Supramolecular delivery of dinuclear ruthenium and osmium MCU inhibitors.

The transmembrane protein known as the mitochondrial calcium uniporter (MCU) mediates the influx of calcium ions (Ca2+) into the mitochondrial matrix. An overload of mitochondrial Ca2+ ( m Ca2+) is directly linked to damaging effects in pathological conditions. Therefore, inhibitors of the MCU are important chemical biology tools and therapeutic agents. Here, two new analogues of previously reported Ru- and Os-based MCU inhibitors Ru265 and Os245, of the general formula [(C10H15CO2)M(NH3)4(µ-N)M(NH3)4(O2CC10H15)](CF3SO3)3, where M = Ru (1) or Os (2), are reported. These analogues bear adamantane functional groups, which were installed to act as guests for the host molecule cucurbit-[7]-uril (CB[7]). These complexes were characterized and analyzed for their efficiency as guests for CB[7]. As shown through a variety of spectroscopic techniques, each adamantane ligand is encapsulated into one CB[7], affording a supramolecular complex of 1 : 2 stoichiometry. The biological effects of these compounds in the presence and absence of two equiv. CB[7] were assessed. Both complexes 1 and 2 exhibit enhanced cellular uptake compared to the parent compounds Ru265 and Os245, and their uptake is increased further in the presence of CB[7]. Compared to Ru265 and Os245, 1 and 2 are less potent as m Ca2+ uptake inhibitors in permeabilized cell models. However, in intact cell systems, 1 and 2 inhibit the MCU at concentrations as low as 1 µM, marking an advantage over Ru265 and Os245 which require an order of magnitude higher doses for similar biological effects. The presence of CB[7] did not affect the inhibitory properties of 1 and 2. Experiments in primary cortical neurons showed that 1 and 2 can elicit protective effects against oxygen-glucose deprivation at lower doses than those required for Ru265 or Os245. At low concentrations, the protective effects of 1 were modulated by CB[7], suggesting that supramolecular complex formation can play a role in these biological conditions. The in vivo biocompatibility of 1 was investigated in mice. The intraperitoneal administration of these compounds and their CB[7] complexes led to time-dependent induction of seizures with no protective effects elicited by CB[7]. This work demonstrates the potential for supramolecular interactions in the development of MCU inhibitors.

Tetranuclear Polypyridylruthenium(II) Complexes as Selective Nucleic Acid Stains for Flow Cytometric Analysis of Monocytic and Epithelial Lung Carcinoma Large Extracellular Vesicles.

Selective staining of extracellular vesicles (EVs) is a major challenge for diagnostic and therapeutic applications. Herein, the EV labeling properties of a new class of tetranuclear polypyridylruthenium(II) complexes, Rubb7-TNL and Rubb7-TL, as phosphorescent stains are described. These new stains have many advantages over standard stains to detect and characterize EVs, including: high specificity for EV staining versus cell staining; high phosphorescence yields; photostability; and a lack of leaching from EVs until incorporation with target cells. As an example of their utility, large EVs released from control (basal) or lipopolysaccharide (LPS)-stimulated THP-1 monocytic leukemia cells were studied as a model of immune system EVs released during bacterial infection. Key findings from EV staining combined with flow cytometry were as follows: (i) LPS-stimulated THP-1 cells generated significantly larger and more numerous large EVs, as compared with those from unstimulated cells; (ii) EVs retained native EV physical properties after staining; and (iii) the new stains selectively differentiated intact large EVs from artificial liposomes, which are models of cell membrane fragments or other lipid-containing debris, as well as distinguished two distinct subpopulations of monocytic EVs within the same experiment, as a result of biochemical differences between unstimulated and LPS-stimulated monocytes. Comparatively, the staining patterns of A549 epithelial lung carcinoma-derived EVs closely resembled those of THP-1 cell line-derived EVs, which highlighted similarities in their selective staining despite their distinct cellular origins. This is consistent with the hypothesis that these new phosphorescent stains target RNA within the EVs.

Regulating through space charge transfer in thermally activated delayed fluorescence molecules via donor architectures: theoretical perspective and molecular design.

In recent studies, thermally activated delayed fluorescence (TADF) molecules with a through space charge transfer (TSCT) feature have attracted wide attention. Nevertheless, studies on the substitution effects on the photophysical properties of TSCT-based TADF molecules are insufficient, and the corresponding theoretical investigations and effective molecular design strategies are highly desired. Herein, in order to reveal the inner mechanisms between the substitution effects from the donor unit and the luminescent properties for TSCT-based TADF molecules, the photophysical properties of nine TSCT-based TADF molecules (including one molecule with dual configurations) are theoretically studied. Based on density functional theory (DFT) and time-dependent density functional theory (TD-DFT) coupled with the thermal vibration correlation function (TVCF) method, basic physical parameters such as geometric changes, electron-donating abilities, adiabatic singlet-triplet energy gaps, TSCT ratios, hole and electron distributions and excited state decay rates are calculated and analyzed. The relationships between molecular structures and luminescent properties are determined. Our results show that molecules with carbazole as the donor possess large oscillator strengths and transition dipole moments, and a prominent radiative decay process is determined. Moreover, molecules with phenazine as the donor present small geometric changes, strong electron-donating capability and tiny adiabatic singlet-triplet energy gap, and all these factors contribute to the effective reverse intersystem crossing process (RISC), and this feature makes these molecules promising TSCT-based TADF molecules. Furthermore, dual configurations for 2CTF molecules are determined (2CTF2.1 and 2CTF2.2), and 2CTF2.1 with a large TSCT ratio possessing a fast fluorescence decay process and high luminescence efficiency can be achieved. As for 2CTF2.2 with a small TSCT ratio, a remarkable RISC process is determined and high exciton utilization can be realized. Thus, 2CTF can be regarded as a self-doping TADF molecule and a remarkable TADF feature is detected. Our investigations provide a perspective for experimental measurements and propose an effective design strategy for efficient TSCT-based TADF molecules.

Theoretical perspective for substitution effect on luminescent properties of through space charge transfer-based thermally activated delayed fluorescence molecules.

Recently, through space charge transfer (TSCT)-based thermally activated delayed fluorescence (TADF) molecules have shown advantages in achieving high efficiencies and tunable emissions. However, the relationships between basic molecular structures and luminescent properties are unclear. Theoretical investigations to reveal the substitution effects with different numbers and positions on excited-state properties are highly desired. Herein, by taking TSCT-based TADF molecules S-CNDF-S-tCz, S-CNDF-D-tCz and T-CNDF-T-tCz as skeletons, a series of promising TADF molecules are designed by adopting ortho, meta and para substitutions with different numbers and positions. Photophysical properties of total 16 molecules are theoretically studied by density functional theory (DFT) and time-dependent density functional theory (TD-DFT) methods in chloroform combined with polarizable continuum model. Results indicate that molecules with ortho-substitution possess small geometric changes and short Donor-Acceptor distances which are induced by the intramolecular van der Waals interactions. Decreased non-radiative consumption and increased TSCT ratio and therefore excellent performance for them can be expected. For molecules with large substitution numbers, twist structures facilitate them to realize small adiabatic energy gaps between the lowest singlet excited state (S1) and the lowest triplet excited state (T1), this designing strategy is consistent with the TADF dendrimers. Thus, the relationships between molecular structures and luminescent properties are revealed and promising TSCT-based TADF molecules with high efficiencies are theoretically proposed. Our investigations provide theoretical perspectives for inner mechanisms of substitution effect, which could further afford meaningful guidance to design new efficient TSCT-based TADF molecules.

Controllable construction of red thermally activated delayed fluorescence molecules based on a spiro-acridine donor.

Red and near-infrared (NIR) thermally activated delayed fluorescence (TADF) molecules show excellent potential applications in organic light-emitting diodes (OLEDs). Due to the lack of systematic studies on the relationship between molecular structures and luminescence properties, both the species and amounts of red and NIR TADF molecules are far from meeting the requirements for practical applications. Herein, four new efficient molecules (DQCN-2spAs, TPCN-2spAs, DPCN-2spAs and BPCN-2spAs) are proposed and their photophysical properties are theoretically predicted based on first-principles calculations and thermal vibration correlation function (TVCF) theory. The results show that all molecules exhibit red or NIR emissions and they have fast radiative decay rates and reverse intersystem crossing (RISC) rates, and the excellent TADF luminescence properties are predicted. Moreover, based on spiro-acridine (spAs) as the donor unit, the combination with different acceptors can change the dihedral angle between the ground state and the excited state, the bending degree of the donor is positively correlated with the reorganization energy, and this feature can have a great influence on the non-radiative process. Furthermore, based on these theoretical predictions, experimental verifications are performed and the synthesized BPCN-2spAs is confirmed to be an efficient NIR TADF molecule. Thus, the relationships between basic molecular structures and photophysical properties are revealed, a feasible design strategy is applied and four promising red and NIR TADF molecules are proposed. All these results could contribute to the development of red and NIR TADF emitters and OLEDs.

A theoretical perspective of the relationship between the structures and luminescence properties of red thermally activated delayed fluorescence molecules.

Orange and red thermally activated delayed fluorescence (TADF) emitters have shown promising applications in organic light emitting diodes (OLEDs) and the bio-medical field. However, both the species and amounts of orange and red molecules are far from meeting the requirement for practical applications; this is due to the lack of systematic studies on the relationship between molecular structures and luminescence properties. Herein, the excited state dynamic processes and photophysical properties of six donor-acceptor (D-A) type orange-red TADF molecules, which possess the same acceptor, are theoretically studied in toluene by using the polarizable continuum model (PCM). Based on density functional theory (DFT) and time-dependent density functional theory (TD-DFT) calculations coupled with the thermal vibration correlation function (TVCF) method, the adiabatic singlet-triplet energy gaps, natural transition orbital properties, reorganization energies, hole and electron distributions, and the radiative and non-radiative as well as the intersystem crossing (ISC) and reverse intersystem crossing (RISC) processes are theoretically analyzed. The results indicate that remarkable geometric changes between the lowest singlet excited state (S1) and the ground state (S0) are mainly caused by the rotation of the donor unit for NAI-R2, NAI-R3 and NAI-DPAC, and the reorganization energy is mainly contributed by the dihedral angle. However, for NAI-DMAC, BTDMAc-NAI and BFDMAc-NAI, remarkable geometric changes are found in the acceptor unit with large contribution of reorganization energy by bond length. These variations bring different non-radiative energy consumption processes. Moreover, small energy gaps between S1 and the lowest triplet excited state (T1) are determined for all studied molecules and an efficient RISC process is detected. Furthermore, enhanced conjugacy in the donor unit and remarkable intramolecular interactions are determined for BTDMAc-NAI and BFDMAc-NAI, which is helpful to promote the up-conversion process. Our investigations give reasonable explanations for previous experimental measurements and the relationship between basic structures and luminescence properties is revealed, which could facilitate the development of new efficient TADF emitters.

Polar Interactions Play an Important Role in the Energetics of the Main Phase Transition of Phosphatidylcholine Membranes.

Conformational changes of membrane proteins are accompanied by deformation in the surrounding lipid bilayer. To gain insight into the energetics of membrane deformation, the phase behavior of dimyristoylphosphatidylcholine (DMPC) membranes in the presence of the dipole potential, ψd, modifiers was investigated by differential scanning calorimetry. 7-Ketocholesterol, which weakens ψd and reduces membrane-perpendicular dipole-dipole repulsion, causes a discrete second peak on the high-temperature side of the main transition, whereas 6-ketocholestanol, which strengthens ψd and increases membrane-perpendicular dipole-dipole repulsion, merely produces a shoulder. Measurements on pure DMPC vesicles showed that the observed temperature profile could not be explained by a single endothermic process, that is, breaking of van der Waals forces between hydrocarbon chains alone. Removal of NaCl from the buffer caused an increase in the main transition temperature and the appearance of an obvious shoulder, implicating polar interactions. Consideration of the phosphatidylcholine (PC) head group dipole moment indicates direct interactions between PC dipoles that are unlikely to account for the additional process. It seems more likely that the breaking of an in-plane hydrogen-bonded network consisting of hydrating water dipoles together with zwitterionic lipid head groups is responsible. The evidence presented supports the idea that the breaking of van der Waals forces between lipid tails required for the main phase transition of PC membranes is coupled to partial breaking of a hydrogen-bonded network at the membrane surface.