Discovery of novel fluorescent azaindoles with cytotoxic action in A2780 ovarian carcinoma cells.

Azaindole scaffold is a privileged structure in medicinal chemistry and some derivatives have demonstrated to be potential anticancer drugs. Herein, a set of novel azaindoles, comprising the four regioisomers, bearing a morpholine (azaindoles 3a-d) and N-methyl-N-benzylamine (azaindoles 4a-d) groups were prepared. Among these compounds, azaindoles 4 exhibited higher cytotoxicity against the ovarian cancer cell line A2780 and normal dermal fibroblasts compared to azaindoles 3. Furthermore, azaindoles 4b and 4c promoted a delay in the cell cycle of the cancer cell line, inspiring an investigation into the intracellular localization of these derivatives.

Exploring the Luminescence, Redox, and Magnetic Properties in a Multivariate Metal-Organic Radical Framework.

Persistent neutral organic radicals are excellent building blocks for the design of functional molecular materials due to their unique electronic, magnetic, and optical properties. Among them, triphenylmethyl radical derivatives have attracted a lot of interest as luminescent doublet emitters. Although neutral organic radicals have been underexplored as linkers for building metal-organic frameworks (MOFs), they hold great potential as organic elements that could introduce additional electronic properties within these frameworks. Herein, we report the synthesis and characterization of a novel multicomponent metal-organic radical framework (PTMTCR@NR-Zn MORF), which is constructed from the combination of luminescent perchlorotriphenylmethyl tricarboxylic acid radical (PTMTCR) and nonemissive nonradical (PTMTCNR) organic linkers and Zn(II) ions. The PTMTCR@NR-Zn MORF structure is layered with microporous one-dimensional channels embedded within these layers. Kelvin probe force microscopy further confirmed the presence of both organic nonradical and radical linkers in the framework. The luminescence properties of the PTMTCR ligand (first studied in solution and in the solid state) were maintained in the radical-containing PTMTCR@NR-Zn MORF at room temperature as fluorescence solid-state quenching is suppressed thanks to the isolation of the luminescent radical linkers. In addition, magnetic and electrochemical properties were introduced to the framework due to the incorporation of the paramagnetic organic radical ligands. This work paves the way for the design of stimuli-responsive hybrid materials with tunable luminescence, electrochemical, and magnetic properties by the proper combination of closed- and open-shell organic linkers within the same framework.

Excited-State Proton Transfer in Luminescent Dyes: From Theoretical Insight to Experimental Evidence.

The effective utilization of luminescent dyes often relies on a comprehensive understanding of their excitation and relaxation pathways. One such pathway, Excited-State Proton Transfer (ESPT), involves the tautomerization of the dye in its excited state, resulting in a new structure that exhibits distinct emission properties, such as a very large Stokes' shift or dual-emission. Although the ESPT phenomenon is well-explained theoretically, its experimental demonstration can be challenging due to the presence of numerous other phenomena that can yield similar experimental observations. In this review, we propose that an all-encompassing methodology, integrating experimental findings, computational analyses, and a thorough evaluation of diverse mechanisms, is essential for verifying the occurrence of ESPT in luminescent dyes. Investigations have offered significant understanding of the elements impacting the ESPT process and the array of approaches that can be used to validate the existence of ESPT. These discoveries hold crucial ramifications for the advancement of molecular probes, sensors, and other applications that depend on ESPT as a detection mechanism.

Curcumin-based molecular probes for fluorescence imaging of fungi.

Fluorescence imaging is a powerful and widely used method to visualize and study living organisms. However, fungi are notoriously difficult to visualize using fluorescence microscopy, given that their cell wall represents a diffusion barrier, and the synthetic organic dyes available are very limited when compared to molecular probes available for other organisms. Moreover, these dyes are usually available in only one colour, preventing co-staining experiments. To fill this gap, curcumin-based molecular probes were designed based on the rationale that curcumin is fluorescent and has moderate toxicity toward fungi, implying its ability to cross the cell wall to reach targets in the intracellular compartments. A family of boron diketonate complexes was synthesized, based on a curcumin backbone, tuning their emission color from blue to red. These probes did not present noticeable toxicity to filamentous fungus and, when applied to their visualization, readily entered the cells and precisely localized in sub-cellular organelles, enabling their visualization.

Three-dimensional nanofibrous and porous scaffolds of poly(ε-caprolactone)-chitosan blends for musculoskeletal tissue engineering.

One of the established tissue engineering strategies relies on the fabrication of appropriate materials architectures (scaffolds) that mimic the extracellular matrix (ECM) and assist the regeneration of living tissues. Fibrous structures produced by electrospinning have been widely used as reliable ECM templates but their two-dimensional structure restricts, in part, cell infiltration and proliferation. A recent technique called thermally-induced self-agglomeration (TISA) allowed to alleviate this drawback by rearranging the 2D electrospun membranes into highly functional 3D porous-fibrous systems. Following this trend, the present research focused on preparing polycaprolactone/chitosan blends by electrospinning, to then convert them into 3D structures by TISA. By adding different amounts of chitosan, it was possible to accurately modulate the physicochemical properties of the obtained 3D nanofibrous scaffolds, leading to highly porous constructs with distinct morphologic and mechanical features. Viability and proliferation studies using adult human chondrocytes also revealed that the biocompatibility of the scaffolds was not impaired after 28 days of cell culture, highlighting their potential to be included into musculoskeletal tissue engineering applications, particularly cartilage repair.

Influence of the Intramolecular Hydrogen Bond on the Fluorescence of 2-ortho-Aminophenyl Pyridines.

The dynamic nature of excited-state intramolecular proton transfer (ESIPT) and its effect on emission spectra is an attractive strategy to create multi-emissive dyes. Here we describe the behavior of a series of hydrogen-bonded triphenylpyridines with a set of donor-acceptor combinations that allowed us to perceive the influence of each substitution on the photophysical properties of the dyes. The susceptibility of these ESIPT moieties to pH variations was also studied, elucidating that the level of protonation had a significant effect on the emission color. The assignment of each emission band was made by using DFT and td-DFT calculations that were in agreement with the experimental results. This study emphasizes the versatility of triphenylpyridines that can be synthesized effortlessly with a logical and independent C-2, C-4 and C-6 substitution in order to have the desired ESIPT modulation and subsequent multi-emission response.

Steroid-Quinoline Hybrids for Disruption and Reversion of Protein Aggregation Processes.

Reversing protein aggregation within cells may be an important tool to fight protein-misfolding disorders such as Alzheimer's, Parkinson's, and cardiovascular diseases. Here we report the design and synthesis of a family of steroid-quinoline hybrid compounds based on the framework combination approach. This set of hybrid compounds effectively inhibited Aß1-42 self-aggregation in vitro by delaying the exponential growth phase and/or reducing the quantity of fibrils in the steady state. Their disaggregation efficacy was further demonstrated against preaggregated Aß1-42 peptides in cellular assays upon their endocytosis by neuroblastoma cells, as they reverted both the number and the average area of fibrils back to basal levels. The antiaggregation effect of these hybrids was further tested and demonstrated in a cellular model of general protein aggregation expressing a protein aggregation fluorescent sensor. Together, our results show that the new cholesterol-quinoline hybrids possess wide and marked disaggregation capacities and are therefore promising templates for the development of new drugs to deal with conformational disorders.

Locking the GFP Fluorophore to Enhance Its Emission Intensity.

The Green Fluorescent Protein (GFP) and its analogues have been widely used as fluorescent biomarkers in cell biology. Yet, the chromophore responsible for the fluorescence of the GFP is not emissive when isolated in solution, outside the protein environment. The most accepted explanation is that the quenching of the fluorescence results from the rotation of the aryl-alkene bond and from the Z/E isomerization. Over the years, many efforts have been performed to block these torsional rotations, mimicking the environment inside the protein ß-barrel, to restore the emission intensity. Molecule rigidification through chemical modifications or complexation, or through crystallization, is one of the strategies used. This review presents an overview of the strategies developed to achieve highly emissive GFP chromophore by hindering the torsional rotations.

Photodynamic control of citrus crop diseases.

Citrus are economically important fruit crops to which infectious diseases like citrus canker caused by Xanthomonas citri subs. citri, citrus variegated chlorosis caused by Xylella fastidiosa, "huanglongbing" associated with the presence of Candidatus liberibacter species, anthracnose caused by Colletotrichum gloeosporioides and citrus black spot caused by Phyllosticta citricarpa, impose significant losses. Control measures involve chemical treatment of orchards but often, eradication of infected plants is unavoidable. To circumvent the environmental impacts of pesticides and the socio-economic impacts of eradication, innovative antimicrobial approaches like photodynamic inactivation are being tested. There is evidence of the susceptibility of Xanthomonas citri subs. citri and C. gloeosporioides to photodynamic damage. However, the realistic assessment of perspectives for widespread application of photodynamic inactivation in the control of citrus diseases, necessarily implies that other microorganisms are also considered. This review intends to provide a critical summary of the current state of research on photodynamic inactivation of citrus pathogens and to identify some of the current limitations to the widespread use of photodynamic treatments in citrus crops.

Benzimidazole-Based N,O Boron Complexes as Deep Blue Solid-State Fluorophores.

Benzimidazole-based boranils were designed and synthesized in order to assess the influence of halogen substituents on their optoelectronic properties. All compounds are photoluminescent in solution and solid state. Compared to the free ligands, the new boranils emit at a lower wavelength, by elimination of the excited-state intramolecular proton transfer observed with the ligands. In the solid state, some of the boranils exhibit a deep blue emission, presenting Commission Internationale de l'Éclairage (CIE) coordinates with an x-component of less than 0.16 and a y-component smaller than 0.04, highly desired values for the development of blue emitting materials.

Tetracyclic Thioxanthene Derivatives: Studies on Fluorescence and Antitumor Activity.

Thioxanthones are bioisosteres of the naturally occurring xanthones. They have been described for multiple activities, including antitumor. As such, the synthesis of a library of thioxanthones was pursued, but unexpectedly, four tetracyclic thioxanthenes with a quinazoline-chromene scaffold were obtained. These compounds were studied for their human tumor cell growth inhibition activity, in the cell lines A375-C5, MCF-7 and NCI-H460. Photophysical studies were also performed. Two of the compounds displayed GI50 values below 10 µM for the three tested cell lines, and structure-activity relationship studies were established. Three compounds presented similar wavelengths of absorption and emission, characteristic of dyes with a push-pull character. The structures of two compounds were elucidated by X-ray crystallography. Two tetracyclic thioxanthenes emerged as hit compounds. One of the two compounds accumulated intracellularly as a bright fluorescent dye in the green channel, as analyzed by both fluorescence microscopy and flow cytometry, making it a promising theranostic cancer drug candidate.

Dependent excited state absorption and dynamic of ß-BF2 substituted metalloporphyrins: The metal ion effect.

Absorption and relaxation dynamics of electronic states of free-base, Co(II), Cu(II) and Zn(II) porphyrins bearing a ß-(2,2-difluoro-1,3,2-dioxaborinin-5-yl) group were investigated in dimethyl sulfoxide by using distinct time-resolved spectroscopic techniques. Furthermore, excited state absorption cross-section spectra were determined by combining white light continuum Z-Scan and transient absorption techniques. In the case of the free-base (2H) and Zn(II) porphyrins, we were able to quantify singlet-triplet conversion by analyzing the evolution of time-resolved fluorescence. Relaxation lifetimes from the excited to the ground state were observed in both porphyrins at nanosecond time scale. However, for Co(II) and Cu(II) metalloporphyrins it was observed in the picosecond time scale through femtosecond transient absorption, indicating that both compounds relax back to the ground state only by internal conversion processes. Co(II) and Cu(II) heavy atoms seem to prohibit the radiative and intersystem crossing processes.

Multicomponent Synthesis of Luminescent Iminoboronates.

A family of iminoboronates was prepared through a one-pot multicomponent reaction, starting from boronic acid, anthranilic acid, and different salicylaldehydes. Their synthesis was straightforward and the complexes were obtained in good to excellent yields. Their photophysical properties were assessed in a diluted solution, and the complexes proved to be faintly luminescent. These chelates demonstrated remarkable Aggregation-Induced Emission Enhancement, which was rationalized using crystal structures.

Photodynamic treatment of melanoma cells using aza-dipyrromethenes as photosensitizers.

In this study, we report for the first time the use of four aza-dipyrromethenes (ADPMs) as photosensitizers for cancer PDT. The synthesis and characterization of the ADPMs and their photodynamic action against B16F10 melanoma cells were assessed. ADPM 2 is the best singlet oxygen generator and the most phototoxic (at 2.5 µM) towards B16F10 cells.

Site-Selective Modification of a Porpholactone-Selective Synthesis of 12,13- and 17,18-Dihydroporpholactones.

The reaction of meso-tetrakis(pentafluorophenyl)porpholactone with azomethine ylides and nitrones affords pyrrolidine-fused and isoxazolidine-fused dihydroporpholactones that display, respectively, isobacteriochlorin- and chlorin-type UV-Vis spectra. These reactions are site-selective, yielding, respectively, 17,18- or 12,13-dihydroporpholactones. The crystal and molecular features of pyrrolidine-fused and isoxazolidine-fused dihydroporpholactones were unveiled from single-crystal X-ray diffraction studies.

Fluorescent Light-up Probe for the Detection of Protein Aggregates.

A fluorescent dye was decorated with water-soluble pyridinium groups in order to be applied in the detection of cyclodextrins or DNA. The dye displays an enhancement of its emission intensity when the internal rotations are restricted due to the formation of an inclusion complex with cyclodextrins or upon interaction with DNA. In vivo, the fluorescent probe can stain protein aggregates with a selectivity comparable to the widely used Proteostat®.

Tunable Color of Aggregation-Induced Emission Enhancement in a Family of Hydrogen-Bonded Azines and Schiff Bases.

A simple synthesis strategy afforded a family of hydrogen-bonded azines and Schiff-bases. Although in dilute solution these dyes are faint light emitters, all exhibit bright luminescence upon aggregation. Changing the peripheral substituents from electron donating to electron withdrawing allows emission fine-tuning in a range from bluish-green to orange-red. The crystal structures of the materials reveal that the restriction of intramolecular rotations is the main mechanism for the aggregation-induced emission enhancement properties.

The Rich Tautomeric Behavior of Campestarenes.

Campestarenes are a new family of Schiff-base macrocycles that form selectively in a one-step synthesis. These macrocycles with five-fold symmetry show solvent-dependent tautomerization and dimerization or aggregation. In this paper, we have prepared new soluble campestarenes that do not aggregate. The initial single-crystal X-ray diffraction study of a campestarene reveals that these macrocycles are nearly flat. The tautomeric behavior of the campestarenes has been extensively studied by variable-temperature, multinuclear NMR spectroscopy, UV/Vis spectroscopy, and IR spectroscopy. In polar solvents, such as DMF, the molecules exist predominantly in their keto-enamine form, but the enol-imine tautomer is dominant in non-polar solvents. A detailed computational study of the tautomeric forms of campestarenes provides a theoretical basis for their behavior and corroborates the experimental data. The results of this study give the first comprehensive understanding of the electronic and spectroscopic properties of these pentagonal macrocycles.

Site-selective hexa-hetero-functionalization of α-cyclodextrin an archetypical C6-symmetric concave cycle.

Access to Cn (n>4) symmetric cyclic concave molecules with a different function on each of their n subunits is an unmet challenge. The reason lies in the lack of a post-functionalization method whose site selectivity is sufficiently understood, predictable and modulable to access most functionalization patterns. Here we disclose a new site-directing rule for a debenzylation reaction on cyclodextrins that solves this problem and allows the unprecedented access to penta- and ultimately hexa-differentiations of such C6 concave cycles. This achievement opens the access to objects with very high-density information.

Sterically-limited self-assembly of Pt4 macrocycles into discrete non-covalent nanotubes: porous supramolecular tetramers and hexamers.

We report a template-free strategy based on steric repulsion for the isolation of discrete columnar aggregates of macrocycles. Specifically, introduction of sterically-demanding trityl-derived substituents at the periphery of Pt(4) Schiff base macrocycles limits the otherwise infinite one-dimensional columnar aggregation to discrete tetrameric and hexameric assemblies. Single crystal X-ray diffraction studies of these compounds reveal discrete nanotubes of finite length that pack inefficiently resulting in three-dimensional networks of interconnected void space. The discrete assemblies were studied by N(2) adsorption and show enhanced surface area when stacked. In the absence of bulky substituents the macrocycles are nonporous. This strategy for engineering discrete supramolecular macrocyclic aggregates may be generalized to other columnar assembling systems.