Tetrahedraphene: A Csp3 -centered 3D Molecular Nanographene Showing Aggregation-Induced Emission.

The bottom-up synthesis of 3D tetrakis(hexa-peri-hexabenzocoronenyl)methane, "tetrahedraphene", is reported. This molecular nanographene constituted by four hexa-peri-hexabenzocoronene (HBC) units attached to a central sp3 carbon atom, shows a highly symmetric arrangement of the HBC units disposed in the apex of a tetrahedron. The X-ray crystal structure reveals a tetrahedral symmetry of the molecule and the packing in the crystal is achieved mostly by CH⋅⋅⋅π interactions since the interstitial solvent molecules prevent the π⋅⋅⋅π interactions. In solution, tetrahedraphene shows the same electrochemical and photophysical properties as the hexa-t Bu-substituted HBC (t Bu-HBC) molecule. However, upon water addition, it undergoes a fluorescence change in solution and in the precipitated solid, showing an aggregation induced emission (AIE) process, probably derived from the restriction in the rotation and/or vibration of the HBCs. Time-Dependent Density Functional Theory (TDDFT) calculations reveal that upon aggregation, the high energy region of the emission band decreases in intensity, whereas the intensity of the red edge emission signal increases and presents a smoother decay, compared to the non-aggregated molecule. All in all, the excellent correlation between our simulations and the experimental findings allows explaining the colour change observed in the different solutions upon increasing the water fraction.

Unveiling Photodegradation and Photosensitization Mechanisms of Unconjugated Pterins.

Invited for the cover of this issue are Enrique M. Arpa (Linköping University) and Inés Corral (Universidad Autónoma de Madrid). The image depicts two examples where pterin chemistry is relevant, the wing coloration of some butterflies and the cytotoxic action in vitiligo. Read the full text of the article at 10.1002/chem.202300519.

Curved Nanographenes: Multiple Emission, Thermally Activated Delayed Fluorescence, and Non-Radiative Decay.

The intriguing and rich photophysical properties of three curved nanographenes (CNG 6, 7, and 8) are investigated by time-resolved and temperature-dependent photoluminescence (PL) spectroscopy. CNG 7 and 8 exhibit dual fluorescence, as well as dual phosphorescence at low temperature in the main PL bands. In addition, hot bands are detected in fluorescence as well as phosphorescence, and, in the narrow temperature range of 100-140 K, thermally activated delayed fluorescence (TADF) with lifetimes on the millisecond time-scale is observed. These findings are rationalized by quantum-chemical simulations, which predict a single minimum of the S1 potential of CNG 6, but two S1 minima for CNG 7 and CNG 8, with considerable geometric reorganization between them, in agreement with the experimental findings. Additionally, a higher-lying S2 minimum close to S1 is optimized for the three CNG, from where emission is also possible due to thermal activation and, hence, non-Kasha behavior. The presence of higher-lying dark triplet states close to the S1 minima provides mechanistic evidence for the TADF phenomena observed. Non-radiative decay of the T1 state appears to be thermally activated with activation energies of roughly 100 meV and leads to disappearance of phosphorescence and TADF at T > 140 K.

Unveiling Photodegradation and Photosensitization Mechanisms of Unconjugated Pterins.

Unconjugated pterins are ubiquitous molecules that participate in countless enzymatic processes and are potentially involved in the photosensitization of singlet oxygen, amino acids, and nucleotides. Following electronic excitation with UV-A light, some of these pterins degrade, producing hydrogen peroxide as the main side product. This process, which is known to take place in vivo, contributes to oxidative stress and melanocyte destruction in vitiligo. In this work, we present for the first time mechanistic insight into the formation of transient triplet species that simultaneously trigger Type I and Type II photosensitizing processes and the initiation of degradation processes. Our calculations reveal that photodegradation of 6-biopterin, which accumulates in the skin of vitiligo patients, leads to 6-formylpterin through a retro-aldol reaction, and subsequently to 6-carboxypterin through a water-mediated aldehyde oxidation. Additionally, we show that the changes in the photosensitizing potential of these systems with pH come from the modulation of their excited-state redox potentials.

Reply to the 'Comment on "The oxidation state in low-valent beryllium and magnesium compounds"' by S. Pan and G. Frenking, Chem. Sci., 2022, 13, DOI: 10.1039/D2SC04231B.

A recent article by Pan and Frenking challenges our assignment of the oxidation state of low valent group 2 compounds. With this reply, we show that our assignment of Be(+2) and Mg(+2) oxidation states in Be(cAACDip)2 and Mg(cAACDip)2 is fully consistent with our data. Some of the arguments exposed by Pan and Frenking were based on visual inspection of our figures, rather than a thorough numerical analysis. We discuss with numerical proof that some of the statements made by the authors concerning our reported data are erroneous. In addition, we provide further evidence that the criterion of the lowest orbital interaction energy in the energy decomposition analysis (EDA) method is unsuitable as a general tool to assess the valence state of the fragments. Other indicators based on natural orbitals for chemical valence (NOCV) deliver a more reliable bonding picture. We also emphasize the importance of using stable wavefunctions for any kind of analysis, including EDA.

Immune-interacting lymphatic endothelial subtype at capillary terminals drives lymphatic malformation.

Oncogenic mutations in PIK3CA, encoding p110α-PI3K, are a common cause of venous and lymphatic malformations. Vessel type-specific disease pathogenesis is poorly understood, hampering development of efficient therapies. Here, we reveal a new immune-interacting subtype of Ptx3-positive dermal lymphatic capillary endothelial cells (iLECs) that recruit pro-lymphangiogenic macrophages to promote progressive lymphatic overgrowth. Mouse model of Pik3caH1047R-driven vascular malformations showed that proliferation was induced in both venous and lymphatic ECs but sustained selectively in LECs of advanced lesions. Single-cell transcriptomics identified the iLEC population, residing at lymphatic capillary terminals of normal vasculature, that was expanded in Pik3caH1047R mice. Expression of pro-inflammatory genes, including monocyte/macrophage chemokine Ccl2, in Pik3caH1047R-iLECs was associated with recruitment of VEGF-C-producing macrophages. Macrophage depletion, CCL2 blockade, or anti-inflammatory COX-2 inhibition limited Pik3caH1047R-driven lymphangiogenesis. Thus, targeting the paracrine crosstalk involving iLECs and macrophages provides a new therapeutic opportunity for lymphatic malformations. Identification of iLECs further indicates that peripheral lymphatic vessels not only respond to but also actively orchestrate inflammatory processes.

Photophysical Characterization of Isoguanine in a Prebiotic-Like Environment.

It is intriguing how a mixture of organic molecules survived the prebiotic UV fluxes and evolved into the actual genetic building blocks. Scientists are trying to shed light on this issue by synthesizing nucleic acid monomers and their analogues under prebiotic Era-like conditions and by exploring their excited state dynamics. To further add to this important body of knowledge, this study discloses new insights into the photophysical properties of protonated isoguanine, an isomorph of guanine, using steady-state and femtosecond broadband transient absorption spectroscopies, and quantum mechanical calculations. Protonated isoguanine decays in ultrafast time scales following 292 nm excitation, consistently with the barrierless paths connecting the bright S1 (ππ*) state with different internal conversion funnels. Complementary calculations for neutral isoguanine predict similar photophysical properties. These results demonstrate that protonated isoguanine can be considered photostable in contrast to protonated guanine, which exhibits 40-fold longer excited state lifetimes.

Cdh5-lineage-independent origin of dermal lymphatics shown by temporally restricted lineage tracing.

The developmental origins of lymphatic endothelial cells (LECs) have been under intense research after a century-long debate. Although previously thought to be of solely venous endothelial origin, additional sources of LECs were recently identified in multiple tissues in mice. Here, we investigated the regional differences in the origin(s) of the dermal lymphatic vasculature by lineage tracing using the pan-endothelial Cdh5-CreER T2 line. Tamoxifen-induced labeling of blood ECs at E9.5, before initiation of lymphatic development, traced most of the dermal LECs but with lower efficiency in the lumbar compared with the cervical skin. By contrast, when used at E9.5 but not at E11.5, 4-hydroxytamoxifen, the active metabolite of tamoxifen that provides a tighter window of Cre activity, revealed low labeling frequency of LECs, and lymphvasculogenic clusters in the lumbar skin in particular. Temporally restricted lineage tracing thus reveals contribution of LECs of Cdh5-lineage-independent origin to dermal lymphatic vasculature. Our results further highlight Cre induction strategy as a critical parameter in defining the temporal window for stage-specific lineage tracing during early developmental stages of rapid tissue differentiation.

The oxidation state in low-valent beryllium and magnesium compounds.

Low-valent group 2 (E = Be and Mg) stabilized compounds have been long synthetically pursued. Here we discuss the electronic structure of a series of Lewis base-stabilized Be and Mg compounds. Despite the accepted zero(0) oxidation state nature of the group 2 elements of some recent experimentally accomplished species, the analysis of multireference wavefunctions provides compelling evidence for a strong diradical character with an oxidation state of +2. Thus, we elaborate on the distinction between a description as a donor-acceptor interaction L(0) ⇆ E(0) ⇄ L(0) and the internally oxidized situation, better interpreted as a diradical L(-1) → E(+2) ← L(-1) species. The experimentally accomplished examples rely on the strengthened bonds by increasing the π-acidity of the ligand; avoiding this interaction could lead to an unprecedented low-oxidation state.

Interplay between the Directing Group and Multifunctional Acetate Ligand in Pd-Catalyzed anti-Acetoxylation of Unsymmetrical Dialkyl-Substituted Alkynes.

The cooperative action of the acetate ligand, the 2-pyridyl sulfonyl (SO2Py) directing group on the alkyne substrate, and the palladium catalyst has been shown to be crucial for controlling reactivity, regioselectivity, and stereoselectivity in the acetoxylation of unsymmetrical internal alkynes under mild reaction conditions. The corresponding alkenyl acetates were obtained in good yields with complete levels of ß-regioselectivity and anti-acetoxypalladation stereocontrol. Experimental and computational analyses provide insight into the reasons behind this delicate interplay between the ligand, directing group, and the metal in the reaction mechanism. In fact, these studies unveil the multiple important roles of the acetate ligand in the coordination sphere at the Pd center: (i) it brings the acetic acid reagent into close proximity to the metal to allow the simultaneous activation of the alkyne and the acetic acid, (ii) it serves as an inner-sphere base while enhancing the nucleophilicity of the acid, and (iii) it acts as an intramolecular acid to facilitate protodemetalation and regeneration of the catalyst. Further insight into the origin of the observed regiocontrol is provided by the mapping of potential energy profiles and distortion-interaction analysis.

2-Oxopurine Riboside: A Dual Fluorescent Analog and Photosensitizer for RNA/DNA Research.

There is significant interest in developing suitable nucleoside analogs exhibiting high fluorescence and triplet yields to investigate the structure, dynamics, and binding properties of nucleic acids and promote selective photosensitized damage to DNA/RNA, respectively. In this study, steady-state, laser flash photolysis, time-resolved IR luminescence, and femtosecond broad-band transient absorption spectroscopies are combined with quantum chemical calculations to elucidate the excited-state dynamics of 2-oxopurine riboside in aqueous solution and to investigate its prospective use as a fluorescent or photosensitizer analog. The Franck-Condon population in the S1 (ππ*) state decays through a combination of solvent and conformational relaxation to its minimum in 1.9 ps. The population trapped in the 1ππ* minimum bifurcates to either fluoresce or intersystem cross to the triplet manifold within ca. 5 ns, while another fraction of the population decays nonradiatively to the ground state. It is demonstrated that 2-oxopurine riboside exhibits both high fluorescent (48%) and significant triplet (between 10% and 52%) yields, leading to a yield of singlet oxygen generation of 10%, making this nucleoside analog a dual fluorescent and photosensitizer analog for DNA and RNA research.

Turn-on Fluorescent Biosensors for Imaging Hypoxia-like Conditions in Living Cells.

We present the synthesis, photophysical properties, and biological application of nontoxic 3-azo-conjugated BODIPY dyes as masked fluorescent biosensors of hypoxia-like conditions. The synthetic methodology is based on an operationally simple N═N bond-forming protocol, followed by a Suzuki coupling, that allows for a direct access to simple and underexplored 3-azo-substituted BODIPY. These dyes can turn on their emission properties under both chemical and biological reductive conditions, including bacterial and human azoreductases, which trigger the azo bond cleavage, leading to fluorescent 3-amino-BODIPY. We have also developed a practical enzymatic protocol, using an immobilized bacterial azoreductase that allows for the evaluation of these azo-based probes and can be used as a model for the less accessible and expensive human reductase NQO1. Quantum mechanical calculations uncover the restructuration of the topography of the S1 potential energy surface following the reduction of the azo moiety and rationalize the fluorescent quenching event through the mapping of an unprecedented pathway. Fluorescent microscopy experiments show that these azos can be used to visualize hypoxia-like conditions within living cells.

Disclosing the Role of C4-Oxo Substitution in the Photochemistry of DNA and RNA Pyrimidine Monomers: Formation of Photoproducts from the Vibrationally Excited Ground State.

Oxo and amino substituted purines and pyrimidines have been suggested as protonucleobases participating in ancient pre-RNA forms. Considering electromagnetic radiation as a key environmental selection pressure on early Earth, the investigation of the photophysics of modified nucleobases is crucial to determine their viability as nucleobases' ancestors and to understand the factors that rule the photostability of natural nucleobases. In this Letter, we combine femtosecond transient absorption spectroscopy and quantum mechanical simulations to reveal the photochemistry of 4-pyrimidinone, a close relative of uracil. Irradiation of 4-pyrimidinone with ultraviolet radiation populates the S1(ππ*) state, which decays to the vibrationally excited ground state in a few hundred femtoseconds. Analysis of the postirradiated sample in water reveals the formation of a 6-hydroxy-5H-photohydrate and 3-(N-(iminomethyl)imino)propanoic acid as the primary photoproducts. 3-(N-(Iminomethyl)imino)propanoic acid originates from the hydrolysis of an unstable ketene species generated from the C4-N3 photofragmentation of the pyrimidine core.

Molecular Identification of the Transient Species Mediating the Deactivation Dynamics of Solvated Guanosine and Deazaguanosine.

Small structural alterations of the purine/pyrimidine core have been related to important photophysical changes, such as the loss of photostability. Similarly to canonical nucleobases, solute-solvent interactions can lead to a change in the excited state lifetimes and/or to the interplay of different states in the photophysics of these modified nucleobases. To shed light on both effects, we here report a complete picture of the absorption spectra and excited state deactivation of deoxyguanosine and its closely related derivative, deoxydeazaguanosine, in water and methanol through the mapping of the excited state potential energy surfaces and molecular dynamics simulations at the TD-DFT level of theory. We show that the N by CH exchange in the imidazole ring of deoxyguanosine translates into a small red-shift of the bright states and slightly faster dynamics. In contrast, changing solvent from water to methanol implies the opposite, i.e., that the deactivation of both systems to the ground state is significantly hindered.

A molecular insight into the photophysics of barbituric acid, a candidate for canonical nucleobases' ancestor.

This work investigates the photophysics of barbituric acid at different pH conditions using ab initio methods. Our calculations ascribe the most intense bands at ca. 260 nm at neutral pH and 210 nm at acidic pH conditions in the absorption spectra of this chromophore to the lowest lying ππ* transitions. Consistently with the ultrashort excited state lifetimes experimentally registered, the potential energy landscapes of both the neutral and deprotonated forms of barbituric acid combined with the interpretation of their transient absorption spectra suggest the deactivation of these systems along the singlet manifold. Compared to uracil, its closest natural nucleobase, barbituric acid presents a red shifted absorption spectrum, due to the lowering by more than 0.5 eV of the lowest-energy ππ* excited state, and a much more complex topography of the S1 potential energy surface, with several energetically accessible local minima. This fact, however, does not affect the excited state lifetimes, which for barbituric acid were experimentally registered in the sub-ps time scale.

Leptin brain entry via a tanycytic LepR-EGFR shuttle controls lipid metabolism and pancreas function.

Metabolic health depends on the brain's ability to control food intake and nutrient use versus storage, processes that require peripheral signals such as the adipocyte-derived hormone, leptin, to cross brain barriers and mobilize regulatory circuits. We have previously shown that hypothalamic tanycytes shuttle leptin into the brain to reach target neurons. Here, using multiple complementary models, we show that tanycytes express functional leptin receptor (LepR), respond to leptin by triggering Ca2+ waves and target protein phosphorylation, and that their transcytotic transport of leptin requires the activation of a LepR-EGFR complex by leptin and EGF sequentially. Selective deletion of LepR in tanycytes blocks leptin entry into the brain, inducing not only increased food intake and lipogenesis but also glucose intolerance through attenuated insulin secretion by pancreatic ß-cells, possibly via altered sympathetic nervous tone. Tanycytic LepRb-EGFR-mediated transport of leptin could thus be crucial to the pathophysiology of diabetes in addition to obesity, with therapeutic implications.

Tanycytic networks mediate energy balance by feeding lactate to glucose-insensitive POMC neurons.

Hypothalamic glucose sensing enables an organism to match energy expenditure and food intake to circulating levels of glucose, the main energy source of the brain. Here, we established that tanycytes of the arcuate nucleus of the hypothalamus, specialized glia that line the wall of the third ventricle, convert brain glucose supplies into lactate that they transmit through monocarboxylate transporters to arcuate proopiomelanocortin neurons, which integrate this signal to drive their activity and to adapt the metabolic response to meet physiological demands. Furthermore, this transmission required the formation of extensive connexin-43 gap junction-mediated metabolic networks by arcuate tanycytes. Selective suppression of either tanycytic monocarboxylate transporters or gap junctions resulted in altered feeding behavior and energy metabolism. Tanycytic intercellular communication and lactate production are thus integral to the mechanism by which hypothalamic neurons that regulate energy and glucose homeostasis efficiently perceive alterations in systemic glucose levels as a function of the physiological state of the organism.

Subphthalocyaninato Boron(III) Hydride: Synthesis, Structure and Reactivity.

Subphthalocyanine (SubPc) chemistry has been limited so far by their high sensitivity toward strong nucleophiles. In particular, the substitution of the axial chlorine atom by a nucleophilic group in the case of less-reactive SubPcs, such as those bearing electron-withdrawing peripheral substituents, presents some limitations and requires harsh conditions. By taking advantage of the electrophilic character of DIBAL-H, it has been possible to prepare for the first time SubPc-hydride derivatives that exhibit high reactivity as hydroboration reagents of aldehydes. This hydride transfer requires using a typical carbonyl activator (trimethylsilyl triflate) and only one equivalent of aldehyde, affording SubPcs with an axial benzyloxy group in good yield. This transformation has proven to be a useful alternative method for the axial functionalisation of dodecafluoroSubPc, a paradigmatic SubPc derivative, by using electrophiles for the first time. Considering the increasing interest in SubPcs as electron-acceptor semiconductors with remarkable absorption in the visible range to replace fullerene in organic photovoltaic (OPV) devices, it is of the utmost importance to develop new synthetic methodologies for their axial functionalisation.