Syntheses of conformationally constricted molecules as potential NAALADase/PSMA inhibitors

Two six-membered ring targeted analogues of PSMA inhibitors (4a and 4b) were designed on the basis of a computational analysis and synthesized. (E,Z)-Diene 10 was subjected to the nitroso Diels-Alder reaction to give the 1,4-trans six-membered ring adduct, 4a. The cis isomer 4b was derived from similar nitroso cycloaddition reactions with the corresponding (E,E)-diene and separately from cyclohexadiene. The IC(50) values of 4a and 4b in a NAALADase assay were found to be 0.9 and 0.1 microM, respectively. [reaction: see text]     

Preparation,X-ray structure and reactivity of a stable glycosyl iodide

Highly selective reaction of methyl tetra-O-pivaloyl-beta-D-glucopyranuronate 2 with iodotrimethylsilane or (Me3Si)2 and I2 affords, in excellent yield, the 'disarmed' glycosyl iodide 1 which has good stability at 20 degrees C and excellent stability at 0 degrees C; the X-ray crystal structure of 1 is described, along with a comparison of its utility as a glycosyl donor to that of the corresponding bromide.     

Synthesis, aggregation and cellular investigations of porphyrin-cobaltacarborane conjugates

A new series of porphyrin-cobaltacarborane conjugates (1-5) that contain four to sixteen carborane clusters per porphyrin macrocycle, were prepared in excellent yields (90-97 %) by means of a ring-opening reaction of the zwitterionic cobaltacarborane [3,3'-Co(8-C(4)H(8)O(2-)-1,2-C(2)B(9)H(10))(1',2'-C(2)B(9)H(11))]. The X-ray structure of one conjugate (3) is presented. The aggregation properties of these conjugates were investigated by using absorption and fluorescence spectrophotometry, and the stages of microcrystal formation were captured by using atomic force microscopy. All conjugates were found to aggregate in aqueous solutions, to form a broad dispersity of particle sizes. The cellular uptake, cytotoxicity, and preferential sites of subcellular localization of this series of conjugates were evaluated in human carcinoma HEp2 cells. The extent of conjugate cellular uptake depends on the number of cobaltacarborane units at the porphyrin periphery, their distribution, and the conjugate aggregation behavior. Conjugates 2 and 4, bearing either two adjacent or three 3,5-dicobaltacarboranephenyl groups, accumulated the most within HEp2 cells and are, therefore, the most promising boron neutron capture therapy agents. All conjugates showed very low dark- and photo-toxicity, probably due to their strong tendency for aggregation in aqueous solutions, and localized subcellularly within vesicles that correlated, to some extent, with the cell lysosomes.     

Synthesis and Preliminary Biological Evaluation of Novel Functionalised Poly(ethylene glycol)‐block‐poly(ester‐carbonate) Copolymers as Biodegradable Polymeric Carriers

Polymer conjugates of anticancer drugs containing bound active moieties are used to improve pharmacokinetics by prolonging antitumour activity and decreasing protein immunogenicity. The first generation of polymer conjugates, N‐(2‐hydroxylpropyl)methacrylamide copolymer or poly(ethylene glycol) conjugates, cannot be considered optimised since their polymer chain lacks biodegradability. The polymeric system proposed here is based on high molecular weight water‐soluble functionalised polyesters containing fumarate or maleate units linked by poly(ethylene glycol) segments by means of carbonate bonds. It shows the following features: a) high molecular weight; b) biodegradable backbone (rate of degradation was determined viscometrically in vitro, under conditions mimicking physiological conditions and c) water solubility. Also the biocompatibility of the polymer and its precursors were assessed using a B16F10 murine melanoma cell line and a haemolysis assay.     

Non-edible babassu oil as a new source for energy production–a feasibility transesterification survey assisted by ultrasound

Ethyl esters of babassu oil were synthesized by alkaline catalysis to make the green production of biodiesel feasible with simple methods and available technology. Babassu oil is a transparent, light yellow oil extracted from the seeds of the babassu palm (Orbinya sp), and due to its high saturated fatty acid composition (83%), it is considered a non-inedible oil. Transesterification using ethanol represents a valid alternative to using methanol because of ethanol’s lower toxicity and the higher yield on weight compared to methanol. Statistical methodology was applied to optimize the transesterification reaction, which was promoted by ultrasonic waves and mechanical agitation. Nuclear magnetic resonance spectroscopy was used to quantify the conversion attained. Alkaline transesterification assisted by ultrasound produced the best results with respect to reaction time and the phase separation step. The model obtained showed that conversions higher than 97% may be achieved in 10 min with correct tuning of the process variables.     

Cytotoxicity of Bacterial-Derived Toxins to Immortal Lung Epithelial and Macrophage Cells

Health risks associated with inhalation and deposition of biological materials have been a topic of great concern due to highly publicized cases of inhalation anthrax, of new regulations on the release of particulate matter, and to increased concerns on the hazards of indoor air pollution. Here, we present an evaluation of the sensitivity of two immortal cell lines (A549, human lung carcinoma epithelia) and NR8383 (rat alveolar macrophages) to a variety of bacterial-derived inhalation hazards and simulants including etoposide, gliotoxin, streptolysin O, and warfarin. The cell response is evaluated through quantification of changes in mitochondrial succinate dehydrogenase activity, release of lactate dehydrogenase, initiation of apoptosis, and through changes in morphology as determined by visible light microscopy and scanning electron microscopy. These cells display dose–response relations to each toxin, except for triton which has a step change response. The first observable responses of the epithelial cells to these compounds are changes in metabolism for one toxin (warfarin) and alterations in membrane permeability for another (gliotoxin). The other four toxins display a similar time course in response as gauged by changes in metabolism and loss of membrane integrity. Macrophages are more sensitive to most toxins; however, they display a lower level of stability. This information can be used in the design of cell-based sensors responding to these and similar hazards.     

Trouble-shooting deployment and recovery options for various stationary passive acoustic monitoring devices in both shallow- and deep-water applications

Deployment of any type of measuring device into the ocean, whether to shallow or deeper depths, is accompanied by the hope that this equipment and associated data will be recovered. The ocean is harsh on gear. Salt water corrodes. Currents, tides, surge, storms, and winds collaborate to increase the severity of the conditions that monitoring devices will endure. All ocean-related research has encountered the situations described in this paper. In collating the details of various deployment and recovery scenarios related to stationary passive acoustic monitoring use in the ocean, it is the intent of this paper to share trouble-shooting successes and failures to guide future work with this gear to monitor marine mammal, fish, and ambient (biologic and anthropogenic) sounds in the ocean-in both coastal and open waters.     

Level-dependent changes in detection of temporal gaps in noise markers by adults with normal and impaired hearing

Compression in the basilar-membrane input-output response flattens the temporal envelope of a fluctuating signal when more gain is applied to lower level than higher level temporal components. As a result, level-dependent changes in gap detection for signals with different depths of envelope fluctuation and for subjects with normal and impaired hearing may reveal effects of compression. To test these assumptions, gap detection with and without a broadband noise was measured with 1,?000-Hz-wide (flatter) and 50-Hz-wide (fluctuating) noise markers as a function of marker level. As marker level increased, background level also increased, maintaining a fixed acoustic signal-to-noise ratio (SNR) to minimize sensation-level effects on gap detection. Significant level-dependent changes in gap detection were observed, consistent with effects of cochlear compression. For the flatter marker, gap detection that declines with increases in level up to mid levels and improves with further increases in level may be explained by an effective flattening of the temporal envelope at mid levels, where compression effects are expected to be strongest. A flatter effective temporal envelope corresponds to a reduced effective SNR. The effects of a reduction in compression (resulting in larger effective SNRs) may contribute to better-than-normal gap detection observed for some hearing-impaired listeners.     

Nanostructures of functionalized gold nanoparticles prepared by particle lithography with organosilanes

Periodic arrays of organosilane nanostructures were prepared with particle lithography to define sites for selective adsorption of functionalized gold nanoparticles. Essentially, the approach for nanoparticle lithography consists of procedures with two masks. First, latex mesospheres were used as a surface mask for deposition of an organosilane vapor, to produce an array of holes within a covalently bonded, organic thin film. The latex particles were readily removed with solvent rinses to expose discrete patterns of nanosized holes of uncovered substrate. The nanostructured film of organosilanes was then used as a surface mask for a second patterning step, with immersion in a solution of functionalized nanoparticles. Patterned substrates were fully submerged in a solution of surface-active gold nanoparticles coated with 3-mercaptopropyltrimethoxysilane. Regularly shaped, nanoscopic areas of bare substrate produced by removal of the latex mask provided sites to bind silanol-terminated gold nanoparticles, and the methyl-terminated areas of the organosilane film served as an effective resist, preventing nonspecific adsorption on masked areas. Characterizations with atomic force microscopy demonstrate the steps for lithography with organosilanes and functionalized nanoparticles. Patterning was accomplished for both silicon and glass substrates, to generate nanostructures with periodicities of 200-300 nm that match the diameters of the latex mesospheres of the surface masks. Nanoparticles were shown to bind selectively to uncovered, exposed areas of the substrate and did not attach to the methyl-terminal groups of the organosilane mask. Billions of well-defined nanostructures of nanoparticles can be generated using this high-throughput approach of particle lithography, with exquisite control of surface density and periodicity at the nanoscale.