A Platinum-Aluminum Bimetallic Salen Complex for Pro-senescence Cancer Therapy.

Cell senescence is defined as irreversible cell cycle arrest, which can be triggered by telomere shortening or by various types of genotoxic stress. Induction of senescence is emerging as a new strategy for the treatment of cancer, especially when sequentially combined with a second senolytic drug capable of killing the resulting senescent cells, however severely suffering from the undesired off-target side effects from the senolytic drugs. Here, we prepare a bimetalic platinum-aluminum salen complex (Alumiplatin) for cancer therapy-a combination of pro-senesence chemotherapy with in situ senotherapy to avoid the side effects. The aluminum salen moiety, as a G-quadruplex stabilizer, enhances the salen's ability to induce cancer cell senescence and this phenotype is in turn sensitive to the cytotoxic activity of the monofunctional platinum moiety. It exhibits an excellent capability for inducing senescence, a potent cytotoxic activity against cancer cells both in vitro and in vivo, and an improved safety profile compared to cisplatin. Therefore, Alumiplatin may be a good candidate to be further developed into safe and effective anticancer agents. This novel combination of cell senescence inducers with genotoxic drugs revolutionizes the therapy options of designing multi-targeting anticancer agents to improve the efficacy of anticancer therapies.

A Gallium(III) Complex that Engages Protein Disulfide Isomerase A3 (PDIA3) as an Anticancer Target.

Gallium(III)-based drugs have gained momentum in cancer therapy due to their iron-dependent anticancer activity. Judicious choice of ligands is critical for improved oral bioavailability, antitumor efficacy, and distinct mechanisms from simple GaIII salts. We describe GaIII complexes with planar tetradentate salen ligands [salen=2,3-bis[(4-dialkylamino-2-hydroxybenzylidene)amino]but-2-enedinitrile)] and labile axial solvent ligands, which display tumor growth inhibition in vitro and in vivo comparable to cisplatin. Confocal fluorescence microscopy, western blotting, mRNA profiling, chemical proteomics, and surface plasmon resonance (SPR) studies provide compelling evidence that PDIA3, a member of the protein disulfide isomerase (PDI) family involved in endoplasmic reticulum (ER) stress, is a direct target of Ga-1. This work offers a new route to designing and synthesizing Ga-based drugs, and also reveals that PDIA3 is an important anticancer target.

Strong Fluorescent Lanthanide Salen Complexes: Photophysical Properties, Excited-State Dynamics, and Bioimaging.

The synthesis, excited-state dynamics, and biological application of luminescent lanthanide salen complexes (Ln = Lu, Gd, Eu, Yb, salen = N, N'-bis(salicylidene)ethylenediamine-based ligands) with sandwich structures are described. Among them, Lu(III) complexes show unusually strong ligand-centered fluorescence with quantum yields up to 62%, although the metal center is close to a chromophore ligand. The excited-state dynamic studies including ultrafast spectroscopy for Ln-salen complexes revealed that their excited states are solely dependent on the salen ligands and the ISC rates are slow (108-109 s-1). Importantly, time-dependent density functional theory calculations attribute the low energy transfer efficiency to the weak spin-orbital coupling (SOC) between the singlet and triplet excited states. More importantly, Lu-salen has been applied as a molecular platform to construct fluorescence probes with organelle specificity in living cell imaging, which demonstrates the advantages of the sandwich structures as being capable of preventing intramolecular metal-ligand interactions and behaviors different from those of the previously reported Zn-salens. Most importantly, the preliminary study for in vivo imaging using a mouse model demonstrated the potential application of Ln coordination complexes in therapeutic and diagnostic bioimaging beyond living cells or in vitro.

A luminescent aluminium salen complex allows for monitoring dynamic vesicle trafficking from the Golgi apparatus to lysosomes in living cells.

The Golgi apparatus is well-known as the center of vesicle trafficking whose malfunction might cause the breakdown of overall cellular architecture and ultimately cell death. The development of fluorescent probes to not only precisely stain the Golgi apparatus but also monitor dynamic vesicle trafficking is of great significance. While fluorescent proteins and fluorescent lipid analogs have been reported, they are sometime limited by either overexpression and toxicity or lack of high selectivity, respectively. We herein report a novel approach based on metal-induced coordination between the phosphate anions of phospholipids and the metal center of a luminescent Alsalen complex AlL, which can in situ track membrane vesicle trafficking from the Golgi apparatus to the lysosomes in living cells. This work opens a new avenue for designing luminescent metal probes based on the Lewis acidity of metal ions and allows the use of metal ions with different charge states, polarities, and reactivities within a similar structural scaffold to expand coordination chemistry for biological studies.

Precise Labeling and Tracking of Lipid Droplets in Adipocytes Using a Luminescent ZnSalen Complex.

Designing two-photon probes for precise labeling of lipid droplets (LDs) and monitoring LD dynamics in adipocytes is of great significance to understand LD homeostasis. We herein report that a luminescent metal complex LD-TPZn can specifically image LDs in adipose cells and tissue using one- or two-photon fluorescence microscopy. Importantly, LD-TPZn exhibited higher specificity to LDs than the commercial dyes Nile Red and Bodipy 493/503, probably due to different cellular uptake pathways, that is, clathrin-mediated endocytosis and non-selectively passive diffusion, respectively. More importantly, LD-TPZn can be applied as a two-photon LD probe to image adipose tissue, one of the most challengeable tissues for traditional one-photon fluorescence microscope imaging due to the strong light scattering. Most importantly, LD-TPZn can be used to monitor LD growth during adipogenesis of preadipocytes, which is highly desirable to unravel the relationship between LD homeostasis and metabolic diseases.

A photoactivatable Znsalen complex for super-resolution imaging of mitochondria in living cells.

We herein report the first example that uses a first-row transition metal complex, Znsalen J-S-Alk, as a photoactivatable probe for super-resolution imaging of mitochondria with a localization precision of ca. 12 nm in living cells.

Gadolinium(III) Porpholactones as Efficient and Robust Singlet Oxygen Photosensitizers.

Construction of Gd(III) photosensitizers is important for designing theranostic agents owing to the unique properties arising from seven unpaired f electrons of the Gd(3+) ion. Combining these with the advantages of porpholactones with tunable NIR absorption, we herein report the synthesis of Gd(III) complexes Gd-1-4 (1, porphyrin; 2, porpholactone; 3 and 4, cis- and trans-porphodilactone, respectively) and investigated their function as singlet oxygen ((1) O2 ) photosensitizers. These Gd complexes displayed (1) O2 quantum yields (ΦΔ s) from 0.64-0.99 with the order Gd-1

Cationic sulfonium functionalization renders Znsalens with high fluorescence, good water solubility and tunable cell-permeability.

In this study, we report for the first time that incorporation of cationic sulfonium to the Znsalens skeleton achieves water soluble fluorescent metal complex probes for living cell imaging. To circumvent Znsalen aggregation arising from intermolecular ZnO interactions (found between Zn and the phenoxyl group of another Znsalen molecule), we synthesized a series of sulfonium Znsalens based on alkylation of the 3-thioether or 3,5-dithioether moieties of salicylaldehydes. Such functionalization not only provides positive charge(s) to enhance electrostatic repulsion, but also increases steric hindrance, which renders the Znsalen complex water soluble as a monomeric species in aqueous media as revealed by diffusion ordered NMR spectroscopy (DOSY). More interestingly, these sulfonium Znsalens display "switched on" fluorescence when compared to thioether analogues, which was attributed to the electron-withdrawing sulfonium moiety that perturbs the photoinduced electron transfer (PET) process as suggested by computational calculations based on time-dependent density functional theory (TD-DFT). Most interestingly, live cell imaging experiments showed that modulation of the sulfonium moieties, such as the number or alkyl substituents, significantly tunes the cell-permeability of the fluorescent Znsalens. Thus, this study has demonstrated the importance of sulfonium functionalization on dissociating the intermolecular metal-ligand interactions and thus, modulating water solubility, photophysical properties and even cell-permeability of the fluorophores, which provides a new approach to the design of functional metal complexes for biological studies.