Differentiable Formation of Chiroptical Lanthanide Heterometallic Lnn Ln'4-n (L6 ) (n=0-4) Tetrahedra with C2 -Symmetrical Bis(tridentate) Ligands.

Construction of lanthanide heterometallic complex is important for engineering multifunction molecular containers. However, it remains a challenge because of the similar ionic radii of lanthanides. Herein we attempt to prepare chiral lanthanide heterometallic tetrahedra. Upon crystallization with a mixture of [Eu2 L3 ] and [Ln2 L3 ] (Ln=Gd, Tb and Dy) helicates, a mixture of heterometallic Eun Ln'4-n (L6 ) (n=0-4) tetrahedra was prepared. Selective formation of heterometallic tetrahedron was observed as MS deconvolution results deviated from statistical results. The formation of heterometallic tetrahedron was found to be sensitive to ionic radii as well as the ratio of the two helicates used in the crystallization.

Reactivation of Epstein-Barr virus by a dual-responsive fluorescent EBNA1-targeting agent with Zn2+-chelating function.

Epstein-Barr nuclear antigen 1 (EBNA1) plays a vital role in the maintenance of the viral genome and is the only viral protein expressed in nearly all forms of Epstein-Barr virus (EBV) latency and EBV-associated diseases, including numerous cancer types. To our knowledge, no specific agent against EBV genes or proteins has been established to target EBV lytic reactivation. Here we report an EBNA1- and Zn2+-responsive probe (ZRL5P4) which alone could reactivate the EBV lytic cycle through specific disruption of EBNA1. We have utilized the Zn2+ chelator to further interfere with the higher order of EBNA1 self-association. The bioprobe ZRL5P4 can respond independently to its interactions with Zn2+ and EBNA1 with different fluorescence changes. It can selectively enter the nuclei of EBV-positive cells and disrupt the oligomerization and oriP-enhanced transactivation of EBNA1. ZRL5P4 can also specifically enhance Dicer1 and PML expression, molecular events which had been reported to occur after the depletion of EBNA1 expression. Importantly, we found that treatment with ZRL5P4 alone could reactivate EBV lytic induction by expressing the early and late EBV lytic genes/proteins. Lytic induction is likely mediated by disruption of EBNA1 oligomerization and the subsequent change of Dicer1 expression. Our probe ZRL5P4 is an EBV protein-specific agent that potently reactivates EBV from latency, leading to the shrinkage of EBV-positive tumors, and our study also suggests the association of EBNA1 oligomerization with the maintenance of EBV latency.

Design of Functional Chiral Cyclen-Based Radiometal Chelators for Theranostics.

A series of water-soluble chiral cyclen-based chelators with chemical handles for selective targeting have been synthesized (cyclen = 1,4,7,10-Tetraazacyclododecane). Optical studies, relaxivity measurements, and competitive titrations were performed to show the versatility of these chiral chelators. The complexations of L3, L4, and L5 with Lu3+, Y3+, Sc3+, and Cu2+ were successfully demonstrated in around 90% to 100% yields. Efficient and rapid radiolabeling of L5 with 177Lu was achieved under mild conditions with 96% yield. The chelators exhibit near quantitative labeling efficiencies with a wide range of radiometal ions, which are promising for the development of targeting specific radiopharmaceutical and molecular magnetic resonance imaging contrast agents.

Unusual Magnetic Field Responsive Circularly Polarized Luminescence Probes with Highly Emissive Chiral Europium(III) Complexes.

Chirality is ubiquitous within biological systems where many of the roles and functions are still undetermined. Given this, there is a clear need to design and develop sensitive chiral optical probes that can function within a biological setting. Here we report the design and synthesis of magnetically responsive Circularly Polarized Luminescence (CPL) complexes displaying exceptional photophysical properties (quantum yield up to 31 % and |glum | up to 0.240) by introducing chiral substituents onto the macrocyclic scaffolds. Magnetic CPL responses are observed in these chiral EuIII complexes, promoting an exciting development to the field of magneto-optics. The |glum | of the 5 D0 → 7 F1 transition increases by 20 % from 0.222 (0 T) to 0.266 (1.4 T) displaying a linear relationship between the Δglum and the magnetic field strength. These EuIII complexes with magnetic CPL responses, provides potential development to be used in CPL imaging applications due to improved sensitivity and resolution.

Synthesis of Water-Soluble Chiral DOTA Lanthanide Complexes with Predominantly Twisted Square Antiprism Isomers and Circularly Polarized Luminescence.

One-step cyclization of a tetraazamacrocycle 5 with 70% yield in a 25-g scale was performed. Its chiral DOTA derivatives, L4, has ∼93% of TSAP coordination isomer in its Eu(III) and Yb(III) complexes in aqueous solution. [GdL4]5- exhibits a high relaxivity, making it a promising and efficient MRI contrast agent. High luminescence dissymmetry factor (glum) values of 0.285 (ΔJ = 1) for [TbL3]- and 0.241 (ΔJ = 1) for [TbL4]5- in buffer solutions were recorded.

Triboluminescence of Centrosymmetric Lanthanide ß-Diketonate Complexes with Aggregation-Induced Emission.

Triboluminescence (TL) is a form of light emission induced upon mechanical forces on the material. However, our understanding of this phenomenon is still unclear and more examples are therefore needed in order to elucidate its mechanism. In this work, two types of TL complexes, [Eu(pp-dbm-Cl2)3phen] and [Eu(mm-dbm-Cl2)3phen], which also displays aggregation-induced emission (AIE) were synthesized and investigated for its photo-physical and crystal structural properties. These complexes were crystallized in a centro-symmetric space group P21/n, and remarkably, displayed TL upon grinding that may be due to the presence of extensive π···π, C-H···π and C-H···Cl-C interactions in the close molecular packing of its structure. This rare example deviates from the widely accepted mechanism of TL, hence widening the scope of our understanding in the area.

Synthesis of a Conformationally Stable Atropisomeric Pair of Biphenyl Scaffold Containing Additional Stereogenic Centers.

The synthesis of a new CF3-containing stereogenic atropisomeric pair of ortho-disubstituted biphenyl scaffold is presented. The atropisomers are surprisingly conformationally stable for isolation. X-ray structures show that their stability comes from an intramolecular hydrogen bond formation from their two hydroxyl groups and renders the spatial arrangement of their peripheral CF3 and CH3 groups very different. The synthesized stereogenic scaffold proved to be effective in catalyzing the asymmetric N-nitroso aldol reaction of enamine and nitrosobenzene. Compared to similar scaffolds without CF3 groups, one of our atropisomer exhibits an increase in enantioselectivity in this reaction.

Catalytic asymmetric oxo-Diels-Alder reactions with chiral atropisomeric biphenyl diols.

New chiral atropisomeric biphenyl diols 3, 4 and 6 containing additional peripheral chiral centers with different steric bulkiness and/or electronic properties were synthesized. The X-ray crystal structure of 3 shows the formation of a supramolecular structure whereas that of 6, containing additional CF3 substituents, shows the formation of a monomeric structure. Diols 1-6 were found to be active organocatalysts in oxo-Diels-Alder reactions in which 2 recorded a 72% ee with trimethylacetaldehyde as a substrate.

Assembly of Lanthanide(III) Cubanes and Dimers with Single-Molecule Magnetism and Photoluminescence.

Discrete lanthanide(III) tetranuclear cubane-like clusters seldom occur throughout the LnIII series and behave as single-molecule magnets (SMMs). Herein, a series of cubanes, [Ln4(µ3-OH)4(µ-tfa)4(hfa)4(phen)4] (1-9, Ln = La-Dy (except Pm), tfa = trifluoroacetate, hfa = hexafluoroacetylacetonate, phen = 1,10-phenanthroline), and dinuclear clusters, [Ln2(µ-OH)2(hfa)4(phen)2] (10-16, Ln = Tb-Lu), were synthesized and characterized. Two types of clusters were formed due to the change of preferred coordination geometry for lighter and heavier LnIII ions which favor nine-coordinated cubanes and eight-coordinated dimers, respectively. A magnetic study shows that 8-Tb4 and 9-Dy4 are ferromagnetically coupled and SMM in nature because of the larger Ln···Ln distance compared to other discrete cubanes. The anisotropic barriers, Ueff, of 9-Dy4 are determined to be 67.0 K. In addition, the photophysical properties of 6-Eu4, 8-Tb4, and 10-Tb2 owing to tfa, hfa, and phen sensitization and O-H quenching are discussed.

Mechanistic Investigation of Inducing Triboluminescence in Lanthanide(III) ß-Diketonate Complexes.

In this work, we synthesized a series of lanthanide(III) ß-diketonate complexes to investigate the induction of triboluminescence. Triboluminescence (TL) spectra, solid-state emission spectra, and luminescence lifetimes of the complexes were obtained to prove consistent emitting species for steady-state and triboluminescence measurements. Detailed analyses of the crystal lattice packing were conducted in an attempt to correlate crystal symmetry, gas discharge, and structural arrangements with "triboexcitation", and it is found that either noncentrosymmetric or centrosymmetic compounds can be TL-active. Furthermore, an intensely TL compound, Eu(dbm)4TMP, was achieved, and its light emission can be seen under daylight upon mechanical stress.

In vivo selective cancer-tracking gadolinium eradicator as new-generation photodynamic therapy agent.

In this work, we demonstrate a modality of photodynamic therapy (PDT) through the design of our truly dual-functional--PDT and imaging--gadolinium complex (Gd-N), which can target cancer cells specifically. In the light of our design, the PDT drug can specifically localize on the anionic cell membrane of cancer cells in which its laser-excited photoemission signal can be monitored without triggering the phototoxic generation of reactive oxygen species--singlet oxygen--before due excitation. Comprehensive in vitro and in vivo studies had been conducted for the substantiation of the effectiveness of Gd-N as such a tumor-selective PDT photosensitizer. This treatment modality does initiate a new direction in the development of "precision medicine" in line with stem cell and gene therapies as tools in cancer therapy.

Interband Absorption Enhanced Optical Activity in Discrete Au@Ag Core-Shell Nanocuboids: Probing Extended Helical Conformation of Chemisorbed Cysteine Molecules.

Detailed understanding of the interaction between a chiral molecule and a noble metal surface is essential to rationalize and advance interfacial self-assembly of amino acids and metal-mediated anchoring of proteins. Here we demonstrate that individual Au@Ag core-shell nanocuboids can serve as a plasmonic reporter of an extended helical network formed among chemisorbed cysteine molecules, through generating an interband absorption enhanced, Ag-surface-exclusive circular dichroism (CD) band in the UV region. The observed unusual, strong CD response in the hybrid Au@Ag-cysteine system can be used to probe in real time conformational evolution and structural rearrangement of biomolecules in general and also monitor the interfacial interaction between a metal surface and an adsorbed molecule, opening up the possibility of using Ag nanostructures as promising stereochemically attuned nanosensors.

New Class of Bright and Highly Stable Chiral Cyclen Europium Complexes for Circularly Polarized Luminescence Applications.

High glum values of +0.30 (ΔJ = 1, 591 nm, in DMSO) and -0.23 (ΔJ = 1, 589 nm, in H2O) were recorded in our series of newly designed macrocyclic europium(III) complexes. A sterically locking approach involving a bidentate chromophore is adopted to control the formation of one stereoisomer, giving rise to extreme rigidity, high stability, and high emission intensity. The combination of a chiral substituent on a macrocyclic chelate for lanthanide ions opens up new perspectives for the further development of circulary polarized luminescent chiral tags in optical and bioapplications.

Effects of Ligand Geometry on the Photophysical Properties of Photoluminescent Eu(III) and Sm(III) 1-Hydroxypyridin-2-one Complexes in Aqueous Solution.

A series of 10 tetradentate 1-hydroxy-pyridin-2-one (1,2-HOPO) ligands and corresponding eight-coordinated photoluminescent Eu(III) and Sm(III) complexes were prepared. Generally, the ligands differ by the linear (nLI) aliphatic linker length, from 2 to 8 methylene units between the bidentate 1,2-HOPO chelator units. The photoluminescent quantum yields (Φtot) were found to vary with the linker length, and the same trend was observed for the Eu(III) and Sm(III) complexes. The 2LI and 5LI bridged complexes are the brightest (Φtotxε). The change in ligand wrapping pattern between 2LI and 5LI complexes observed by X-ray diffraction (XRD) is further supported by density functional theory (DFT) calculations. The bimodal Φtot trends of the Eu(III) and Sm(III) complexes are rationalized by the change in ligand wrapping pattern as the bridge (nLI) is increased in length.

New insights into structure and luminescence of Eu(III) and Sm(III) complexes of the 3,4,3-LI(1,2-HOPO) ligand.

We report the preparation and new insight into photophysical properties of luminescent hydroxypyridonate complexes [M(III)L](-) (M = Eu or Sm) of the versatile 3,4,3-LI(1,2-HOPO) ligand (L). We report the crystal structure of this ligand with Eu(III) as well as insights into the coordination behavior and geometry in solution by using magnetic circular dichroism. In addition TD-DFT calculations were used to examine the excited states of the two different chromophores present in the 3,4,3-LI(1,2-HOPO) ligand. We find that the Eu(III) and Sm(III) complexes of this ligand undergo a transformation after in situ preparation to yield complexes with higher quantum yield (QY) over time. It is proposed that the lower QY in the in situ complexes is not only due to water quenching but could also be due to a lower degree of f-orbital overlap (in a kinetic isomer) as indicated by magnetic circular dichroism measurements.

Highly luminescent Sm(III) complexes with intraligand charge-transfer sensitization and the effect of solvent polarity on their luminescent properties.

Samarium complexes with the highest quantum yields to date have been synthesized, and their luminescence properties were studied in 12 solvents. Sensitization via a nontriplet intraligand charge-transfer pathway was also successfully demonstrated in solution states with good quantum yields.

Design and synthesis of chiral DOTA-based MRI contrast agents with remarkable relaxivities.

Due to the adverse effects of de-metallation in past concerning FDA-approved gadolinium-based contrast agents (GBCAs), researchers have been focusing on developing safer and more efficient alternatives that could avoid toxicity caused by free gadolinium ions. Herein, two chiral GBCAs, Gd-LS with sulfonate groups and Gd-T with hydroxyl groups, are reported as potential candidates for magnetic reasonance imaging (MRI). The r1 relaxivities of TSAP, SAP isomers of Gd-LS and SAP isomer of Gd-T at 1.4 T, 37 °C in water are 7.4 mM-1s-1, 14.5 mM-1s-1 and 5.2 mM-1s-1, respectively. Results show that the hydrophilic functional groups introduced to the chiral macrocyclic scaffold of Gd-T and Gd-LS both give constructive influences on the second-sphere relaxivity and enhance the overall r1 value. Both cases indicate that the design of GBCAs should also focus on the optimal window in Solomon-Bloembergen-Morgan (SBM) theory and the effects caused by the second-sphere and outer-sphere relaxivity.

Circularly polarized luminescence of curium: a new characterization of the 5f actinide complexes.

A key distinction between the lanthanide (4f) and the actinide (5f) transition elements is the increased role of f-orbital covalent bonding in the latter. Circularly polarized luminescence (CPL) is an uncommon but powerful spectroscopy which probes the electronic structure of chiral, luminescent complexes or molecules. While there are many examples of CPL spectra for the lanthanides, this report is the first for an actinide. Two chiral, octadentate chelating ligands based on orthoamide phenol (IAM) were used to complex curium(III). While the radioactivity kept the amount of material limited to micromole amounts, spectra of the highly luminescent complexes showed significant emission peak shifts between the different complexes, consistent with ligand field effects previously observed in luminescence spectra.

Biomimetic multifunctional persistent luminescence nanoprobes for long-term near-infrared imaging and therapy of cerebral and cerebellar gliomas.

Glioma is the most common malignant primary brain tumor, and the accurate diagnosis of glioma has always been a challenge. Moreover, cerebellar glioma, which is difficult to be detected by magnetic resonance imaging, is not usually diagnosed until after the appearance of clinical symptoms. In this study, TRZD, a near-infrared (NIR) persistent luminescence (PL) nanoparticle with a dual function of imaging and therapy, was synthesized based on ZnGa2O4:Cr3+,Sn4+. TRZD showed excellent rechargeable NIR PL for more than 30 hours in vivo with good tissue penetration for long-term autofluorescence-free imaging. The tumor growth of both the subcutaneous and orthotropic glioma models was significantly inhibited by TRZD. This is the first-time approach using NIR PL nanoprobes for both diagnosis and therapy of glioma. This is also the first-time report of nanotechnology-based diagnosis and therapy of cerebellar gliomas. This study offers a highly promising multifunctional nanoparticle for theranostics of a wide range of brain diseases.