Lung cancer following inhalation in rodents is a major concern regarding exposure to cobalt substances. However, little information is available on adverse effects and toxicity following long-term inhalation exposure to poorly soluble cobalt substances with low bioavailability. Thus, the present study focused on pulmonary effects of the poorly soluble tricobalt tetraoxide (5, 20, 80 mg/m³) in a 28-day inhalation exposure study. Lung weights increased with increasing exposures. Bronchoalveolar lavage fluid analysis and histopathology revealed lung tissue inflammation at the mid-dose with increasing severity in the high-dose group and post-exposure persistency. Markers for cellular damage and cell proliferation were statistically significantly increased. No increase in 8-OH-dG lesions was observed, indicating an absence of oxidative DNA lesions. The primary effect of inhaled Co3O4 particles is inflammation of the respiratory tract strongly resembling responses of inhaled "inert dust" substances, with a NOAEC of 5 mg/m³ under the conditions of this test.
The potential of molybdenum substances to cause genotoxic effects has been studied previously. However, a review of existing in vitro data, including an assessment of relevance and reliability, has shown that inconsistent results have been observed in the past. To resolve the inconsistencies, new studies were performed with the highly soluble sodium molybdate dihydrate according to OECD test guidelines. In a bacterial reverse mutation assay sodium molybdate dihydrate did not induce reverse mutations in five strains of Salmonella typhimurium. No mutagenic or clastogenic effect was observed at the tk locus of L5178Y mouse lymphoma cells. In a micronucleus test in cultured human peripheral blood lymphocytes no clastogenic or aneugenic effects were seen. These results can be read across to other inorganic molybdenum substances, that all release the molybdate ion [MoO4]2- under physiological conditions as the only toxicologically relevant species. In summary, a weight of evidence assessment of all available in vitro data shows no evidence of genotoxicity of molybdenum substances.
Abstract In order to apply newly developed non‐invasive in‐situ microscope systems for the monitoring of microcarrier‐based cultivations, appropriate image analysis systems must be available. Thus a simple, but effective greyscale distribution scan algorithm was tested for the evaluation of images generated by either a standard phase‐contrast microscope or an in‐situ microscope. The images were analyzed according to their greyscale pattern in order to examine whether the greyscale distribution is a possibility to gain information about the covering ratio. The mouse fibroblast cell line (NIH–3T3) was grown on different microcarrier spheres. At first, different microcarriers were tested with respect to their suitability for microscopic observation. In a second part, the phase‐contrast pictures and in‐situ microscope pictures of the microcarrier were separately analyzed using the histogram function of CorelPhotopaint, which analyzes the greyscale distribution within the chosen area. Due to the low optical density of the polydextrin matrix, the images of Cytodex 1 microcarriers proved to be an ideal model for the image analysis. Significant differences in the greyscale distribution of this microcarrier without cells and with increased cell density were observed. Therefore a relationship between the cell density on the microcarriers and the greyscale pattern can be assumed. After automating this image analysis and calibrating the cell number/greyscale pattern relationship, it should be possible to analyze the plating efficiency/covering ratio on the microcarrier online by in‐situ microscopy.
Abstract Callystatin A is a prominent member of a class of natural products which display promising growth inhibition of cancer cells in their biological profile. The challenging structure and the interesting biological activity of (−)‐callystatin A fueled our interest in the synthesis of this marine natural product. We achieved the total synthesis using a highly convergent approach joining four subunits together with a Wittig olefination, a selective Heck reaction and an aldol reaction as the pivotal steps. The aldol reaction as one of the final transformations during the synthesis opens fast access to a variety of structural analogues and circumvents tedious protecting group manipulations. Here we report an improved synthesis utilizing a modified vinyl iodide which shortens the synthesis by two steps. Additionally, first biological results will be reported.
The total synthesis of ratjadone enables a thorough investigation of its mode of action and of structure–activity relationships. In this highly convergent approach, three subunits are joined together by a Wittig olefination and a selective Heck reaction as the pivotal steps. Diastereomeric ratjadones were synthesized by using enantiomeric subunits. They display a range of biological activities that can be correlated to their overall conformational preferences. The overlay of two diastereomers shows that the configuration at C10 induces a helix-like conformation (see picture). Supporting information for this article is available on the WWW under http://www.chembiochem.com or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
