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Indenoisoquinoline topoisomerase I (Top1) inhibitors are a novel class of anticancer agents with two compounds in clinical trials. Recent metabolism studies of indotecan (LMP400) led to the discovery of the biologically active 2-hydroxylated analogue and 3-hydroxylated metabolite, thus providing strategically placed functional groups for the preparation of a variety of potential ester prodrugs of these two compounds. The current study details the design and synthesis of two series of indenoisoquinoline prodrugs, and it also reveals how substituents on the O-2 and O-3 positions of the A ring, which are next to the cleaved DNA strand in the drug-DNA-Top1 ternary cleavage complex, affect Top1 inhibitory activity and cytotoxicity. Many of the indenoisoquinoline prodrugs were very potent antiproliferative agents with GI50 values below 10 nM in a variety of human cancer cell lines. [ABSTRACT FROM AUTHOR]

Tyrosyl-DNAphosphodiesterase I (TDP1) repairs stalled topoisomeraseI (Top1)–DNA covalent complexes and has been proposed to bea promising and attractive target for cancer treatment. Inhibitorsof TDP1 could conceivably act synergistically with Top1 inhibitorsand thereby potentiate the effects of Top1 poisons. This study describesthe successful design and synthesis of 2-position-modified indenoisoquinolinesas dual Top1–TDP1 inhibitors using a structure-based drug designapproach. Enzyme inhibition studies indicate that indenoisoquinolinesmodified at the 2-position with three-carbon side chains ending withamino substituents show both promising Top1 and TDP1 inhibitory activity.Molecular modeling of selected target compounds bound to Top1 andTDP1 was used to rationalize the enzyme inhibition results and structure–activityrelationship analysis. [ABSTRACT FROM AUTHOR]

Magic-angle-spinning (MAS) nuclear magnetic resonance (NMR) experiments and molecular dynamics (MD) simulations were employed to investigate Na 2 O-B 2 O 3 -SiO 2 and MgO-Na 2 O-B 2 O 3 -SiO 2 glass structures up to ≈0.3 nm. This encompassed the {Na [ p ] }, {Mg [ p ] }, and {B [3] , B [4] } speciations and the {Si, B [ p ] , M [ p ] }-BO and {Si, B [ p ] , M [ p ] }-NBO interatomic distances to the bridging oxygen (BO) and nonbridging oxygen (NBO) species, where the superscript indicates the coordination number. The MD simulations revealed the dominance of Mg [5] coordinations, as mirrored in average Mg 2+ coordination numbers in the 5.2-5.5 range, which are slightly lower than those of the larger Na + cation but with a narrower coordination distribution stemming from the higher cation field strength (CFS) of the smaller divalent Mg 2+ ion. We particularly aimed to elucidate such Na + /Mg 2+ CFS effects, which primarily govern the short-range structure but also the borosilicate (BS) glass network order, where both MD simulations and heteronuclear double-resonance 11 B/ 29 Si NMR experiments revealed a reduction of B [4] -O-Si linkages relative to B [3] -O-Si upon Mg 2+ -for-Na + substitution. These effects were quantified and discussed in relation to previous literature on BS glasses, encompassing the implications for simplified structural models and descriptions thereof.

N 2 O is a dominant atmosphere pollutant, causing ozone depletion and global warming. Currently, electrochemical reduction of N 2 O has gained increasing attention to remove N 2 O, but its product is worthless N 2 . Here, we propose a direct eight-electron (8 e ) pathway to electrochemically convert N 2 O into NH 3 . As a proof of concept, using density functional theory calculation, an Fe 2 double-atom catalyst (DAC) anchored by N-doped porous graphene (Fe 2 @NG) was screened out to be the most active and selective catalyst for N 2 O electroreduction toward NH 3 via the novel 8 e pathway, which benefits from the unique bent N 2 O adsorption configuration. Guided by theoretical prediction, Fe 2 @NG DAC was fabricated experimentally, and it can achieve a high N 2 O-to-NH 3 Faradaic efficiency of 77.8% with a large NH 3 yield rate of 2.9 mg h -1 cm -2 at -0.6 V vs RHE in a neutral electrolyte. Our study offers a feasible strategy to synthesize NH 3 from pollutant N 2 O with simultaneous N 2 O removal.

Inverse diffusion flame (IDF) is an effective and widely used reaction form in the process of noncatalytic partial oxidation (NC-POX) of gaseous hydrocarbons (such as natural gas and coke oven gas). However, soot is generated in the combustion chamber in the case of unreasonable feeding conditions, and thus causes serious damage to the wall and nozzle. In this study, the effects of the equivalence ratio ([O/C] e ), the oxygen flow rate, and the Reynolds number on the soot and CH* emission characteristics of CH 4 /O 2 inverse diffusion flame were comprehensively analyzed based on a hyperspectral imaging system. In addition, the relationship between CH* and soot is explored using Ansys Fluent simulation. The experimental results show that the soot radiation core generation area is located in the outer ring of the flame, and the radial distribution of the radiation intensity is bimodal. With the increase in [O/C] e , the initial position for soot radiation and the overall radiation intensity of soot decrease. In addition, the CH* radiation intensity decreases as [O/C] e increases, and CH* exists in the whole flame. The simulation results clearly show that the existence of CH* is conducive to soot production. The emission intensity and the core area of soot formation increase with the increase in the oxygen velocity. Additionally, the soot emission region increases and the flame tip changes from a round blunt to symmetrical tip with the increase in the Reynolds number., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

Micron-sized praseodymium oxide powders are prepared successfully from the praseodymium oxalate in a microwave field at 750 °C for 2 h in the present study. X-ray diffraction (XRD) analysis demonstrates that the presence of cubic structured crystalline Pr 6 O 11 and complete decomposition of the precursor are confirmed by Fourier transform infrared (FT-IR) analysis. The scanning electron microscopy (SEM) results show yield powders with the desired particle size and uniform morphologies. Particle size analysis demonstrates that the median diameter ( D 50 ) becomes stable at 750 °C. The D 50 , average surface area, pore diameter, and pore volume calculated by Brunauer -Emmett-Teller (BET) are 4.32 μm, 6.628 m 2 /g, 1.86 nm, and 0.026 cm 3 /g at 750 °C for 2 h, respectively. Moreover, loss on ignition (L.O.I.) analysis indicates that the L.O.I. is as low as 0.39%, meeting the enterprise requirement (<1%). In comparison, conventional calcination experiments are carried out in the electric furnace. Both XRD and FT-IR analyses are in consistence with thermogravimetry-differential scanning calorimetry, which indicates that the temperature required for the decomposition of praseodymium oxalate hydrate is higher than that of microwave heating. Furthermore, SEM, particle size distribution, and BET analysis indicate that agglomeration generates, particle size enlarges, and average surface area increases. In all, it is confirmed that preparing rare-earth oxides from rare-earth oxalates is feasible using microwave heating to replace conventional heating., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

Ultrasound (US)-driven sonodynamic therapy (SDT) has demonstrated wide application prospects in the eradication of deep-seated bacterial infections due to its noninvasiveness, site-confined irradiation, and high-tissue-penetrating capability. However, the ineffective accumulation of sonosensitizers at the infection site, the hypoxic microenvironment, as well as rapid depletion of oxygen during SDT greatly hamper the therapeutic efficacy of SDT. Herein, an US-switchable nanozyme system was proposed for the controllable generation of catalytic oxygen and sonosensitizer-mediated reactive oxygen species during ultrasound activation, thereby alleviating the hypoxia-associated barrier and augmenting SDT efficacy. This nanoplatform (Pd@Pt-T790) was easily prepared by bridging enzyme-catalytic Pd@Pt nanoplates with the organic sonosensitizer meso -tetra(4-carboxyphenyl)porphine (T790). It was really interesting to find that the modification of T790 onto Pd@Pt could significantly block the catalase-like activity of Pd@Pt, whereas upon US irradiation, the nanozyme activity was effectively recovered to catalyze the decomposition of endogenous H 2 O 2 into O 2 . Such "blocking and activating" enzyme activity was particularly important for decreasing the potential toxicity and side effects of nanozymes on normal tissues and has potential to realize active, controllable, and disease-loci-specific nanozyme catalytic behavior. Taking advantage of this US-switchable enzyme activity, outstanding accumulation in infection sites, as well as excellent biocompatibility, the Pd@Pt-T790-based SDT nanosystem was successfully applied to eradicate methicillin-resistant Staphylococcus aureus (MRSA)-induced myositis, and the sonodynamic therapeutic progression was noninvasively monitored by photoacoustic imaging and magnetic resonance imaging. The developed US-switchable nanoenzyme system provides a promising strategy for augmenting sonodynamic eradication of deep-seated bacterial infection actively, controllably, and precisely.

Microstructural modifications of a thermally sprayed MCrAlY bond coat subjected to high-current pulsed electron beam (HCPEB) and their relationships with thermal cycling behavior of thermal barrier coatings (TBCs) were investigated. Microstructural observations revealed that the rough surface of air plasma spraying (APS) samples was significantly remelted and replaced by many interconnected bulged nodules after HCPEB irradiation. Meanwhile, the parallel columnar grains with growth direction perpendicular to the coating surface were observed inside these bulged nodules. Substantial Y-rich Al 2 O 3 bubbles and varieties of nanocrystallines were distributed evenly on the top of the modified layer. A physical model was proposed to describe the evaporation-condensation mechanism taking place at the irradiated surface for generating such surface morphologies. The results of thermal cycling test showed that HCPEB-TBCs presented higher thermal cycling resistance, the spalling area of which after 200 cycles accounted for only 1% of its total area, while it was about 34% for APS-TBCs. The resulting failure mode, i.e., in particular, a mixed delamination crack path, was shown and discussed. The irradiated effects including compact remelted surface, abundant nanoparticles, refined columnar grains, Y-rich alumina bubbles, and deformation structures contributed to the formation of a stable, continuous, slow-growing, and uniform thermally grown oxide with strong adherent ability. It appeared to be responsible for releasing stress and changing the cracking paths, and ultimately greatly improving the thermal cycling behavior of HCPEB-TBCs.

As tumors grow, vasculature is often deficient or malformed, resulting in many localized areas of hypoxia. Cells located in these hypoxic regions exhibit an altered gene expression pattern that can significantly alter resistance to conventional anticancer treatments such as ionizing radiation and chemotherapeutic drugs. A priori knowledge of the level of hypoxia within a tumor may better guide clinical care. In an effort to create a hypoxia specific imaging agent, a ligand for the tissue hypoxia marker, carbonic anhydrase IX (CA IX), was synthesized and used as a targeting ligand to deliver an attached (99m)Tc-chelating agent. Binding of the resulting conjugates to hypoxic cancer cells was first characterized in vitro. Whole animal imaging and biodistribution studies then were performed to determine tumor specificity in vivo. Several conjugates were found to bind selectively to CA IX expressing tumors in a receptor-dependent manner. We suggest that such conjugates could prove useful in identifying hypoxic cancers and/or quantitating the level of hypoxia within a tumor.

Proof-of-principle studies in ovarian, lung, and brain cancer patients have shown that fluorescence-guided surgery can enable removal of otherwise undetectable malignant lesions, decrease the number of cancer-positive margins, and permit identification of disease-containing lymph nodes that would have normally evaded resection. Unfortunately, the current arsenal of tumor-targeted fluorescent dyes does not permit identification of all cancers, raising the need to design new tumor-specific fluorescent dyes to illuminate the currently undetectable cancers. In an effort to design a more universal fluorescent cancer imaging agent, we have undertaken to synthesize a fluorophore that could label all hypoxic regions of tumors. We report here the synthesis, in vitro binding, and in vivo imaging of a near-infrared (NIR) fluorescent dye that is targeted to carbonic anhydrase IX (CA IX), i.e., a widely accepted marker of hypoxic tissues. The low molecular weight NIR probe, named Hypoxyfluor, is shown to bind CA IX with high affinity and accumulate rapidly and selectively in CA IX positive tumors. Because nearly all human cancers contain hypoxic regions that express CA IX abundantly, this NIR probe should facilitate surgical resection of a wide variety of solid tumors.

Inspired by a surface functional monomer-directing prepolymerization system, a straightforward and effective synthesis method was first developed to prepare highly regenerate and perm-selective molecularly imprinted composite membranes of artemisinin (Ars) molecules. Attributing to the formation of the prepolymerization system, Ars molecules are attracted and bound to the membrane surface, hence promoting the growth of homogeneous and high-density molecular recognition sites on the surface of membrane materials. Afterward, a two-step-temperature imprinting procedure was carried out to prepare the novel surface functional monomer capping molecularly imprinted membranes (FMIMs). The as-prepared FMIMs not only exhibited highly adsorption capacity (11.91 mg g(-1)) but also showed an outstanding specific selectivity (imprinting factor α is 4.50) and excellent perm-selectivity ability (separation factor β is 10.60) toward Ars molecules, which is promising for Ars separation and purification.

Peptide-based therapies have emerged as one of the most promising therapeutics strategy in cancer-targeted therapy. Using our laboratory newly identified peptide TMTP1 and diphtheria toxin, we developed a new fusion protein that showed remarkable ability to target highly metastatic tumors. Fusion protein toxins were generated by fusing the first 390 amino acids of diphtheria toxin [truncated diphtheria toxin (DT390)] to different repeats of peptide TMTP1 (DT390-TMTP1, DT390-biTMTP1, and DT390-triTMTP1). Efficacies of the recombinant fusion proteins on tumor growth and metastasis were evaluated in vitro and in vivo. DT390-triTMTP1 showed the most powerful toxicity against cancer, which led to tumor growth retardation or regression and prolonged survival of human prostate cancer PC-3M-1E8 subcutaneously bearing or gastric cancer MKN-45 orthotopic nude mice. Increased TUNEL and caspase-3 staining and reduced ki67 staining in tumor cells suggested that the anticancer effects of DT390-triTMTP1 were through selectively inducing apoptosis and inhibiting proliferation of cancer cells. In a murine model of human orthotopic gastric carcinoma, DT390-biTMTP1 significantly inhibited metastases to liver and spleen, while DT390-triTMTP1 not only totally suppressed metastasis but also reduced primary tumors by 66.6%. In the biodistribution test, DT390-triTMTP1 was observed to home to tumor tissue rapidly and lasted over 48 h, with only a transient appearance in liver and kidney immediately after injection. Thus, our present study provided a novel recombinant fusion protein DT390-triTMTP1 with preferential targeting and high cytotoxicity, which may be a promising strategy for the targeted therapy of cancer metastasis.

Hydroxylated analogues of the anticancer topoisomerase I (Top1) inhibitors indotecan (LMP400) and indimitecan (LMP776) have been prepared because (1) a variety of potent Top1 poisons are known that contain strategically placed hydroxyl groups, which provides a clear rationale for incorporating them in the present case, and (2) the hydroxylated compounds could conceivably serve as synthetic standards for the identification of metabolites. Indeed, incubating LMP400 and LMP776 with human liver microsomes resulted in two major metabolites of each drug, which had HPLC retention times and mass fragmentation patterns identical to those of the synthetic standards. The hydroxylated indotecan and indimitecan metabolites and analogues were tested as Top1 poisons and for antiproliferative activity in a variety of human cancer cell cultures and in general were found to be very potent. Differences in activity resulting from the placement of the hydroxyl group are explained by molecular modeling analyses.

An enhanced photoinduced reversible switching of graphene oxide-azobenzene (GO-AZO) hybrid was investigated as a highly sensitive photoswitch. The internal short-range ordered crystalline structure of GO-AZO hybrid was advantageous to charge transfer. The AZO moieties on GO underwent a rapid trans-cis photoisomerization upon ultraviolet irradiation due to the electron interaction between AZO and GO. The GO-AZO hybrid film showed an enhanced reversible photoswitching performance with high on/off ratio of 8 and fast response time less than 500 ms. The high sensitivity of GO-AZO switch arises from the intramolecular donor-acceptor architecture with efficient charge transfer.