A naphthalimide-based fluorescent platform for endoplasmic reticulum targeted imaging.

A series of naphthalimide dyes (TRNATR, MOTNAMOT, MPNAMP, TYNATY, PNAP and IZNAIZ) were designed and synthesized by altering the side chains of the naphthalimide. Without the need for ER-targeting groups, the first five dyes were found to specifically target the ER, likely due to their well-suited lipophilic properties. Furthermore, TRNATR and TYNATY were proven effective for studying ER stress, showing promise in tracking ER autophagy in living cells triggered by tunicamycin and nutritional starvation.

Advances in metal-organic framework-based nanozymes in ROS scavenging medicine.

Reactive oxygen species (ROS) play important roles in regulating various physiological functions in the human body, however, excessive ROS can cause serious damage to the human body, considering the various limitations of natural enzymes as scavengers of ROS in the body, the development of better materials for the scavenging of ROS is of great significance to the biomedical field, and nanozymes, as a kind of nanomaterials which can show the activity of natural enzymes. Have a good potential for the development in the area of ROS scavenging. Metal-organic frameworks (MOFs), which are porous crystalline materials with a periodic network structure composed of metal nodes and organic ligands, have been developed with a variety of active nanozymes including catalase-like, superoxide dismutase-like, and glutathione peroxidase-like enzymes due to the adjustability of active sites, structural diversity, excellent biocompatibility, and they have shown a wide range of applications and prospects. In the present review, we first introduce three representative natural enzymes for ROS scavenging in the human body, methods for the detection of relevant enzyme-like activities and mechanisms of enzyme-like clearance are discussed, meanwhile, we systematically summarize the progress of the research on MOF-based nanozymes, including the design strategy, mechanism of action, and medical application, etc. Finally, the current challenges of MOF-based nanozymes are summarized, and the future development direction is anticipated. We hope that this review can contribute to the research of MOF-based nanozymes in the medical field related to the scavenging of ROS.

A mitochondria-targeted fluorescent probe for imaging of endogenous carbon monoxide in living cells.

Carbon monoxide (CO), a vital gasotransmitter, plays critical functions in many physiological processes. Mitochondrial CO is closely related to mitochondrial respiration, thus the detection and imaging of mitochondrial CO in living cells is very important and has attracted much attention recently. In this paper, we developed a hemicyanine-based off-on fluorescent probe, CO-H1, which was used for monitoring endogenous mitochondrial CO levels in living cells. After reacted with CO in the presence of PdCl2, the fluorescence of CO-H1 was enhanced notably, accompanied by a significant red shift of absorption. CO-H1 exhibits low cytotoxicity, high sensitivity (detection limit of 0.048 µM), and good selectivity for CO. When incubated with living cells, probe CO-H1 mainly entered the mitochondria. CO-H1 was successfully applied to imaging the exogenous/endogenous mitochondrial CO in living cells, suggesting its potential application for further studying the biological functions of mitochondrial CO in living cells.

A mitochondria-targeted near-infrared fluorescent probe for detection and imaging of HSO3- in living cells.

Sulfur dioxide, an essential gas signaling molecule mainly produced in mitochondria, plays important roles in many physiological and pathological processes. Herein, a near-infrared fluorescent probe, A1, with good mitochondria targeting ability was developed for colorimetric and fluorescence detection of HSO3-. Probe A1 has a conjugated cyanine structure that can selectively react with HSO3- through the nucleophilic addition. The reaction with HSO3- destroys the conjugated structure of probe A1, resulting in fluorescence quenching, and accompaniedby color change of probe A1 solution from purple-red to colorless. Probe A1 showed high selectivity and good sensitivity to HSO3- in PBS. And the limit of detection was calculated to be 1.28 and 0.037 µM for colorimetry and fluorescence spectrophotometry respectively. In addition, probe A1 mainly entered the mitochondria in living cells, and was successfully used for imaging the exogenous/endogenous HSO3- in cells. These results suggest the potential applications of probe A1 in biological systems.

p-Aminostyryl thiazole orange derivatives for monitoring mitochondrial viscosity in live cells.

Viscosity of cell microenvironment plays a significant role in maintaining the normal life activities of cells. Particularly, the abnormal viscosity in mitochondria is closely associated with lots of diseases and cellular dysfunctions. Herein, we developed a group of p-aminostyryl thiazole orange derivatives with different amino side chains. These probes showed good fluorescence response to viscosity with twisted intramolecular charge transfer mechanism, among them, the probes with diethylamino (TOB), dibutylamino (TOC) and pyrrolidin (TOE) side chains showed better response to the viscosity with 78-fold, 55-fold, and 88-fold fluorescence enhancement in 95% glycerol solution respectively. TOB, TOC, and TOE could enter live cells and mainly located in mitochondria. Treatment HeLa cells with nystatin, lipopolysaccharide or oleic acid caused significant fluorescence enhancement of these probes, suggesting the good potential for monitoring the variation of mitochondrial viscosity, as well as for investigating the related physiological process of inflammation and lipid metabolism.

Thiazole Orange Styryl Derivatives as Fluorescent Probes for G-Quadruplex DNA.

G-quadruplex (G4) forming sequences commonly exist in the genome and are closely related to gene regulation and expression. Development of a fluorescent probe that can specifically recognize G4 is essential for studying its structures and biological functions. Thiazole orange (TO) is an often used nucleic acid dye that is reported to have higher affinity to G4 DNA than double-stranded (ds) DNA. Here, four TO derivatives were designed and synthesized by introducing different styryl groups to obtain highly specific G4 probes. The spectroscopic studies revealed that different groups affected the G4 binding ability greatly, in which TO modified with 4-(diethylamino)styryl (5a) showed better selectivity to G4s, and that modified with 4-(methylpiperazin-1-yl)styryl (5b) showed higher affinity to antiparallel G4s. 5a and 5b bound to parallel G4s with a 1:1 molar binding ratio, in which the binding mode of 5b to parallel G4s was end-stacking. In addition, the obtained fluorescent probes were tested for cell staining, which showed the potential application in cell imaging and DNA/RNA biosensing.

Dicyanomethylene Substituted Benzothiazole Squaraines: The Efficiency of Photodynamic Therapy In Vitro and In Vivo.

The lack of ideal photosensitizers limits the clinicalapplication of photodynamic therapy (PDT). Here we report the PDT efficiency of dicyanomethylene substituted benzothiazole squaraine derivatives. This class of squaraine derivatives possess strong absorption and long excitation and emission wavelengths (ex/em, 685/720nm). They show negligible dark toxicity, but can generate singlet oxygen under irradiation resulting in the apoptosis and necrosis of cells (phototoxicity). Changing the side chains of these compounds greatly influences their albumin-binding rate, cellular uptake and their phototoxicity. One of the squaraine derivatives with two methyl butyrate side chains shows high PDT efficiency in a mouse subcutaneous xenograft model under the irradiation of a 690nm laser. These results show the great potential of dicyanomethylene substituted benzothiazole squaraines to be the leading compound of near-infrared photosensitizers in PDT.

Development of squaraine based G-quadruplex ligands using click chemistry.

The G-quadruplex (G4) structures of nucleic acids are considered to play an intrinsic role in gene expression. To this end, the development of new G4 ligands has attracted extensive research interests towards potential applications as G4-targeted drugs and molecular probes. To date, the majority of G4 ligands have been composed of an extended planar aromatic scaffold that interacts with the terminal G-tetrad plane via π-π interactions, and various side chains that interact with the sugar-phosphate backbone, loops or grooves of the G4 structures. The side chains act to modulate the affinity and selectivity of the G4 ligands, alongside influencing their biodistribution. Here, we present a click chemistry methodology to generate a series of squaraine-based G4 ligand derivatives based on our previously reported G4 probe (named CSTS) but with varing side chains. We find that importantly these new G4 ligand derivatives retain the G4 selectivity, optical properties and low cytotoxicity of CSTS, but exhibit different binding behaviors to G4 structures, and distinct cellular uptake efficiencies. Indeed, of these new complexes, several exhibit much higher affinity and cellular uptake than CSTS. Overall, this novel, facile and highly effective strategy has significant future potential for the high-throughput screening of G4 ligands or probes targeted towards in vivo applications.

Design, synthesis and anticancer activity of oxoaporphine alkaloid derivatives.

A series of new oxoaporphine derivatives were synthesized and their inhibitory activity of topoisomerase I, cytotoxicity and DNA-binding properties were studied. Oxoaporphine can strongly inhibit topoisomerase I at concentrations of 5-50 µM and the cytotoxicity of the derivatives are more potent than their lead compound. Hypochromism, broadening and red shift in the absorption spectra were observed when these compounds bind to calf thymus DNA (CT DNA). These spectral characteristics were consistent with the intercalative binding of these compounds.

Synthesis, characterization and anti-diabetic therapeutic potential of a new benzyl acid-derivatized kojic acid vanadyl complex.

Vanadium complexes are potent hypoglycemic agents and of great potential for therapeutical treatment of diabetes. In the present work, a novel vanadium compound, bis ((5-hydroxy-4-oxo-4H-pyran-2-yl)methyl benzoatato) oxovanadium (IV) (BBOV) has been synthesized. Treatment of STZ-induced diabetic rats with BBOV restored the blood glucose to normal level and ameliorated glucose tolerance. The hypoglycemic effect of BBOV is similar to that of bis (maltolato) oxovanadium but is less toxic in median lethal dose. Overall, the present work will provide useful information for further development of new anti-diabetic vanadium compounds.

A new salicylic acid-derivatized kojic acid vanadyl complex: synthesis, characterization and anti-diabetic therapeutic potential.

The molecular mechanisms of vanadium toxicity suggest that incorporation of antioxidant groups in the structure of vanadium complexes could be a preferable strategy in designing novel hypoglycemic vanadium complexes with proper efficacy and safety. By conjugating a pyrone skeleton to provide a coordination group and antioxidative motifs, we synthesized a novel complex of bis ((5-hydroxy-4-oxo-4H-pyran-2-yl) methyl 2-hydroxy- benzoatato) oxovanadium (IV) (BSOV). Evaluation of the anti-diabetic effects of BSOV using streptozotocin (STZ)-induced diabetic rats with bis (maltolato) oxovanadium (BMOV) as a positive control showed that BSOV effectively lowered blood glucose level, ameliorated damages of hepatic and renal function in diabetic rats and improved lipid metabolism. The signs of potential alteration of renal function caused by BSOV and BMOV were observed and are discussed. Overall, the experimental results suggest BSOV as a potent hypoglycemic agent and further studies using this strategy for anti-diabetic agents.

Synthesis, biological evaluation and molecular modeling of oxoisoaporphine and oxoaporphine derivatives as new dual inhibitors of acetylcholinesterase/butyrylcholinesterase.

Aporphine alkaloids, isolated from Chinese medicinal herb, are important natural products. We recently reported that synthetic derivatives of oxoisoaporphine alkaloids exhibited high acetylcholinesterase inhibitory activity and high selectivity for AChE over BuChE (Bioorg. Med. Chem. Lett. 2007, 17, 3765-3768). In this paper, further research results were presented. A series of novel derivatives of oxoaporphine alkaloids (5a-j, 4-carboxylic amide-7-oxo-7H-dibenzo[de,g]quinoline, Ar-CONH(CH(2))(n)NR) and their quaternary methiodide salts (6a-h, Ar-CONH(CH(2))(n)N(+)(CH(3))RI(-)) were designed and synthesized as acetylcholinesterase (AChE) and/or butyrylcholinesterase (BuChE) inhibitors. The AChE inhibition potency of synthetic oxoaporphine derivatives was decreased about 2-3 orders of magnitude as compared with that of oxoisoaporphine derivatives. Non-competitive binding mode was found for both kinds of derivatives. Molecular docking simulations on the oxoisoaporphine derivatives 7 series and oxoaporphine derivatives 6 series with AChE from Torpedo californica have demonstrated that the ligands bound to the dual-site of the enzyme.

Oxoisoaporphine alkaloid derivatives: synthesis, DNA binding affinity and cytotoxicity.

A series of novel oxoisoaporphine alkaloid derivatives, 9-aminoalkanamido-1-azabenzanthrone (general formula Ar-NHCO(CH(2))(n)NR(2), Ar=1-azabenzanthrone, n=1, 2 or 3), had been synthesized. Compared with 1-azabenzanthrone, the derivatives had significantly higher DNA binding affinity with calf thymus DNA, and higher potent cytotoxicity against different tumor cell lines. The cytotoxicity and the structure-activity relationship of the prepared compounds were studied. The derivatives with two methylene groups (n=2), and piperidine or ethanolamine functional group in the side chain exhibited highest DNA binding affinity and cytotoxicity.

Derivatives of oxoisoaporphine alkaloids: a novel class of selective acetylcholinesterase inhibitors.

A series of 9-aminoalkanamido-1-azabenzanthrones derviatives (3a-i Ar-NHCO(CH(2))(n)NR(1)R(2)) and their quaternary methiodide salts (4a-g Ar-NHCO(CH(2))(n)N(+)(CH(3))R(1)R(2)I(-)) were designed and synthesized as acetylcholinesterase (AChE) or butyrylcholinesterase (BuChE) inhibitors. The synthetic compounds exhibited high AChE inhibitory activity with IC(50) values in the nanomolar range and high selectivity for AChE over BuChE (45- to 1980-fold). The structure-activity relationships (SARs) were discussed.