Substrate-Responsive Pillar[5]arene-Based Organic Room-Temperature Phosphorescence.

Room-temperature phosphorescence (RTP) is a photophysical phenomenon typically associated with a long-lived emission that can be detected by the unaided eye. Several natural proteins display RTP, as do certain artificial polymers. In both cases, the RTP is ascribed to effective intramolecular through-space electronic communication. However, small molecules with internal electronic communication that enable RTP are relatively rare. Herein, we describe an alkyl halide-responsive RTP system consisting of a meta-formylphenyl-bearing pillar[5]arene derivative that supports effective through-space charge transfer (TSCT) within the pillararene cavity. Treatment with bromoethane, a heavy atom-containing guest for the pillar[5]arene host, serves to enhance the emission. An isomeric para-formylphenyl-bearing pillar[5]arene system proved ineffective in producing an RTP effect. Quantum chemical calculations based on single-crystal X-ray diffraction analyses provided insights into the structural determinants governing TSCT between the 1,4-dimethoxybenzene donor units and the formylphenyl groups of the pillar[5]arene, as well as the associated energy gaps and intersystem crossing channels. We believe that the present system and the associated mechanistic analysis provide the foundation for design of new small molecule with tunable RTP features.

Reversible Macrocycle-to-Macrocycle Interconversion Driven by Solvent Selection.

Macrocycle-to-macrocycle interconversions are of interest because they can allow access to a variety of structures. However, reversible interconversion between different sized macrocycles remains challenging to control. Herein, we report a facile one-pot synthesis of a series of self-assembled macrocycles from readily prepared α,α'-linked oligopyrrolic dialdehydes and various alkyl diamines. The condensation of pyridine-bridged oligopyrrolic dialdehyde 3 and simple alkyl diamines proved independent of solvent, always yielding the [2 + 2] macrocyclic products. However, when 3 was condensed with 2,2'-oxybis(ethylamine) 14, either ([1 + 1] or [2 + 2]) products are obtained depending on the choice of solvent. Reaction of 3 and 14 in methanol, ethanol, or chloroform gave the [1 + 1] macrocycle as the sole product. In contrast, condensation of 3 and 14 in dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), or acetonitrile (MeCN) yielded the [2 + 2] macrocycle as the major product in the form of a precipitate. Reversible interconversion between the [1 + 1] and [2 + 2] macrocycles could be achieved by tuning the solvent, with the ratio driven by thermodynamic and solubility considerations.

Xanthene Separated 24 π-Electron Antiaromatic Rosarin Dimer.

Antiaromatic molecules have recently received attention because of their intrinsic properties, such as high reactivity and their narrow HOMO-LUMO gaps. Stacking of antiaromatic molecules has been predicted to induce three-dimensional aromaticity via frontier orbital interactions. Here, we report a covalently linked π-π stacked rosarin dimer that has been examined experimentally by steady-state absorption and transient absorption measurements and theoretically by quantum chemical calculations, including TD-DFT, ACID, and NICS. Relative to the corresponding monomer, the dimer exhibits diminished antiaromaticity upon lowering the temperature to 77K, a finding ascribed to intramolecular interactions between the macrocyclic rosarin subunits.

Room temperature phosphorescence from natural wood activated by external chloride anion treatment.

Producing afterglow room temperature phosphorescence (RTP) from natural sources is an attractive approach to sustainable RTP materials. However, converting natural resources to RTP materials often requires toxic reagents or complex processing. Here we report that natural wood may be converted into a viable RTP material by treating with magnesium chloride. Specifically, immersing natural wood into an aqueous MgCl2 solution at room temperature produces so-called C-wood containing chloride anions that act to promote spin orbit coupling (SOC) and increase the RTP lifetime. Produced in this manner, C-wood exhibits an intense RTP emission with a lifetime of ~ 297 ms (vs. the ca. 17.5 ms seen for natural wood). As a demonstration of potential utility, an afterglow wood sculpture is prepared in situ by simply spraying the original sculpture with a MgCl2 solution. C-wood was also mixed with polypropylene (PP) to generate printable afterglow fibers suitable for the fabrication of luminescent plastics via 3D printing. We anticipate that the present study will facilitate the development of sustainable RTP materials.

A dual-action niclosamide-based prodrug that targets cancer stem cells and inhibits TNBC metastasis.

Chemotherapy typically destroys the tumor mass but rarely eradicates the cancer stem cells (CSCs) that can drive metastatic recurrence. A key current challenge is finding ways to eradicate CSCs and suppress their characteristics. Here, we report a prodrug, Nic-A, created by combining a carbonic anhydrase IX (CAIX) inhibitor, acetazolamide, with a signal transducer and transcriptional activator 3 (STAT3) inhibitor, niclosamide. Nic-A was designed to target triple-negative breast cancer (TNBC) CSCs and was found to inhibit both proliferating TNBC cells and CSCs via STAT3 dysregulation and suppression of CSC-like properties. Its use leads to a decrease in aldehyde dehydrogenase 1 activity, CD44high/CD24low stem-like subpopulations, and tumor spheroid-forming ability. TNBC xenograft tumors treated with Nic-A exhibited decreased angiogenesis and tumor growth, as well as decreased Ki-67 expression and increased apoptosis. In addition, distant metastases were suppressed in TNBC allografts derived from a CSC-enriched population. This study thus highlights a potential strategy for addressing CSC-based cancer recurrence.

Fluorescent copolymer aggregate sensor for lithium chloride.

We report a copolymeric fluorescent sensor that is selective for lithium chloride. The two constituent polymers comprise pendent triphenylethylene (TPE) moieties for aggregate induced emission (AIE) along with either strapped-calix[4]pyrrole or secondary ammonium groups that drive aggregation via self-assembly upon polymer mixing. Addition of LiCl in acetonitrile disrupts the strapped-calix[4]pyrrole/secondary ammonium chloride salt host-guest crosslinks leading to disaggregation of the polymer chains and a decrease in TPE emission. The lack of AIE perturbation upon addition of NaCl, KCl, MgCl2 or CaCl2 provides for high selectivity for LiCl relative to potential interferants. This supramolecular dual polymer approach could serve as a complement to more traditional sensor systems.

Phenotyping of Methicillin-Resistant Staphylococcus aureus Using a Ratiometric Sensor Array.

Chemical tools capable of classifying multidrug-resistant bacteria (superbugs) can facilitate early-stage disease diagnosis and help guide precision therapy. Here, we report a sensor array that permits the facile phenotyping of methicillin-resistant Staphylococcus aureus (MRSA), a clinically common superbug. The array consists of a panel of eight separate ratiometric fluorescent probes that provide characteristic vibration-induced emission (VIE) profiles. These probes bear a pair of quaternary ammonium salts in different substitution positions around a known VIEgen core. The differences in the substituents result in varying interactions with the negatively charged cell walls of bacteria. This, in turn, dictates the molecular conformation of the probes and affects their blue-to-red fluorescence intensity ratios (ratiometric changes). Within the sensor array, the differences in the ratiometric changes for the probes result in "fingerprints" for MRSA of different genotypes. This allows them to be identified using principal component analysis (PCA) without the need for cell lysis and nucleic acid isolation. The results obtained with the present sensor array agree well with those obtained using polymerase chain reaction (PCR) analysis.

Photon-Controlled Pyroptosis Activation (PhotoPyro): An Emerging Trigger for Antitumor Immune Response.

Pyroptosis refers to the process of gasdermin-mediated lytic programmed cell death (PCD) characterized by the release of pro-inflammatory cytokines. Our knowledge of pyroptosis has expanded beyond the cellular level and now includes extracellular responses. In recent years, pyroptosis has attracted considerable attention due to its potential to induce host immunity. For instance, at the 2022 International Medicinal Chemistry of Natural Active Ligand Metal-Based Drugs (MCNALMD) conference, numerous researchers demonstrated an interest in photon-controlled pyroptosis activation ("PhotoPyro"), an emerging pyroptosis-engineered approach for activating systemic immunity via photoirradiation. Given this enthusiasm, we share in this Perspective our views on this emerging area and expound on how and why "PhotoPyro" could trigger antitumor immunity (i.e., turning so-called "cold" tumors "hot"). In doing so, we have tried to highlight cutting-edge breakthroughs in PhotoPyro while suggesting areas for future contributions. By providing insights into the current state of the art and serving as a resource for individuals interested in working in this area, it is hoped that this Perspective will set the stage for PhotoPyro to evolve into a broadly applicable cancer treatment strategy.

Chiral Calix[3]pyrrole Derivatives: Synthesis, Racemization Kinetics, and Ring Expansion to Calix[9]- and Calix[12]pyrrole Analogues.

Chiral pyrrolic macrocycles continue to attract interest. However, their molecular design remains challenging. Here, we report a calixpyrrole-based chiral macrocyclic system, calix[1]furan[1]pyrrole[1]thiophene (1), synthesized from an oligoketone. Macrocycle 1 adopts a partial cone conformation in the solid state, and undergoes racemization via ring inversion. Molecular dynamics simulations revealed that inversion of the thiophene is the rate determining step. Pyrrole N-methylation suppressed racemization and permitted chiral resolution. Enantioselective N-methylation also occurred in the presence of a chiral ammonium salt, although the stereoselectivity is modest. A unique feature of 1 is that it acts as a useful synthetic precursor to yield several calix[n]furan[n]pyrrole[n]thiophene products (n=2-4), including a calix[12]pyrrole analogue that to our knowledge constitutes the largest calix[n]pyrrole-like species to be structurally characterized.

Cu(ii)-BODIPY photosensitizer for CAIX overexpressed cancer stem cell therapy.

Chemoresistance originating from cancer stem cells (CSCs) is a major cause of cancer treatment failure and highlights the need to develop CSC-targeting therapies. Although enormous progress in both photodynamic therapy (PDT) and chemodynamic therapy (CDT) has been made in recent decades, the efficacy of these modalities against CSC remains limited. Here, we report a new generation photosensitizer, CA9-BPS-Cu(ii), a system that combines three subunits within a single molecule, namely a copper catalyst for CDT, a boron dipyrromethene photosensitizer for PDT, and acetazolamide for CSC targeting via carbonic anhydrase-9 (CA9) binding. A therapeutic effect in MDA-MB-231 cells was observed that is ascribed to elevated oxidative stress mediated by a combined CDT/PDT effect, as well as through copper-catalysed glutathione oxidation. The CSC targeting ability of CA9-BPS-Cu(ii) was evident from the enhanced affinity of CA9-BPS-Cu(ii) towards CD133-positive MDA-MB-231 cells where CA9 is overexpressed vs. CD133-negative cells. Moreover, the efficacy of CA9-BPS-Cu(ii) was successfully demonstrated in a xenograft mouse tumour model.

Cyclo[2]carbazole[2]pyrrole: a preorganized calix[4]pyrrole analogue.

A cyclo[2]carbazole[2]pyrrole (2) consisting of two carbazoles and two pyrroles has been synthesized by directly linking the carbazole 1- and 8-carbon atoms to the pyrrole α-carbon atoms. Macrocycle 2 is an extensively conjugated 16-membered macrocyclic ring that is fixed in a pseudo-1,3-alternate conformation. This provides a preorganized anion binding site consisting of two pyrrole subunits. 1H NMR spectroscopic analysis revealed that only the two diagonally opposed pyrrole NH protons, as opposed to the carbazole protons, take part in anion binding. Nevertheless, cyclo[2]carbazole[2]pyrrole 2 binds representative anions with higher affinity in CD2Cl2 than calix[4]pyrrole (1), a well-studied non-conjugated tetrapyrrole macrocycle that binds anions via four pyrrolic NH hydrogen bond interactions. On the basis of computational studies, the higher chloride anion affinity of receptor 2 relative to 1 is rationalized in terms of a larger binding energy and a lower host strain energy associated with anion complexation. In the presence of excess fluoride or bicarbonate anions, compound 2 loses two pyrrolic NH protons to produce a stable dianionic macrocycle [2-2H]2- displaying a quenched fluorescence.

Cyclic Carbaporphyrin Arrays.

Two cyclic carbaporphyrin arrays (trimer 6 and tetramer 7) were synthesized from a dibrominated carbaporphyrin precursor (5) via a one-pot Yamamoto-type coupling. Single-crystal X-ray diffraction analyses revealed that 6 and 7 contain three and four covalently linked carbaporphyrin (formally dicarbacorrole) units, respectively. Trimer 6 adopts a roughly planar conformation and tetramer 7 adopts an up-and-down zig-zag conformation. Both 6 and 7 contain a [n]cyclo-meta-phenylene ([n]CMP) core, namely, [6]- and [8]CMP for 6 and 7, respectively. Transient absorption (TA) anisotropy and pump-power-dependent excited-state decay studies provided evidence for excitation energy transfer (EET) within both trimer 6 and tetramer 7. The exciton energy hopping (EEH) times were estimated to be 18 and 35 ps for 6 and 7, respectively, as inferred from pump-power-dependent TA measurements. Since the center-to-center distances between adjacent carbaporphyrin units are similar in 6 and 7, the different EEH times are attributed to differences in the orientation of the transition dipoles in these two congeneric arrays. The orientation factor κ2, the key parameter defining the Förster resonance energy transfer efficiency, was calculated to be 2.15 and 1.03 for 6 and 7, respectively, a finding that supports the shorter excitation energy hopping time seen in the case of trimer 6. To our knowledge, this is the first time that covalently linked cyclic carbaporphyrin arrays were synthesized using a single carbaporphyrin as the starting point and that EET between carbaporphyrin subunits constrained within a well-defined polycyclic framework has been correlated with structural differences.

Supramolecular Recognition within a Nanosized "Buckytrap" That Exhibits Substantial Photoconductivity.

We report here a nanosized "buckytrap", 1, constructed from two bis-zinc(II) expanded-TTF (exTTF) porphyrin subunits. Two forms, 1a and 1b, differing in the axial ligands, H2O vs tetrahydrofuran (THF), were isolated and characterized. Discrete host-guest inclusion complexes are formed upon treatment with fullerenes as inferred from a single-crystal X-ray structural analyses of 1a with C70. The fullerene is found to be encapsulated within the inner pseudohexagonal cavity of 1a. In contrast, the corresponding free-base derivative (2) was found to form infinite ball-and-socket type supramolecular organic frameworks (3D-SOFs) with fullerenes, (2•C60)n or (2•C70)n. This difference is ascribed to the fact that in 1a and 1b the axial positions are blocked by a H2O or THF ligand. Emission spectroscopic studies supported a 1:1 host-guest binding stoichiometry, allowing association constants of (2.0 ± 0.5) × 104 M-1 and (4.3 ± 0.9) × 104 M-1 to be calculated for C60 and C70, respectively. Flash-photolysis time-resolved microwave conductivity (FP-TRMC) studies of solid films of the Zn-complex 1a revealed that the intrinsic charge carrier transport, i.e., pseudo-photoconductivity (ϕ∑µ), increases upon fullerene inclusion (e.g., ϕ∑µ = 1.53 × 10-4 cm2 V-1 s-1 for C60⊂(1a)2 and ϕ∑µ = 1.45 × 10-4 cm2 V-1 s-1 for C70⊂(1a)2 vs ϕ∑µ = 2.49 × 10-5 cm2 V-1 s-1 for 1a) at 298 K. These findings provide support for the notion that controlling the nature of self-assembly supramolecular constructs formed from exTTF-porphyrin dimers through metalation or choice of fullerene can be used to regulate key functional features, including photoconductivity.

Pillararene-Based Variable Stoichiometry Co-Crystallization: A Versatile Approach to Diversified Solid-State Superstructures.

Variable stoichiometry co-crystals are important in solid-state supramolecular chemistry as they allow studies of structure-property relationships while permitting the synthesis of new scaffolds using identical synthons. In this work, we extend the concept of variable stoichiometry co-crystals into the realm of pillararene chemistry and show that this permits the rational construction of a diverse set of supramolecular structures in the solid state. Specifically, we report a series of variable stoichiometry co-crystals based on pillar[n]arenes and tetracyanobenzene (TCNB) and show that the combination of in-cavity complexation by pillar[n]arenes (n = 5,6) and outside binding with TCNB allows several types of co-crystals with different self-assembled superstructures to be isolated. The variable stoichiometry co-crystals of this study display different solid-state physicochemical properties, including colors and luminescence features. Among these pillar[n]arene-based co-crystals, we discovered unique crystallographic architectures wherein two sets of individual host-guest complexes co-exist in the solid state. These mixed co-crystal systems allow for vapochromic-based detection of n-bromoalkanes. This work highlights a new strategy for the construction of self-assembled superstructures in the solid state and for tuning their intrinsic characteristics, including their luminescent and substrate-responsive features.

Quinoxaline-fused octaphyrin(2.0.0.0.2.0.0.0). A rudimentary chemosensor.

A quinoxaline-fused octaphyrin(2.0.0.0.2.0.0.0) was synthesized by the FeCl3-induced oxidative coupling of an α-free quinoxaline-fused tetrapyrrole. This macrocycle adopts a figure-of-eight conformation in the solid state and acts as a rudimentary chemosensor in solution. The Lewis basic anions fluoride and hydroxide induce a colour change via a deprotonation mechanism.

Di-2,7-pyrenidecaphyrin(1.1.0.0.0.1.1.0.0.0) and Its Bis-Organopalladium Complexes: Synthesis and Chiroptical Properties.

A non-aromatic expanded carbaporphyrinoid, incorporating two built-in 2,7-pyrenylene moieties was synthesized. The intrinsically labile topographic structure was demonstrated by proton-triggered conformational changes between the figure-of-eight and quasi-Möbius conformers. Upon treatment with Pd(OAc) 2 , the reaction produces two bis-Pd II complexes with distinct coordination modes. Metal coordination serves to fix the oligopyrrolic macrocyclic frame-works with the net result that both bis-Pd II complexes could be resolved by chiral high-performance liquid chromatography (HPLC). The isolated enantiomers showed considerable configurational stability and persistent chiroptical properties as evidenced by the intense response in the circular dichroism (CD) spectra from 300-850 nm and the record high absorption dissymmetry factors ( g abs of up to 0.038) seen in the near-infrared spectral region. In addition, the mutual interconversion of the enantiomers was found to be stereospecific and to favor the more stable isomers in the presence of the weakly acidic solvent deuterated chloroform.

Photoacoustic image-guided biomimetic nanoparticles targeting rheumatoid arthritis.

The high level of reactive oxygen species (ROS) in the rheumatoid arthritis (RA) microenvironment (RAM) and its persistent inflammatory nature can promote damage to joints, bones, and the synovium. Targeting strategies that integrate effective RAM regulation with imaging-based monitoring could lead to improvements in the diagnosis and treatment of RA. Here, we report the combined use of small interfering RNAs (siRNAsT/I) and Prussian blue nanoparticles (PBNPs) to silence the expression of proinflammatory cytokines TNF-α/IL-6 and scavenge the ROS associated with RAM. To enhance the in vitro and in vivo biological stability, biocompatibility, and targeting capability of the siRNAsT/I and PBNPs, macrophage membrane vesicles were used to prepare biomimetic nanoparticles, M@P-siRNAsT/I. The resulting constructs were found to suppress tumor necrosis factor-α/interleukin-6 expression and overcome the hypoxic nature of RAM, thus alleviating RA-induced joint damage in a mouse model. The M@P-siRNAsT/I of this study could be monitored via near-infrared photoacoustic (PA) imaging. Moreover, multispectral PA imaging without the need for labeling permitted the real-time evaluation of M@P-siRNAsT/I as a putative RA treatment. Clinical microcomputed tomography and histological analysis confirmed the effectiveness of the treatment. We thus suggest that macrophage-biomimetic M@P-siRNAsT/I and their analogs assisted by PA imaging could provide a new strategy for RA diagnosis, treatment, and monitoring.

Sheet-like 2D Manganese(IV) Complex with High Photothermal Conversion Efficiency.

We report a stable, water-soluble, mononuclear manganese(IV) complex [MnIV(H2L)]·5H2O (Mn-HDCL) that acts as an efficient photothermal material. This system is based on a hexahydrazide clathrochelate ligand (L/HDCL) and is obtained via an efficient one-pot templated synthesis that avoids the need for harsh reaction conditions. Scanning tunneling microscopy images reveal that Mn-HDCL exists as a 2D sheet-like structure. In Mn-HDCL, the manganese(IV) ion is trapped within the cavity of the cage-like ligand. This effectively shields the Mn(IV) ion from the external environment while providing adequate water solubility. As a result of orbital transitions involving the coordinated manganese(IV) ion, as well as metal-to-ligand charge transfer effects, Mn-HDCL possesses a large extinction coefficient and displays a photothermal performance comparable to single-wall carbon nanotubes in the solid state. A high photothermal conversion efficiency (ca. 71%) was achieved in aqueous solution when subjected to near-infrared 730 nm laser photo-irradiation. Mn-HDCL is paramagnetic and provides a modest increase in the T1-weighted contrast of magnetic resonance images both in vitro and in vivo. Mn-HDCL was found to target tumors passively and allow tumor margins to be distinguished in vivo in a mouse model. In addition, it also exhibited an efficient laser-triggered photothermal therapy effect in vitro and in vivo. We thus propose that Mn-HDCL could have a role to play as a tumor-targeting photothermal sensitizer.

Calix[4]pyrrole-Based Azo-Bridged Porous Organic Polymer for Bromine Capture.

The toxicity, corrosiveness, and volatility of elemental bromine presents challenges for its safe storage and transportation. Purification from other halogens is also difficult. Here, we report an easy-to-prepare calix[4]pyrrole-based azo-bridged porous organic polymer (C4P-POP) that supports efficient bromine capture. C4P-POP was found to capture bromine as a vapor and from a cyclohexane source phase with maximum uptake capacities of 3.6 and 3.4 g·g-1, respectively. Flow-through adsorption experiments revealed that C4P-POP removes 80% of the bromine from a 4.0 mM cyclohexane solution at a flow rate of 45 mL·h-1. C4P-POP also allowed the selective capture of bromine from a 1:1 mixture of bromine and iodine in cyclohexane.

Calix[4]pyrrole-Based Molecular Capsule: Dihydrogen Phosphate-Promoted 1:2 Fluoride Anion Complexation.

A molecular capsule (1) consisting of two calix[4]pyrroles connected via ethylene diamide linkers has been prepared as an anion receptor. 1H NMR spectroscopic studies carried out in CD2Cl2 revealed that receptor 1 recognizes a variety of anions with different binding modes and stoichiometries. For instance, receptor 1 binds fluoride and acetate with 1:2 receptor/anion stoichiometry and other test anions with 1:1 stoichiometry in solution when their respective tetrabutylammonium (TBA+) salts were used. In contrast, with tetraethylammnium (TEA+) salts, receptor 1 forms 1:2 complexes with chloride and bromide in addition to fluoride, overcoming expected Columbic repulsions between the anions co-bound in close proximity. Receptor 1 is also able to bind oxoanions, such as oxalate (C2O42-), dihydrogen phosphate (H2PO4-), sulfate (SO42-), and hydrogen pyrophosphate (HP2O73-), in the form of 1:1 complexes as the result of presumed cooperation between the two calix[4]pyrrole subunits. The selectivity of receptor 1 for fluoride versus dihydrogen phosphate varies depending on their relative concentrations. For instance, in the presence of less than 1.0 equiv of an equimolar mixture of fluoride and dihydrogen phosphate, receptor 1 shows high selectivity for dihydrogen phosphate. In contrast, in the presence of ≥2.0 anion equiv, receptor 1 binds fluoride preferentially, forming a 1:2 complex. Moreover, when treated with F-, the preformed 1:1 H2PO4- complex of receptor 1 is converted to the corresponding 1:2 receptor/fluoride complex with the release of the prebound dihydrogen phosphate anion. As inferred from gas-phase computations, this seemingly counterintuitive behavior is rationalized in terms of the precomplexed dihydrogen phosphate serving to reduce the reorganization energy required to bind two fluoride anions. The presence of a water molecule in addition to the bound fluoride anions may also favor the formation of the 1:2 F- complex. The present study provides a new approach for fine-tuning the binding selectivity of polytopic anion receptors.