were divided into those with excellent and fair usability. Those tasks with high usability scores were evaluated to detect whether they also had low energy consumption during task performance. Significant differences were found in PatientsLikeMe with respect to the Error heuristic and the power supply (212.39 ± 18.85W). Significant differences were also found in Health Companion with respect to the Match heuristic and the power supply (199.91 ± 7.19W). The results were discussed to reveal the fundamentals of how implementing usability can impact on energy costs when running client applications.

Corrigendum to "Energy efficiency in software: A case study on sustainability in personal health records" [J. Clean. Prod. 282 (2021) 124262].

[This corrects the article DOI: 10.1016/j.jclepro.2020.124262.].

Energy efficiency in software: A case study on sustainability in personal health records.

A personal health record is an eHealth technology in which users can observe their progress over time for a given condition. A research gap was identified in the literature concerning the study of the amount of energy that these systems need for their operation, and the energy efficiency that may be attained depending on their design. After the selection of five representative personal health records, a total of 20 tasks commonly done, and based on previous work, were performed with regard to two proposed scenarios, namely patient use and health personnel usage. The power consumption of the main components of a host machine was measured during the performance of the proposed duties. To that end, a hardware tool called the Energy Efficiency Tester was employed. The data collected were analyzed statistically, and significant differences were found in the respective consumption of the display (χ2 (4) = 23.782, p = 0.000), the processor (χ2 (4) = 29.018, p = 0.000) and the whole PC (χ2 (4) = 28.582, p = 0.000). For all of these components, NoMoreClipBoard was the personal health record that required the least energy (57.699 W for the display, 3.162 W for the processor and 181.113 W for the whole PC). A total of two strong correlations were found in the energy consumption between the hard disk and the graphics card (r = 0.791, p < 0.001), and the processor and the PC (r = 0.950, p < 0.001). Some features generated special amounts of power consumption, such as the news wall found on PatientsLikeMe, or the use of load icons that had an impact on most PC components. In addition, an in-depth analysis of the user interfaces was performed. A discussion was carried out on the design of the user interfaces, also taking into account recommendations drawn from the literature, checking for their implementation in the personal health records selected. With the aim of promoting sustainability among software developers, a best practice guideline on sustainable software design was proposed. Basic sustainability recommendations were collected for professionals to consider when developing a software system in general, and a personal health record in particular.

Effective Encapsulation of C60 by Metal-Organic Frameworks with Polyamide Macrocyclic Linkers.

A flexible benzylic amide macrocycle, functionalized with two carboxylic acid groups, was employed as the organic ligand for the preparation of robust copper(II)- and zinc(II)-based metal-organic frameworks. These polymers crystallized in the C2/m space group of the monoclinic crystal system, creating non-interpenetrated channels in one direction with an extraordinary solvent-accessible volume of 46 %. Unlike metal-organic rotaxane frameworks having benzylic amide macrocycles as linkers, the absence of the thread in these novel reticular materials causes a decrease of dimensionality and an improvement of pore size and dynamic guest adaptability. We studied the incorporation of fullerene C60 inside the adjustable pocket generated between two macrocycles connected to the same dinuclear clusters, occupying a remarkable 98 % of the cavities inside the network. The use of these materials as hosts for the selective recognition of different fullerenes was evaluated, mainly encapsulating the smaller size fullerene derivative in several mixtures of C60 and C70 .

Copper-Linked Rotaxanes for the Building of Photoresponsive Metal Organic Frameworks with Controlled Cargo Delivery.

We have prepared a photoresponsive metal-organic framework by using an amide-based [2]rotaxane as linker and copper(II) ions as metal nodes. The interlocked linker was obtained by the hydrogen bond-directed approach employing a fumaramide thread as template of the macrocyclic component, this latter incorporating two carboxyl groups. Single crystal X-ray diffraction analysis of the metal-organic framework, prepared under solvothermal conditions, showed the formation of stacked 2D rhombohedral grids forming channels decorated with the interlocked alkenyl threads. A series of metal-organic frameworks differing in the E/Z olefin ratio were prepared either by the previous isomerization of the linker or by postirradiation of the reticulated materials. By dynamic solid state 2H NMR measurements, using deuterium-labeled materials, we proved that the geometry of the olefinic axis of the interlocked struts determined the obtention of materials with different independent local dynamics as a result of the strength of the intercomponent noncovalent interactions. Moreover, the usefulness of these novel copper-rotaxane materials as molecular dosing containers has also been assayed by the diffusion and photorelease of p-benzoquinone, evaluated in different solvents and temperatures.

Light-driven exchange between extended and contracted lasso-like isomers of a bistable [1]rotaxane.

The synthesis of a set of benzylic amide [1]rotaxanes via a self-templating clipping approach is described. This methodology supposes the 1 + 1 coupling of isophthaloyl dichloride with an acyclic diamine precursor incorporating a templating arm. The structure of the threaded compounds was determined both in solution and in the solid state. The conversion into the corresponding unthreaded isomers, also obtained by deslipping of [2]rotaxane models, was evaluated in competitive and non-competitive hydrogen-bonding solvents. The switch of the extended and contracted lasso-like isomers of a bistable [1]rotaxane by an olefin isomerization promoted by UV light irradiation was also accomplished and their ring positional integrity was examined.

Enantioselective Formation of 2-Azetidinones by Ring-Assisted Cyclization of Interlocked N-(α-Methyl)benzyl Fumaramides.

The synthesis of optically active interlocked and non-interlocked 2-azetidinones by intramolecular cyclization of N-(α-methyl)benzyl fumaramide [2]rotaxanes is described. Two different strategies of asymmetric induction were tested in which the chiral group was located either proximal or distal to the reacting center of the thread. During these experiments, an interesting equilibration process inside the macrocyclic void occurred, thus leading to the cyclization through the (α-methyl)benzyl carbon atom and giving rise to ß-lactams, with a quaternary carbon atom, in an enantio- and diastereocontrolled manner. This cyclization also proceeds in kinetically stable chiral pseudo[2]rotaxanes, thus allowing further dethreading to provide enantioenriched 3,4-disubstituted trans-2-azetidinones. The stereochemical outcomes of the cyclizations inside and outside the macrocycle demonstrated noticeable differences.

Photoinduced Pedalo-Type Motion in an Azodicarboxamide-Based Molecular Switch.

Well-defined structural changes of molecular units that can be triggered by light are crucial for the development of photoactive functional materials. Herein, we report on a novel switch that has azodicarboxamide as its photo-triggerable element. Time-resolved UV-pump/IR probe spectroscopy in combination with quantum-chemical calculations shows that the azodicarboxamide functionality, in contrast to other azo-based chromophores, does not undergo trans-cis photoisomerization. Instead, a photoinduced pedalo-type motion occurs, which because of its volume-conserving properties enables the design of functional molecular systems with controllable motion in a confined space.

Effects on Rotational Dynamics of Azo and Hydrazodicarboxamide-Based Rotaxanes.

The synthesis of novel hydrogen-bonded [2]rotaxanes having two pyridine rings in the macrocycle and azo- and hydrazodicarboxamide-based templates decorated with four cyclohexyl groups is described. The different affinity of the binding sites for the benzylic amide macrocycle and the formation of programmed non-covalent interactions between the interlocked components have an important effect on the dynamic behavior of these compounds. Having this in mind, the chemical interconversion between the azo and hydrazo forms of the [2]rotaxane was investigated to provide a chemically-driven interlocked system enable to switch its circumrotation rate as a function of the oxidation level of the binding site. Different structural modifications were carried out to further functionalize the nitrogen of the pyridine rings, including oxidation, alkylation or protonation reactions, affording interlocked azo-derivatives whose rotation dynamics were also analyzed.

Stereocontrolled Synthesis of ß-Lactams within [2]Rotaxanes: Showcasing the Chemical Consequences of the Mechanical Bond.

The intramolecular cyclization of N-benzylfumaramide [2]rotaxanes is described. The mechanical bond of these substrates activates this transformation to proceed in high yields and in a regio- and diastereoselective manner, giving interlocked 3,4-disubstituted trans-azetidin-2-ones. This activation effect markedly differs from the more common shielding protection of threaded functions by the macrocycle, in this case promoting an unusual and disfavored 4-exo-trig ring closure. Kinetic and synthetic studies allowed us to delineate an advantageous approach toward ß-lactams based on a two-step, one-pot protocol: an intramolecular ring closure followed by a thermally induced dethreading step. The advantages of carrying out this cyclization in the confined space of a benzylic amide macrocycle are attributed to its anchimeric assistance.