Synthesis of novel structural hybrids between aza-heterocycles and azelaic acid moiety with a specific activity on osteosarcoma cells

Nine compounds bearing pyridinyl (or piperidinyl, benzimidazolyl, benzotriazolyl) groups bound to an azelayl moiety through an amide bond were synthesized. The structural analogy with some histone deacetylase inhibitors inspired their syntheses, seeking new selective histone deacetylase inhibitors (HDACi). The azelayl moiety recalls part of 9-hydroxystearic acid, a cellular lipid showing antiproliferative activity toward cancer cells with HDAC as a molecular target. Azelayl derivatives bound to a benzothiazolyl moiety further proved to be active as HDACi. The novel compounds were tested on a panel of both normal and tumor cell lines. Non-specific induction of cytotoxicity was observed in the normal cell line, while three of them induced a biological effect only on the osteosarcoma (U2OS) cell line. One of them induced a change in nuclear shape and size. Cell-cycle alterations are associated with post-transcriptional modification of both H2/H3 and H4 histones. In line with recent studies, revealing unexpected HDAC7 function in osteoclasts, molecular docking studies on the active molecules predicted their proneness to interact with HDAC7. By reducing side effects associated with the action of the first-generation inhibitors, the herein reported compounds, thus, sound promising as selective HDACi

In Vivo Mapping of Vascular Inflammation Using Multimodal Imaging

Plaque vulnerability to rupture has emerged as a critical correlate to risk of adverse coronary events but there is as yet no clinical method to assess plaque stability in vivo. In the search to identify biomarkers of vulnerable plaques an association has been found between macrophages and plaque stability--the density and pattern of macrophage localization in lesions is indicative of probability to rupture. In very unstable plaques, macrophages are found in high densities and concentrated in the plaque shoulders. Therefore, the ability to map macrophages in plaques could allow noninvasive assessment of plaque stability. We use a multimodality imaging approach to noninvasively map the distribution of macrophages in vivo. The use of multiple modalities allows us to combine the complementary strengths of each modality to better visualize features of interest. Our combined use of Positron Emission Tomography and Magnetic Resonance Imaging (PET/MRI) allows high sensitivity PET screening to identify putative lesions in a whole body view, and high resolution MRI for detailed mapping of biomarker expression in the lesions.Macromolecular and nanoparticle contrast agents targeted to macrophages were developed and tested in three different mouse and rat models of atherosclerosis in which inflamed vascular plaques form spontaneously and/or are induced by injury. For multimodal detection, the probes were designed to contain gadolinium (T1 MRI) or iron oxide (T2 MRI), and Cu-64 (PET). PET imaging was utilized to identify regions of macrophage accumulation; these regions were further probed by MRI to visualize macrophage distribution at high resolution. In both PET and MR images the probes enhanced contrast at sites of vascular inflammation, but not in normal vessel walls. MRI was able to identify discrete sites of inflammation that were blurred together at the low resolution of PET. Macrophage content in the lesions was confirmed by histology.The multimodal imaging approach allowed high-sensitivity and high-resolution mapping of biomarker distribution and may lead to a clinical method to predict plaque probability to rupture

Chocolate consumers and lymphocyte-to-monocyte ratio: a working hypothesis from a preliminary report of a pilot study in celiac subjects

Background and aim: The aim of this work was to evaluate the relationship between platelet-to-lymphocyte ratio (PLR) and lymphocyte-to-monocyte ratio (LMR) with habitual consumption of dark chocolate in a group of celiac subjects in which chocolate consumption and lower neutrophil-to-lymphocyte ratio (NLR) association had already been observed. Additionally, due to the known anti-nutrient effect on iron absorption, we evaluated red blood cell count (RBC), mean corpuscular volume (MCV) and hemoglobin (Hb) values. Methods: Chocolate consumers and non-consumers were matched for sex, menopausal status, NLR values over the previously suggested cut off (2.32) for celiac patients, and co-morbidities. Results: Chocolate consumers had high LMR compared to non-consumers, whereas no differences were observed between chocolate consumers and non-consumers in RBC, MCV, Hb and PLR. However, similar number of subjects had PLR higher than the previously suggested cut off (143.7) for celiac disease. Conclusions: This preliminary report suggests a working hypothesis for larger studies aimed at establishing cut off values for LMR in celiac patients and the modulation of this marker by dietary antioxidants

Fluorous dienophiles are powerful diene scavengers in diels-alder reactions

(Matrix presented) Three fluorous dienophiles have been synthesized, and their value in scavenging an excess diene after Diels-Alder reactions is shown. The resulting fluorous derivatives are separated by solid-phase extraction on fluorous silica gel (FSPE). The fluorous [1,2,4]triazoline-3,5-dione 10 reacted with most dienes within seconds or minutes