Coordination-Assisted Reversible Photoswitching of Spiropyran-Based Platinum Macrocycles.

Control over the stimuli-responsive behavior of smart molecular systems can influence their capability to execute complex functionalities. Herein, we report the development of a suite of spiropyran-based multi-stimuli-responsive self-assembled platinum(II) macrocycles (5-7), rendering coordination-assisted enhanced photochromism relative to the corresponding ligands. 5 showed shrinking and swelling during photoreversal, while 6 and 7 are fast and fatigue-free supramolecular photoswitches. 6 turns out to be a better fatigue-resistant photoswitch and can retain an intact photoswitching ability of up to 20 reversible cycles. The switching behavior of the macrocycles can also be precisely controlled by tuning the pH of the medium. Our present strategy for the construction of rapid stimuli-responsive supramolecular architectures via coordination-driven self-assembly represents an efficient route for the development of smart molecular switches.

Topological Characterization of Coordination-Driven Self-assembly Complexes: Applications of Ion Mobility-Mass Spectrometry.

Coordination-driven self-assembly (CDSA) is increasingly used to synthesize coordination complexes containing metal-centered electron acceptors and typically nitrogen-containing electron donors. Characterization of the structures obtained from CDSA via crystallographic or spectroscopic means is limited due to difficulties in forming single crystals for X-ray studies and overlapping precursor and product signals in NMR. Here, we employ ion mobility-mass spectrometry (IM-MS), which provides a direct measure of size and shape of the CDSA complexes, to study the intact reaction products of a rhomboid-shaped complex. This approach negates the need for product isolation and crystallization and allows for tracking of the product distribution as a function of time. A potential challenge of IM-MS is that the size/shape of the observed CDSA complexes can vary with internal energy; however, we show that proper tuning of the instrument reduces the effects of collisional activation thereby allowing for retention of ion conformations that reflect solution-phase ion structures. Graphical Abstract.

Endo- and Exo-Functionalized Tetraphenylethylene M12L24 Nanospheres: Fluorescence Emission inside a Confined Space.

The intrinsic relationship between the properties of green fluorescent protein (GFP) and its encapsulated small molecular light machine has spurred many biomimicking studies, aiming at revealing the detailed mechanism and further promoting its wide applications in different disciplines. However, how to build a similar confined microenvironment to mimic the cavity of a ß-barrel and the fluorescence turn-on process is a fundamental challenge for both chemists and biologists. Herein, two distinct exo- and endo-functionalized tetraphenylethylene (TPE)-based M12L24 nanospheres with precise distribution of anchored TPE moieties and unique photophysical properties were constructed by means of a coordination-driven self-assembly strategy. Under dilute conditions, the nanospheres fluoresce more strongly than the corresponding TPE subcomponents. Meanwhile, the endo-functionalized sphere is able to induce a higher local concentration and more restrained motion of the enclosed 24 TPE units compared with exo-functionalized counterpart and thus induces much stronger emission due to the restriction of the rotation of the pendant TPE units. The biomimetic methodology developed here represents a promising way to understand and construct artificial GFP materials on the platforms of supramolecular coordination complexes.

Host-guest complexation-mediated codelivery of anticancer drug and photosensitizer for cancer photochemotherapy.

Although platinum-based anticancer drugs prevail in cancer treatment, their clinical applications are limited by the severe side effects as well as their ineffectiveness against drug resistant cancers. A precise combination of photodynamic therapy (PDT) and chemotherapy can synergistically improve the therapeutic outcome and thereby may overcome drug resistance through a multipronged assault. Herein, we employ the well-defined cavity of a discrete organoplatinum(II) metallacage (M) to encapsulate octaethylporphine (OEP), a photosensitizer, forming a dual-functionalized system M⊃OEP that is wrapped into the hydrophobic core of the nanoparticles (MNPs) self-assembled from an amphiphilic diblock copolymer. Using a copper-free click reaction, a targeting ligand is conjugated on the surface of the MNPs, aiming to specifically deliver a chemotherapeutic drug and a photosensitizer to cancer cells. Benefiting from the enhanced permeability and retention effect and active targeting capability, high tumor accumulation of MNPs is achieved, leading to an improved therapeutic outcome and reduced side effects. In vivo studies demonstrate that the combination of chemotherapy and PDT exhibits a superior antitumor performance against a drug-resistant tumor model attributed to their synergistic anticancer efficacy.

Designed Conformation and Fluorescence Properties of Self-Assembled Phenazine-Cored Platinum(II) Metallacycles.

A series of platinum(II) metallacycles were prepared via the coordination-driven self-assembly of a phenazine-cored dipyridyl donor with a 90° Pt(II) acceptor and various dicarboxylate donors in a 1:1:2 ratio. While the metallacycles display similar absorption profiles, they exhibit a trend of blue-shifted fluorescence emission with the decrease in the bite angles between the carboxylate building blocks. Comprehensive spectroscopic and dynamic studies as well as a computational approach were conducted, revealing that the difference in the degree of constraint imposed on the excited-state planarization of the phenazine core within these metallacycles results in their distinct photophysical behaviors. As such, a small initial difference in the dicarboxylate building blocks is amplified into distinct photophysical properties of the metallacycles, which is reminiscent of the efficient functional tuning observed in natural systems. In addition to the pre-assembly approach, the photophysical properties of a metallacycle can also be modulated using a post-assembly modification to the dicarboxylate building block, suggesting another strategy for functional tuning. This research illustrated the potential of coordination-driven self-assembly for the preparation of materials with precisely tailored functionalities at the molecular level.

Metallacycle-Cored Supramolecular Polymers: Fluorescence Tuning by Variation of Substituents.

Herein, we present a method for the preparation of supramolecular polymers with tunable fluorescence via the combination of metal-ligand coordination and phenanthrene-21-crown-7 (P21C7)-based host-guest interactions. A suite of rhomboidal metallacycles with different substituents were prepared via the coordination-driven self-assembly of a P21C7-based 60° diplatinum(II) acceptor and 120° dipyridyl donors. Upon variation of the substituents on the dipyridyl donors, the metallacycles exhibit emission wavelengths spanning the visible region (λmax = 427-593 nm). Metallacycle-cored supramolecular polymers were obtained via host-guest interactions between bis-ammonium salts and P21C7. The supramolecular polymers exhibit emission wavelengths similar to those of the individual metallacycles and higher fluorescent efficiency in solution and thin films. Utilizing a yellow-emitting supramolecular polymer thin film with high quantum yield (0.22), a white-light-emitting LED was fabricated by painting the thin film onto an ultraviolet LED. This study presents an efficient approach for tuning the properties of fluorescent supramolecular polymers and the potential of the metallacycle-cored supramolecular polymers as a platform for the fabrication of light-emitting materials with good processability and tunability.

A discrete organoplatinum(II) metallacage as a multimodality theranostic platform for cancer photochemotherapy.

Photodynamic therapy is an effective alternative to traditional treatments due to its minimally invasive nature, negligible systemic toxicity, fewer side effects, and avoidance of drug resistance. However, it is still challenging to design photosensitizers with high singlet oxygen (1O2) quantum yields (QY) due to severe aggregation of the hydrophobic photosensitizers. Herein, we developed a discrete organoplatinum(II) metallacage using therapeutic cis-(PEt3)2Pt(OTf)2 as the building block to improve the 1O2 QY, thus achieving synergistic anticancer efficacy. The metallacage-loaded nanoparticles (MNPs) with tri-modality imaging capability allow precise diagnosis of tumor and real-time monitoring the delivery, biodistribution, and excretion of the MNPs. MNPs exhibited excellent anti-metastatic effect and superior anti-tumor performance against U87MG, drug resistant A2780CIS, and orthotopic tumor models, ablating the tumors without recurrence after a single treatment. Gene chip analyses confirmed the contribution of different therapeutic modalities to the tumor abrogation. This supramolecular platform holds potential in precise cancer theranostics.

Hierarchical Self-Assembly of a Water-Soluble Organoplatinum(II) Metallacycle into Well-Defined Nanostructures.

A water-soluble metallosupramolecular hexagon containing pendant methyl viologen (MV) and trimethylammonium units at the vertices has been synthesized via an organoplatinum(II) ← pyridyl coordination-driven self-assembly reaction. The MV units of the metallacycle were further utilized in the formation of a heteroternary complex with cucurbit[8]uril and a galactose-functionalized naphthalene derivative, yielding a metallacycle-cored carbohydrate cluster that was subsequently ordered into nanospheres and tapes, depending upon the concentration.

Self-Assembly of Metallacages into Multidimensional Suprastructures with Tunable Emissions.

Cubic metallacages were arranged into multidimensional (one-, two-, and three-dimensional) suprastructures via multistep assembly. Four new shape-controllable, hybrid metallacages with modified substituents and tunable electronic properties were prepared using dicarboxylate ligands with various substituents (sodium sulfonate, nitro, methoxyl, and amine), tetra-(4-pyridylphenyl) ethylene, and cis-(PEt3)2Pt(OTf)2. The as-prepared metallacages were used as building blocks for further assembly. Diverse suprastructures with tunable emissions (λmax from 451 to 519 nm) and various substituents (-SO3Na, -NO2, -OCH3, and -NH2) were prepared depending on the substituents and solvents used.

Hierarchical Assemblies of Supramolecular Coordination Complexes.

Hierarchical self-assembly (HAS) is a multilevel organization process that first assembles elementary molecular units into ordered secondary structures via noncovalent interactions, which further act as the building blocks to form more complex multifunctional superstructures at the next level(s). The HAS strategy has been used as a versatile method for the preparation of soft-matter nanoarchitectures of defined size and morphologies, tunable luminescence, and biological importance. However, such preparation can be greatly simplified if well-defined dynamic structures are employed as the cores that upon linking form the desired nanoarchitectures. Discrete supramolecular coordination complexes (SCCs) with well-defined shapes, sizes, and internal cavities have been widely employed to construct hierarchical systems with functional diversity. This Account summarizes the prevailing strategies used in recent years in the preparation of SCC-based HASs and illustrates how the combination of dynamic metal-ligand coordination with other interactions was used to obtain hierarchical systems with interesting properties. HASs with dual orthogonal interactions involving coordination-driven self-assembly and hydrogen bonding/host-guest interaction generally result in robust and flexible supramolecular gels. Likewise, hybridization of SCCs with a suitable dynamic covalent network via a hierarchical strategy is useful to prepare materials with self-healing properties. The intrinsic positive charges of the SCCs also make them suitable precursors for the construction of HASs via electrostatic interactions with negatively charged biological/abiological molecules. Furthermore, the interplay between the hydrophilic and lipophilic characters of HASs by varying the number and spacial orientation of alkyl/oxyethylene chains of the SCC is a simple yet controllable approach to prepare ordered and tunable nanostructures. Certain SCC-cored hierarchical systems exhibit reversible polymorphism, typically between micellar, nanofiber, and vesicular phases, in response to various external perturbations: heat, photoirradiation, pH-variance, redox-active agents, etc. At the same time, multiple noncovalent interaction mediated HASs are growing in numbers and are promising candidates for obtaining functionally diverse materials. The photophysical properties of SCC-based HASs have been used in many analytical applications. For example, embedding tetraphenylethene (TPE)-based pyridyl ligands within metallo-supramolecular structures partially restricts the molecular rotations of its phenyl rings, endowing the resultant SCCs with weak emissions. Further aggregation of such HASs in suitable solvents results in a marked enhancement in emission intensity along with quantum yields. They act as sensitive sensors for different analytes, including pathogens, drugs, etc. HASs are also useful to develop multidrug systems with cooperative chemotherapeutic effects. Hence, the use of HASs with theranostic SCCs combining cell-imaging agents and chemotherapeutic scaffolds is a promising drug delivery strategy for cancer theranostics. At the same time, their responsiveness to stimuli, oftentimes due to the dynamic nature of the metal-ligand interactions, play an important role in drug release via a disassembly mechanism.

Orthogonal self-assembly of an organoplatinum(II) metallacycle and cucurbit[8]uril that delivers curcumin to cancer cells.

Curcumin (Cur) is a naturally occurring anticancer drug isolated from the Curcuma longa plant. It is known to exhibit anticancer properties via inhibiting the STAT3 phosphorylation process. However, its poor water solubility and low bioavailability impede its clinical application. Herein, we used organoplatinum(II) ← pyridyl coordination-driven self-assembly and a cucurbit[8]uril (CB[8])-mediated heteroternary host-guest complex formation in concert to produce an effective delivery system that transports Cur into the cancer cells. Specifically, a hexagon 1, containing hydrophilic methyl viologen (MV) units and 3,4,5-Tris[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]benzoyl groups alternatively at the vertices, has been synthesized and characterized by several spectroscopic techniques. The MV units of 1 underwent noncovalent complexation with CB[8] to yield a host-guest complex 4. Cur can be encapsulated in 4, via a 1:1:1 heteroternary complex formation, resulting in a water-soluble host-guest complex 5. The host-guest complex 5 exhibited ca 100-fold improved IC50 values relative to free Cur against human melanoma (C32), melanoma of rodents (B16F10), and hormone-responsive (MCF-7) and triple-negative (MDA-MB231) breast cancer cells. Moreover, strong synergisms of Cur with 1 and 4 with combinatorial indexes of <1 across all of the cell lines were observed. An induced apoptosis with fragmented DNA pattern and inhibited expression of phosphor-STAT3 supported the improved therapeutic potential of Cur in heteroternary complex 5.

Temperature-Responsive Fluorescent Organoplatinum(II) Metallacycles.

The synthesis, characterization, and temperature-responsive properties of two fluorescent organoplatinum(II) metallacycles are reported. Metallacycles M1 and M2 were prepared via the coordination-driven self-assembly of a 120° triarylamine ligand L1 and a 120° diplatinum(II) acceptor Pt-1 or 180° diplatinum(II) acceptor Pt-2, respectively. M1 and M2 are hexagonal metallacycles, comprising of three or six freely rotating anthracene pendants on their periphery, respectively. In response to the temperature variation between -20 and 60 °C, the ligand displays irregular emission changes, whereas both metallacycles show reversible absorption and emission spectral changes in THF. The changes in their green emission intensity also exhibit a linear correlation with the temperature variation, with an average sensitivity of -0.67% and -0.77% per °C for M1 and M2, respectively. Furthermore, in coordinating solvents, such as DMF and CH3CN, M1 and M2 show different behaviors: in the lower temperature range, i.e., below 30 °C, their spectral changes are similar to those observed in THF; however, at a higher temperature the metallacycles were presumably destroyed by the solvents and displayed ratiometric fluorescent responses, including a cyan emission of the ligand L1.

Alanine-Based Chiral Metallogels via Supramolecular Coordination Complex Platforms: Metallogelation Induced Chirality Transfer.

Chiral self-assemblies constantly attract great interest because of their potential to provide insight into biological systems and materials science. Herein we report on the efficient preparation of alanine-based chiral metallacycles, rhomboids 1D and 1L and hexagons 2D and 2L using a Pt(II) ← pyridyl directional bonding approach. The metallacycles are subsequently assembled into nanospheres at low concentration, that generate chiral metallogels at high concentration driven by hydrogen bonding, hydrophobic and π-π interactions. The gels consist of microscopic chiral nanofibers with well-defined helicity, as confirmed by circular dichroism (CD) and scanning (SEM) and transmission electron (TEM) microscopies. Given these results, we expect this technique will not only unlock interesting new approaches to understand homochirality in nature but also allow the design of versatile soft materials containing chiral supramolecular cores.

Memory of Chirality Concept in Asymmetric Intermolecular Michael Addition of α-Amino Ester Enolates to Enones and Nitroalkenes.

A highly stereoselective asymmetric intermolecular conjugate addition of α-amino ester derivatives to cyclic enones via the memory of chirality (MOC) concept in high yields with excellent diastereo- and enantioselectivity (dr >99:1, up to 99% ee) is reported. The applicability and the generality of the strategy was demonstrated by its further exploration to acyclic α,ß-unsaturated ketone and aromatic nitroalkenes, resulting in the formation of δ-keto-α-amino ester derivative and γ-nitro-α-amino ester derivatives, respectively, with excellent ee and dr.

Cationic Ti Complexes with Three [N,O]-Type Tetrazolyl Ligands: Ti↔Fe Transmetalation within Fe Metallascorpionate Complexes.

Herein, we report the synthesis of two novel ionic Ti complexes possessing three [N,O]-type bidentate ligands from the reaction of Fe metallascorpionate ligands possessing extended alcohol groups and TiCl4. The reaction of substituted hydroxyphenyl tetrazole and Fe(ClO4)3 in a molar ratio of 3:1 afforded iron scorpionate metalloligands possessing extended arms, which were characterized by IR spectroscopy and ESI-TOF-MS spectrometry. Their molecular structures were also confirmed as neutral Fe-centered scorpionate complexes by X-ray crystallography, in which the extended alcohol groups adopted a tripodal geometry. Moreover, two different crystals of iron scorpionate metalloligand grown from CH2Cl2 and CH3OH were studied, revealing that, in the latter crystal, the tripod arms are folded and aligned toward the C3-rotational axis of the molecule, whereas the tripod arms are unfolded and spread outward from the rotational axis in the former crystal. These metalloligands are solvatochromatic; a bathochromic shift was observed as the solvent polarity increased. From the reaction, the aforesaid Fe complexes were further reacted with TiCl4 in a molar ratio of 1:1 to produce ionic [TiL3]+[FeCl4]- (L = substituted hydroxyphenyl tetrazole) complexes from the transmetalation of Ti and Fe. The complexes were characterized by various analytical methods including UV/vis and IR spectroscopies, electrospray time-of-flight mass spectrometry (ESI-TOF-MS), and X-ray crystallography.

Antitumor Activity of a Unique Polymer That Incorporates a Fluorescent Self-Assembled Metallacycle.

Despite the well-known anticancer activity of mono- and multinuclear platinum complexes, studies of the antitumor performances of platinum-based supramolecular coordination complexes are rare. Herein, we report on the synthesis of a four-armed amphiphilic copolymer, Pt-PAZMB-b-POEGMA, containing a metallacycle M, in which the tetraphenylethene derivative acts as an aggregation-induced emissive fluorescent probe for live cell imaging and the 3,6-bis[trans-Pt(PEt3)2]phenanthrene (PhenPt) is an anticancer drug. This copolymer was further self-assembled into nanoparticles of different sizes and vesicles depending upon the experimental conditions. The impacts of the morphology and size of the assemblies on their endocytic pathways, uptake rates, internalization amounts, and cytotoxicities were investigated. The self-assemblies were further employed to encapsulate doxorubicin (DOX) to achieve a synergistic anticancer effect. Controlled drug release was also realized via amphiphilicity changes and was driven by a glutathione-induced cascade elimination reaction. The DOX-loaded nanoparticles of around 50 nm in size exhibited an excellent antitumor performance as well as a low systemic toxicity, due to an enhanced permeability and retention effect.

Platinum(II)-Based Convex Trigonal-Prismatic Cages via Coordination-Driven Self-Assembly and C60 Encapsulation.

The development of three-dimensional (3D) supramolecular coordination complexes is of great interest from both fundamental and application points of view because these materials are useful in molecular catalysis, separation and purification, sensing, etc. Herein, we describe the synthesis of two Klärner's molecular-clip-based tetrapyridyl donors, which possess a C-shaped structure as shown by X-ray analysis, and subsequently use them to prepare four convex trigonal-prismatic cages via coordination-driven self-assembly with two 180° diplatinum(II) acceptors. The cages are fully characterized by multinuclear NMR (31P and 1H) analysis, diffusion-ordered spectroscopy, electrospray ionization time-of-flight mass spectrometry, and UV/vis absorption spectroscopy. Moreover, the incorporation of molecular-clip-based ligands provides these cages with free cavities to encapsulate fullerene C60 via aromatic interactions, which may be useful for fullerene separation and purification. The studies described herein enlarge the scope of the platinum(II)-based directional bonding approach in the preparation of curved 3D metallacages and their host-guest chemistry.

Metallacycle-cored supramolecular assemblies with tunable fluorescence including white-light emission.

Control over the fluorescence of supramolecular assemblies is crucial for the development of chemosensors and light-emitting materials. Consequently, the postsynthetic modification of supramolecular structures via host-guest interactions has emerged as an efficient strategy in recent years that allows the facile tuning of the photophysical properties without requiring a tedious chemical synthesis. Herein, we used a phenanthrene-21-crown-7 (P21C7)-based 60° diplatinum(II) acceptor 8 in the construction of three exohedral P21C7 functionalized rhomboidal metallacycles 1-3 which display orange, cyan, and green emission colors, respectively. Although these colors originate from the dipyridyl precursors 10-12, containing triphenylamine-, tetraphenylethene-, and pyrene-based fluorophores, respectively, the metal-ligand coordination strongly influences their emission properties. The metallacycles were further linked into emissive supramolecular oligomers by the addition of a fluorescent bis-ammonium linker 4 that forms complementary host-guest interactions with the pendant P21C7 units. Notably, the final ensemble derived from a 1:1 mixture of 1 and 4 displays a concentration-dependent emission. At low concentration, i.e., <25 µM, it emits a blue color, whereas an orange emission was observed when the concentration exceeds >5 mM. Moreover, white-light emission was observed from the same sample at a concentration of 29 µM, representing a pathway to construct supramolecular assemblies with tunable fluorescence properties.

Multicomponent Platinum(II) Cages with Tunable Emission and Amino Acid Sensing.

The syntheses, characterization, and emission properties of three tetragonal prismatic cages, 4a-4c, constructed from eight 90° Pt(II) acceptors, four linear dipyridyl ligands, and two tetraphenylethene (TPE)-based sodium benzoate ligands, are described. These cages are emissive in dilute solutions due to the metal-coordination-induced partial restriction of intramolecular rotation of their TPE units, while the dipyridyl moieties, which act as the pillars as well as the solvents, strongly influence these emissions. Specifically, cages 4a and 4b, bearing a 4,4'-dipyridine and a 1,2-di(4-pyridyl)ethylene as their pillar parts, respectively, display good emissions in common organic solvents at 485-493 nm that are derived from the TPE units. In contrast, cage 4c, with its BODIPY-based dipyridyl unit, exhibits two emission bands at 462-473 and 540-545 nm, originating from the TPE and BODIPY fluorophores, respectively. Moreover, cage 4b has been employed as a turn-on fluorescent sensor for thiol-containing amino acids via a self-destructive reaction, while the cage can also be regenerated via the addition of Pt(II) acceptors. The studies described herein not only enrich the ongoing research on fluorescent materials but also pave the way to prepare stimuli-responsive supramolecular coordination complexes.

Fe-Pt Twisted Heterometallic Bicyclic Supramolecules via Multicomponent Self-Assembly.

Herein, we describe a novel multicomponent self-assembly approach that has the prospect of furnishing unprecedented heterometallic bicyclic architectures with a high level of constitutional control. The methodology relies on the coordination directionality, and the stoichiometry of the individual precursor units, as well as on the difference of the coordination preference of the associated metal ions. As a proof-of-concept example, two aesthetically pleasing Fe-Pt heterometallic bicyclic metallacycles 6a and 6b, consisting of nine communicative components from four unique species, were prepared in ca. 70% isolated yields and fully characterized by multinuclear NMR, 2D NMR, electrospray ionization time-of-flight mass, and UV-vis spectroscopies. Furthermore, density functional theory based computations suggest that each of these supramolecular constructs encompasses two twisted [organo-Pt(II)←pyridine] coordination based irregular hexagons that are joined via a robust [terpyridine→Fe(II)←terpyridine] hinge.