Latest ArticlesA range of bench-stable carbazole-containing hypervalent iodine(Ⅲ) reagents were synthesized by I-N bond formation in good yields. This kind of benziodoxolone reagents was used for a C-N coupling reaction to introduce a carbazole group to aromatic heterocycle compounds.
In this study, we designed and synthesized a series of phthalazinone acridine derivatives as dual PARP and Topo inhibitors. MTT assays indicated that most of the compounds significantly inhibited multiple cancer cells proliferation. In addition, all the compounds displayed Topo Ⅱ inhibition activity at 10 mol/L, and also possessed good PARP-1 inhibitory activities. Subsequent mechanistic studies showed that compound 9a induced remarkable apoptosis and caused prominent S cell cycle arrest in HCT116 cells. Our study suggested that 9a inhibiting Topo and PARP concurrently can be a potential lead compound for cancer therapy.
Here, a new designed core/satellite gold nanoprobe was developed for detecting trace mount of benzoyl peroxide (BPO) based on its deboronation. This gold nanoassembly (the BE-AuNPs12/65) was constructed via borate ester formation between large 4-mercaptophenylboronic acid (MPBA) modified AuNPs (the MPBA-AuNPs65, as cores)and smalldopamine modifiedAuNPs (theDPA-AuNPs12, assatellites).Particularly, upon addition of BPO, it would trigger the deboronation for the BE-AuNPs12/65 probes accompanying with distinct color changes from blue, purple to wine red, which implied the disassembly of the core/satellite nanostructure after the breakage of carbon to boron chemical bond. By measuring the absorbance ratio at 665 nm and 545 nm, quantification of BPO was achieved in the range of 10.0-100.0 nmol/L, which could also be easilyobserved bynaked eyes. The nanoprobeutilized a boronate deprotection mechanism and the LSPR properties of AuNPs to provide high selectivity for detecting BPO over similar ROS/RNS with the limit of detection as low as 7.2 nmol/L. The practical applicability of this assay was verified through successful determining BPO in flour samples, which demonstrated its great potentials in food safety field.
Polymyxin B (PB), as the last-line of defense against multidrug-resistant Gram-negative bacteria, has caused resistance to P. aeruginosa recently. Fortunately, synergistic treatment could preserve the last class of antibiotics and reduce the emergency of drug resistance. Here, we performed a screen of 970 approved drugs synergized with PB against the P. aeruginosa DK2, which is severely resistant to PB, MIC = 512 μg/mL. Encouragingly, we found fluoroquinolones could synergy with PB and achieved an obvious reduction in MIC of PB below the clinical susceptible breakpoint (2 μg/mL). Especially, gemifloxacin achieved the highest synergistic effect with PB, leading to a 4096-fold MIC reduction (reduced from 512 μg/mL to 0.125 μg/mL). Furthermore, synergistic effect was also observed in the combination of gemifloxacin and colistin. Finally, outer membrane permeabilization assay showed that gemifloxacin could increase the permeability of bacterial cell membranes for P. aeruginosa which partly explained the synergy mechanism. These results indicate that fluoroquinolones represent attractive synergists to address the emerging threat of polymyxin-resistant infections.
An organocatalytic asymmetric [3+2] cycloaddition of trifluoromethyl-containing azomethine ylides with cyclic 2, 4-dienones was developed. The process enables efficient incorporation of CF3 groups into functionalized spiro[pyrrolidin-3, 2'-oxindoles] in high yields with good to excellent enantio-and diastereoselectivities.
X-ray imaging functionalization of biodegradable polyesters is a great demand and challenge in biomedical applications. In this work, a strategy of in-chain functionalization through the combination of ring opening copolymerization and oxime "Click" postfunctionalization was developed towards X-ray opaque polylactide copolymers. A functionalized cyclic carbonate was first synthesized and used as comonomer of polylactide copolymers, which were subjected to postfunctionalization of oxime "Click" reaction towards iodinated polylactide copolymers. The chemical structure and physical properties of the target products were traced and confirmed. In vitro cytotoxicity evaluation with 3T3-Swiss albino by Alamar blue demonstrated a low cytotoxicity. The X-ray radiopacity was analyzed by Micro-CT and quantified by Hounsfield Units value, which could be tailorable by the feedstock. It is a promising X-ray visible implantable biomaterial in biomedical applications.
Targeting bromodomain-containing protein 4 (BRD4) has been proved to be an effective strategy for cancer therapy. To date, numerous BRD4 inhibitors and degraders have been identified, some of which have advanced into clinical trials. In this work, a focused library of new [1, 2, 4]triazolo[1, 5-a]pyrimidine derivatives were discovered to be able to inhibit BRD4. WS-722 inactivated BRD4 (BD1/BD2), BRD2 (BD1/BD2) and BRD3 (BD1/BD2) broadly with the IC50 values less than 5 μmol/L. Besides, WS-722 inhibited growth of THP-1 cells with an IC50 value of 3.86 μmol/L. Like (+)-JQ1, WS-722 inhibited BRD4 in a reversible manner and enhanced protein stability. Docking studies showed that WS-722 occupied the central acetyl-lysine (Kac) binding cavity and formed a hydrogen bond with Asn140. In THP-1 cells, WS-722 showed target engagement to BRD4. Cellular effects of WS-722 on THP-1 cells were also examined, showing that WS-722 could block c-MYC expression, induce G0/G1 phase arrest and p21 up-regulation, and promote differentiation of THP-1 cells. BRD4 inhibition by WS-722 resulted in cell apoptosis and upregulated expression of cleaved caspased-3/7 and PARP in THP-1 cell lines. The [1, 2, 4]triazolo[1, 5-a] pyrimidine is a new template for the development of new BRD4 inhibitors.
The concentration of free zinc within insulin-storing vesicles is important for vesicle maturity and therefore requires accurate measurement. However, common small-molecule intensity-based probes and most available genetically encoded Förster resonance energy transfer (FRET)-based sensors for zinc are unsuitable for estimating the free zinc concentration in insulin-storing vesicles. Therefore, we have developed a novel FRET-based zinc sensor based on the RING motif of TRIM72, referred to as ZnT72R, which has an approximate Kd that varies from 6.07±0.28 μmol/L to 7.84±0.42 μmol/L in vitro and a cytosol-calibrated Kd of approximately 55.56±4.59 μmol/L in HEK293 T cells. To pinpoint the free zinc concentration of insulin-storing vesicles, we initially targeted ZnT72R to beta-cell vesicles by fusing them to NPY (neuropeptide Y). Following NPY-ZnT72R labeling, the FRET intensity ratios of vesicles were quantified. We found that the free zinc concentration in insulin-storing vesicles of diabetic db/db mice (28.30±1.33 μmol/L) was significantly lower than that of control mice (41.46±3.53 μmol/L).
In this work, a multi-functional analysis platform by coupling a microfluidic chip to a mass spectrometry (MS) detector was described. We constructed a three-dimensional tumor-endothelial co-culture model for simulating drug resistance during tumor treatment. On this specially designed integrated platform, the first step was to prepare heterogeneous cell-encapsulated alginate microcapsules for threedimensional co-culture, and the second step was to achieve on-line perfusion culture and continuous drug stimulation on chip. It facilitates cell proliferation analysis and the collection of metabolism medium. After micro solid phase extraction column (SPE) pretreatment, subsequent mass spectrometry could detect drug metabolism. The high activity of two kinds of cells (A549 and HUVEC) shows the biocompatibility of the platform. Paclitaxel was used as a model drug, the distinctions of drug absorption between the mono-culture group and co-culture group were clearly observed by electrospray ionization quadrupole time-of-flight mass spectrometry (ESI-Q-TOF MS). Therefore, the integrated platform has shown promise as a high throughput, low cost for cell metabolism research and drug screening processes.
Nowadays, tremendous researches have been focused on the core-shell lipid-polymer nanoparticles (LPNs) due to the advantages of both liposomes and polymer nanoparticles. In this work, LPNs were applied to encapsulate brinzolamide (Brz-LPNs) for achieving sustained drug release, improving drug corneal permeation and enhancing drug topical therapeutic effect. The structure of Brz-LPNs was composed of poly(lactic-co-glycolic) acid (PLGA) nanocore which encapsulated Brz (Brz-NPs) and lipid shell around the core. Brz-LPNs were prepared by a modified thin-film dispersion method. With the parameters optimization of Brz-LPNs, optimal Brz-LPNs showed an average particle size of 151.23±1.64 nm with a high encapsulation efficiency (EE) of 86.7%±2.28%. The core-shell structure of Brz-LPNs were confirmed by transmission electronic microscopy (TEM). Fourier transformed infrared spectra (FTIR) analysis proved that Brz was successfully entrapped into Brz-LPNs. Brz-LPNs exhibited obvious sustained release of Brz, compared with AZOPT® and Brz-LPs. Furthermore, the corneal accumulative permeability of Brz-LPNs significantly increased compared to the commercial available formulation (AZOPT®) in vitro. Moreover, Brz-LPNs (1 mg/mL Brz) showed a more sustained and effective intraocular pressure (IOP) reduction than Brz-LPs (1 mg/mL) and AZOPT® (10 mg/mL Brz) in vivo. In conclusion, Brz-LPNs, as promising ocular drug delivery systems, are well worth developing in the future for glaucoma treatment.
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