Activiteit

Macrophage elastase [matrix metalloproteinase (MMP)-12] is the most upregulated MMP in abdominal aortic aneurysm (AAA) and, hence, MMP-12-targeted imaging may predict AAA progression and rupture risk. Here, we report the design, synthesis, and evaluation of three novel hydroxamate-based selective MMP-12 inhibitors (CGA, CGA-1, and AGA) and the methodology to obtain MMP-12 selectivity from hydroxamate-based panMMP inhibitors. Also, we report two 99mTc-radiotracers, 99mTc-AGA-1 and 99mTc-AGA-2, derived from AGA. 99mTc-AGA-2 displayed faster blood clearance in mice and better radiochemical stability compared to 99mTc-AGA-1. Based on this, 99mTc-AGA-2 was chosen as the lead tracer and tested in murine AAA. 99mTc-AGA-2 uptake detected by autoradiography was significantly higher in AAA compared to normal aortic regions. Specific binding of the tracer to MMP-12 was demonstrated through ex vivo competition. Accordingly, this study introduces a novel family of selective MMP-12 inhibitors and tracers, paving the way for further development of these agents as therapeutic and imaging agents.Tropomyosin receptor kinases (TRKs) are promising cancer therapeutic targets. Chen ( J. Med. Chem. 2020, DOI 10.1021/acs.jmedchem.0c01342) report the discovery of CG416 and CG428 as two potent small-molecule proteolysis-targeting chimera (PROTAC) degraders selective for TRKA over TRKB and TRKC. CG416 and CG428 are valuable research tool compounds for in vitro and in vivo studies and promising lead compounds for further optimization.Nuciferine (NF) is one of the main constituents of Lotus (Nelumbo nucifera) leaves which have been widely used in both food and drug formulations in China. Although possessing a broad spectrum of bioactivities, the metabolic characteristics of NF are inadequately unknown after oral gavage with this NF. The present study was performed to characterize its metabolism in vivo and in vitro. After NF oral gavage with mice, a total of 55 metabolites, containing 14 novel phase I metabolites and 18 novel phase II metabolites, were identified with high-resolution mass spectrometry-based metabolomics. Recombinant enzyme screenings showed that multiple cytochrome P450s, two UDP-glucuronosyltransferases (UGT1A4, UGT1A9), and several sulfotransferases (SULTs) participated in the metabolism of NF. In silico prediction and molecular docking of NF to the polymorphic enzymes (CYPs) provided additional support for the above experiments. This research details metabolic characteristics and provides an important reference basis for further application of NF.The oxidation of [Re(η6-C10H8)2]+ with AgI in acetonitrile yields [Re(NCCH3)6]2+. This fully solvated ReII compound was characterized by spectroscopic methods and X-ray structure analyses. We show that [Re(NCCH3)6]2+ acts as a precursor complex for a variety of substitution reactions. Treatment with monodentate triphenylphosphine (PPh3) and bidentate 1,2-bis(diphenylphosphino)ethane (dppe) yields the complexes [trans-Re(PPh3)2(NCCH3)4]2+ and [trans-Re(dppe)2(NCCH3)2]+, respectively. [trans-Re(dppe)2(NCCH3)2]+ is oxidized under mild conditions by AgI to its ReII analogue [trans-Re(dppe)2(NCCH3)2]2+. Reactions of [Re(NCCH3)6]2+ with a halide mixture consisting of NaX and AgX (X = Cl, I) result in the formation of the corresponding ReIII complexes [trans-ReX2(NCCH3)4]+. [trans-ReBr2(NCCH3)4]+ can be obtained directly from [Re(η6-C10H8)2]+ by oxidation with FeBr3 in acetonitrile. The title compound is thus a convenient starting material for ReII and ReIII complexes by simple solvent exchange, which are otherwise difficult to access.Fabrication protocols of transparent conducting electrodes (TCEs), including those which produce TCEs of high values of figure of merit, often fail to address issues of scalability, stability, and cost. When it comes to working with high-temperature stable electrodes, one is left with only one and that too, an expensive choice, namely, fluorine-doped SnO2 (FTO). It is rather difficult to replace FTO with a low-cost TCE due to stability issues. In the present work, we have shown that an Al nanomesh fabricated employing the crack template method exhibits extreme thermal stability in air even at 500 °C, compared with that of FTO. In order to fill in the non-conducting island regions present in between the mesh wires, a moderately conducting material SnO2 layer was found adequate. The innovative step employed in the present work relates to the SnO2 deposition without damaging the underneath Al, which is a challenge in itself, as the commonly used precursor, SnCl2 solution, is quite corrosive toward Al. Optimization of spray coating of the precursor while the Al mesh on a glass substrate held at an appropriate temperature was the key to form a stable hybrid electrode. The resulting Al/SnO2 electrode exhibited an excellent transparency of ∼83% at 550 nm and a low sheet resistance of 5.5 Ω/□. SnO2 coating additionally made the TCE scratch-proof and mechanically stable, as the adhesion tape test showed only 8% change in sheet resistance after 1000 cycles. Further, to give FTO-like surface finish, the SnO2 surface was fluorinated by treating with a Selectfluor solution. As a result, the Al/F-SnO2 hybrid film exhibited one order higher surface conductivity with negligible sensitivity toward humidity and volatile organics, while becoming robust toward neutral electrochemical environments. Finally, a custom-designed projection lithography technique was used to pixelate the Al/SnO2 hybrid film for optoelectronic device applications.Microbial-based cancer therapy is nowadays considered as an interesting approach, especially with viruses which are attracting more attention owing to their simple structure and nanoscale. However, because of the need for cumbersome genetic modification and poor biosafety, its application is seriously limited. Here, nonpathogenic natural Sendai viruses (SEVs) are used as an alternative immune agonist after being mineralized by calcium ions. Both in vitro and in vivo studies indicated that virus-inorganic hybrids can effectively excite antigen-presenting cells (APCs). Then, the tumor antigens were released in large amounts by photothermal damage. Meanwhile, these released antigens were presented to lymph nodes to mature antitumor T lymphocytes via the peritumoral APCs previously recruited by the SEV. Veliparib chemical structure Our results demonstrated that even after administration at one point, the nanohybrids could still effectively stimulate systemic antitumor immune response to suppress the potential cancer metastatic spread. The bio-inorganic hybrid nongenetically modified virus-inorganic nanocomposites might serve as an alternative strategy for synergistic immune therapy.