Search

The synthesis and antiplasmodial evaluation of new hybrids combining the pharmacophore structures of artemisinin, ciprofloxacin or norfloxacin, and 7-chloroquinoline are reported in this study. The first step for all of the syntheses is the obtainment of key piperazine esters intermediates bearing the drugs ciprofloxacin and norfloxacin. Using these platforms, 18 final compounds were synthesized through a multistep procedure with overall yields ranging between 8 and 20%. All compounds were screened for their antiplasmodial activity against the chloroquine-resistant Plasmodium falciparum FcB1 strain. Compounds 20, 21, 22, and 28, bearing an artesunate fragment with ciprofloxacin, exhibited IC50 values in the range of 3.5–5.4 nM and excellent selectivity indices. Among the compounds bearing the artesunate moiety on the norfloxacin, two of them, 23 and 24, afforded IC50 values of 1.5 nM and 1.9 nM, respectively. They also showed excellent selectivity indices. The most potent compounds were also evaluated against the CQ-resistant Dd2 strain of Plasmodium falciparum, demonstrating that those compounds incorporating the artesunate fragment were the most potent. Finally, the combination of artesunate with either ciprofloxacin or norfloxacin moieties in a single molecular entity proved to substantially enhance the activity and selectivity when compared to the administration of the unconjugated counterparts artesunate/ciprofloxacin and artesunate/norfloxacin. [ABSTRACT FROM AUTHOR]

The application of liposomes (LPs) to central nervous system disorders could represents a turning point in the therapy and quality of life of patients. Indeed, LPs have demonstrated their ability to cross the blood– brain barrier (BBB) and, as a consequence, to enhance the therapeutics delivery into the brain. Some approaches for BBB crossing involve the modification of LP surfaces with biologically active ligands. Among them, the Apolipoprotein E-modified peptide (mApoE) has been used for several LP-based nanovectors under investigation. In this study, we propose Surface Plasmon Resonance imaging (SPRi) for the characterization of multifunctionalized LPs for Glioblastoma treatment. LPs were functionalized with mApoE and with a metallo-protease sensitive lipopeptide to deliver and guarantee the localized release of an encapsulated drug in diseased areas. The SPRi analysis was optimized in order to evaluate the binding affinity between LPs and mApoE receptors, finding that mApoE-LPs generated SPRi signals referred to interactions between mApoE and receptors mainly present in the brain. Moreover, a significant binding between LPs and VCAM-1 (endothelial receptor) was observed, whereas LPs did not interact significantly with peripheral receptors expressed on monocytes and lymphocytes. SPRi results confirmed not only the presence of mApoE on LP surfaces, but also its binding affinity, thanks to the specific interaction with selected receptors. In conclusion, the high sensitivity and the multiplexing capability associated with the low volumes of sample required and the minimal sample preparation, make SPRi an excellent technique for the characterization of multifunctionalized nanoparticles-based formulations. [ABSTRACT FROM AUTHOR]

A potent nontoxic antitumor drug, 2-hydroxyoleic acid (6, 2OHOA) used for membrane lipid therapy, was selected as a self-assembly inducer due to its ability to form nanoparticles (NPs) in water. For this purpose, it was conjugated with a series of anticancer drugs through a disulfide-containing linker to enhance cell penetration and to secure drug release inside the cell. The antiproliferative evaluation of the synthesized NP formulations against three human tumor cell lines (biphasic mesothelioma MSTO-211H, colorectal adenocarcinoma HT-29, and glioblastoma LN-229) showed that nanoassemblies 16–22a,bNPs exhibit antiproliferative activity at micromolar and submicromolar concentrations. Furthermore, the ability of the disulfide-containing linker to promote cellular effects was confirmed for most nanoformulations. Finally, 17bNP induced intracellular ROS increase in glioblastoma LN-229 cells similarly to free drug 8, and such elevated production was decreased by pretreatment with the antioxidant N-acetylcysteine. Also, nanoformulations 18bNP and 21bNP confirmed the mechanism of action of the free drugs. [ABSTRACT FROM AUTHOR]

Instabilities that develop at the contact interface of solid rollers or airless tires while in motion can lead to increased energy losses and reduced service life. This manuscript describes an instrument that can give better insight into the origin of such instabilities by monitoring both local and global roller mechanics. This is done by simultaneously obtaining force and displacement data from sensors as well as optical measurements and local deformation fields across two different planes, extracted from images taken by a high-speed camera. Multiple loading configurations are possible, ranging from static normal loading of the roller to free rolling and rolling with a propulsive or a braking torque. Instrument functions, elements, and design are presented in detail and its capabilities are demonstrated by obtaining measurements such as width of the contact interface under normal loading, strain fields of the roller sidewall and contact interface under normal loading, and the roller's resistance to motion for free and forced rolling. [ABSTRACT FROM AUTHOR]

Dehydroabietic Acid (DHA, 1) derivatives are known for their antiproliferative properties, among others. In the context of this work, DHA was initially modified to two key intermediates bearing a C18 methyl ester, a phenol moiety at C12, and an acetyl or formyl group at C13 position. These derivatives allowed us to synthesize a series of DHA-chalcone hybrids, suitable for structure–activity relationship studies (SARS), following their condensation with a variety of aryl-aldehydes and methyl ketones. The antiproliferative evaluation of the synthesized DHA-chalcone hybrids against three breast cancer cell lines (the estrogen-dependent MCF-7 and the estrogen-independent MDA-MB-231 and Hs578T) showed that eight derivatives (33, 35, 37, 38, 39, 41, 43, 44) exhibit low micromolar activity levels (IC50 2.21–11.5 μΜ/MCF-7). For instance, some of them showed better activity compared to the commercial anticancer drug 5-FU against MCF-7 cells (33, 41, 43, 44) and against MDA-MB231 (33 and 41). Hybrid 38 is a promising lead compound for the treatment of MCF-7 breast cancer, exhibiting comparable activity to 5-FU and being 12.9 times less toxic (SI = 22.7). Thus, our findings suggest that DHA-chalcone hybrids are drug candidates worth pursuing for further development in the search for novel breast cancer therapies. [ABSTRACT FROM AUTHOR]

A novel synthetic route to the chemoselectively protected N,S-ditritylglutathione monomethyl ester is described involving the chemical modification of the commercially available glutathione (GSH). The synthetic value of this building block in the facile preparation of GSH bioconjugates in a satisfying overall yield was exemplified by the case of trypanothione disulfide (TS2), a GSH-spermidine bioconjugate, involved in the antioxidative stress protection system of parasitic protozoa, such as trypanosoma and leishmania parasites. [ABSTRACT FROM AUTHOR]

We propose a methodology for performing high resolution Digital Image Correlation (DIC) analysis during high-temperature mechanical tests. Specifically, we describe a technique for producing a stable, high-quality pattern on metal surfaces along with a simple optical system that uses a visible-range camera and a long-range microscope. The results are analyzed with a high-quality open-source DIC software developed by us. Using the proposed technique, we successfully acquired high-resolution strain maps of the crack tip field in a nickel superalloy sample at 1000 ?C. [ABSTRACT FROM AUTHOR]

New, small moleculeHedgehog (Hh) pathway inhibitors, such as thefuranoditerpenoid taepeenin D, are of high medicinal importance. Toestablish key structure–activity relationships (SARs) for thislead, a synthetic sequence has been developed for the expedient preparationof several derivatives and their evaluation as Hh inhibitors exploitingits structural similarity to abietic acid. While C(14) substitutionis not essential for biological activity, the presence of a hydrogenbond acceptor at C(6) and an intact benzofuran moiety are. [ABSTRACT FROM AUTHOR]

Nanoindentation is used to assess mechanical properties of ordered mesoporous titania thin films with pore sizes in the range of 8-16 nm. Estimates of strut properties are obtained under the standard scaling assumptions widely used in porous media. The inferred hardness and fracture toughness of individual struts are found to correspond to anatase titania, indicating the absence of obvious size effects in the nanostructured ceramic. This is in marked contrast to nanoporous metals, where size effects often play a crucial role in determining material properties at similar length scales. [ABSTRACT FROM AUTHOR]

We synthesize nanoporous copper (NP Cu) through electrochemical dealloying of amorphous Cu0.41Si0.59 under compressive residual stress. Transmission Electron Microscopy reveals that struts are nanocrystalline with grain size equal to the strut thickness. Moreover, a significant population of twins with spacing ∼7 nm is present within each imaged grain. The hardness of this nanocrystalline, nanotwinned NP Cu is approximately one order of magnitude greater than reports on NP Cu in the literature. The yield strength of individual struts inferred through dimensional analysis is approximately an order of magnitude greater than bulk copper and compares well with other nanostructured copper systems. [ABSTRACT FROM AUTHOR]

We report on the strength of Al–Al interfaces and the effects of chemical segregation and interfacial void formation on bond strength using microcantilever bend testing. Interfaces are synthesised via hot isostatic pressing. Microcantilevers of several nominal dimensions were fabricated via focused ion beam and deformed in a nanoindenter. We find increased cantilever strength as a function of decreasing sample size, with a linear dependence of the yield strength on the inverse square root of the length scale characteristic to the cantilever cross-section. The presence of pores and chemical segregation decreases the yield strength of the material by 17% and the accommodated strain energy by 10–15% for strain values in the 6–12% range. [ABSTRACT FROM PUBLISHER]

Nanoporous metal foams synthesized by dealloying inherently undergo dimensional changes (shrinkage). If these changes are unaccounted for in the measurement of relative density, this can be underestimated, causing up to an order of magnitude error in weight-normalized properties. In constrained samples the shrinkage leads to build-up of tensile stress that modifies the porosity and may lead to crack formation. A relationship between shrinkage, relative density and atomic fraction is proposed and experimentally verified. [ABSTRACT FROM AUTHOR]

We examine the influence of electrochemical parameters on transversely isotropic nanoporous (NP) platinum foam synthesized from amorphous PtxSi1−x by dealloying. The externally applied potential controls the size of the Voronoi polyhedra on the free surface with sizes ranging from 0.01–0.35μm2. The shape of the amperometric curve is governed by the dealloying front progression that in turn advances faster than the rate of diffusion of Si in the electrolyte. [Copyright &y& Elsevier]

We synthesize nanoporous platinum (np-Pt) through electrochemical dealloying in aqueous HF from cosputtered PtxSi1-x amorphous films for different initial composition and sputter bias conditions. We demonstrate that, in addition to the expected isotropic open cell np-Pt foam, anisotropic (columnar and Voronoi) np-Pt is obtained. There are two levels of anisotropy: on the micron scale, 100 nm columns or 1 μm Voronoi polygons form. Inside the columnar and Voronoi hyperstructures, the ligaments and pores are anisotropic ranging from 5 to 25 nm. The ligament diameter and grain size is 5 nm for all reported structures. A processing-structure map is developed that correlate np-Pt structures to processing conditions. [ABSTRACT FROM AUTHOR]

Malaria, despite many efforts, remains among the most problematic infectious diseases worldwide, mainly due to the development of drug resistance by Plasmodium falciparum. The antibiotic fosmidomycin (FSM) is also known for its antimalarial activity by targeting the non-mevalonate isoprenoid synthesis pathway, which is essential for the malaria parasites but is absent in mammalians. In this study, we synthesized and evaluated against the chloroquine-resistant P. falciparum FcB1/Colombia strain, a series of FSM analogs, derivatives, and conjugates with other antimalarial agents, such as artemisinin (ART) and aminochloroquinoline (ACQ). The biological evaluation revealed four new compounds with higher antimalarial activity than FSM: two FSM-ACQ derivatives and two FSM-ART conjugates, with 3.5–5.4 and 41.5–23.1 times more potent activities than FSM, respectively. [ABSTRACT FROM AUTHOR]

Pimasertib, a potent antiproliferative drug, has been extensively studied for treating cancers characterized by dysregulation in the ERK/MAPK signaling pathway, such as melanoma. However, its therapeutic efficacy would greatly benefit from an increased selectivity for tumour cells and a longer half-life. Such improvements may be achieved by combining the rational design of a prodrug with its encapsulation in a potential nanodelivery system. For this reason, we synthesized a glutathione (GSH)-responsive putative prodrug of pimasertib (PROPIMA), which contains a redox-sensitive disulphide linker that can be processed by GSH to activate pimasertib. The synthesis of PROPIMA and its in vitro biological activity on a human melanoma cell line as a model are described. The results showed that PROPIMA, either free or embedded in liposomes, selectively inhibits cell proliferation and cell viability, reducing by about 5-fold the levels of pERK. Additionally, PROPIMA shows stronger inhibition of the cancer cell migration than the parent drug., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Dual functionalized liposomes were developed to cross the blood−brain barrier (BBB) and to release their cargo in a pathological matrix metalloproteinase (MMP)-rich microenvironment. Liposomes were surface-functionalized with a modified peptide deriving from the receptor-binding domain of apolipoprotein E (mApoE), known to promote cargo delivery to the brain across the BBB in vitro and in vivo; and with an MMP-sensitive moiety for an MMP-triggered drug release. Different MMP-sensitive peptides were functionalized at both ends with hydrophobic stearate tails to yield MMP-sensitive lipopeptides (MSLPs), which were assembled into mApoE liposomes. The resulting bi-functional liposomes (i) displayed a < 180 nm diameter with a negative ζ-potential; (ii) were able to cross an in vitro BBB model with an endothelial permeability of 3 ± 1 × 10−5 cm/min; (iii) when exposed to functional MMP2 or 9, efficiently released an encapsulated fluorescein dye; (iv) showed high biocompatibility when tested in neuronal cultures; and (v) when loaded with glibenclamide, a drug candidate with poor aqueous solubility, reduced the release of proinflammatory cytokines from activated microglial cells.

Cell membranes perform important biological roles including compartmentalization, signaling, and transport of nutrients. Supported lipid membranes mimic the behavior of cell membranes and are an important model tool for studying membrane properties in a controlled laboratory environment. Lipid membranes may be supported on solid substrates; however, protein and lipid interactions with the substrate typically result in their denaturation. In this report, we demonstrate the formation of intact lipid membranes tethered on nanoporous metal thin films obtained via a dealloying process. Uniform lipid membranes were formed when the surface defect density of the nanoporous metal film was significantly reduced through a two-step dealloying process reported here. We show that the tethered lipid membranes on nanoporous metal substrates maintain both fluidity and electrical resistivity, which are key attributes to naturally occurring lipid membranes. The lipid assemblies supported on nanoporous metals provide a new platform for investigating lipid membrane properties, and potentially membrane proteins, for numerous applications including next generation biosensor platforms, targeted drug-delivery, and energy harvesting devices.