Osmium Models of Intermediates Involved in Catalytic Reactions of Alkylidenecyclopropanes

The complex [OsCp­{κ³-<i>P</i>,<i>C</i>,<i>C</i>-PⁱPr₂[C­(CH₃)CH₂]}­(CH₃CN)]­PF₆ (<b>1</b>) reacts with (2-pyridyl)­methylenecyclopropane, at room temperature, to give initially the cyclobutylidene derivative [Os­(η⁵-C₅H₅)­(CCH₂CH₂CH-<i>o</i>-C₅H₄N)­{PⁱPr₂[C­(Me)CH₂]}]­PF₆ (<b>2</b>), as a result of the ring expansion of the alkylidenecyclopropane unit. Over time complex <b>2</b> rearranges into the cyclobutene derivative [Os­(η⁵-C₅H₅)­{η²-C­(CHCH₂CH₂)-<i>o</i>-C₅H₄N}­{PⁱPr₂[C­(Me)CH₂]}]­PF₆ (<b>3</b>). The reaction of <b>1</b> with (2-pyridyl)­methylenecyclopropane at room temperature also affords the phosphinomethanide metallacycle [Os­(η⁵-C₅H₅)­{κ⁴-<i>P</i>,<i>C</i>^a,<i>C</i>^b,<i>N</i>-PⁱPr₂[C^a(Me)­CH₂CH)­(C^bCH₂CH₂-<i>o</i>-C₅H₄N]}]­PF₆ (<b>4</b>) as a minor product, which becomes the major product of the reaction at 45 °C. This osmacyclopentane results from the C–C coupling of the isopropenyl substituent of the phosphine ligand and the organic substrate. In acetone at 75 °C, the reaction of <b>1</b> with (2-pyridyl)­methylenecyclopropane leads to the 2-alkylidene-1-osmacyclobutane [Os­(η⁵-C₅H₅)­{κ³-<i>N</i>,<i>C</i>^a,<i>C</i>^b-C^a(CH₂C^bH₂)­(CH-<i>o</i>-C₅H₄N)}­{PⁱPr₂[C­(Me)CH₂]}]­PF₆ (<b>5</b>), as a consequence of the oxidative addition of one of the C­(sp²)–C­(sp³) bonds of the cyclopropane unit of the substrate to the osmium atom, along with <b>6</b>, a diastereomer of <b>4</b>. Complexes <b>3</b>–<b>5</b> have been characterized by X-ray diffraction analysis. DFT calculations suggest that all of the reaction products are derived from a common key 1-osma-2-azacyclopent-3-ene intermediate (<b>D</b>)

Osmium Models of Intermediates Involved in Catalytic Reactions of Alkylidenecyclopropanes

The complex [OsCp­{κ³-<i>P</i>,<i>C</i>,<i>C</i>-PⁱPr₂[C­(CH₃)CH₂]}­(CH₃CN)]­PF₆ (<b>1</b>) reacts with (2-pyridyl)­methylenecyclopropane, at room temperature, to give initially the cyclobutylidene derivative [Os­(η⁵-C₅H₅)­(CCH₂CH₂CH-<i>o</i>-C₅H₄N)­{PⁱPr₂[C­(Me)CH₂]}]­PF₆ (<b>2</b>), as a result of the ring expansion of the alkylidenecyclopropane unit. Over time complex <b>2</b> rearranges into the cyclobutene derivative [Os­(η⁵-C₅H₅)­{η²-C­(CHCH₂CH₂)-<i>o</i>-C₅H₄N}­{PⁱPr₂[C­(Me)CH₂]}]­PF₆ (<b>3</b>). The reaction of <b>1</b> with (2-pyridyl)­methylenecyclopropane at room temperature also affords the phosphinomethanide metallacycle [Os­(η⁵-C₅H₅)­{κ⁴-<i>P</i>,<i>C</i>^a,<i>C</i>^b,<i>N</i>-PⁱPr₂[C^a(Me)­CH₂CH)­(C^bCH₂CH₂-<i>o</i>-C₅H₄N]}]­PF₆ (<b>4</b>) as a minor product, which becomes the major product of the reaction at 45 °C. This osmacyclopentane results from the C–C coupling of the isopropenyl substituent of the phosphine ligand and the organic substrate. In acetone at 75 °C, the reaction of <b>1</b> with (2-pyridyl)­methylenecyclopropane leads to the 2-alkylidene-1-osmacyclobutane [Os­(η⁵-C₅H₅)­{κ³-<i>N</i>,<i>C</i>^a,<i>C</i>^b-C^a(CH₂C^bH₂)­(CH-<i>o</i>-C₅H₄N)}­{PⁱPr₂[C­(Me)CH₂]}]­PF₆ (<b>5</b>), as a consequence of the oxidative addition of one of the C­(sp²)–C­(sp³) bonds of the cyclopropane unit of the substrate to the osmium atom, along with <b>6</b>, a diastereomer of <b>4</b>. Complexes <b>3</b>–<b>5</b> have been characterized by X-ray diffraction analysis. DFT calculations suggest that all of the reaction products are derived from a common key 1-osma-2-azacyclopent-3-ene intermediate (<b>D</b>)

Structure–Activity Relationship of a New Series of Reversible Dual Monoacylglycerol Lipase/Fatty Acid Amide Hydrolase Inhibitors

The two endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), play independent and nonredundant roles in the body. This makes the development of both selective and dual inhibitors of their inactivation an important priority. In this work we report a new series of inhibitors of monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH). Among them, (±)-oxiran-2-ylmethyl 6-(1,1′-biphenyl-4-yl)­hexanoate (<b>8</b>) and (2<i>R</i>)-(−)-oxiran-2-ylmethyl­(4-benzylphenyl)­acetate (<b>30</b>) stand out as potent inhibitors of human recombinant MAGL (IC₅₀ (<b>8</b>) = 4.1 μM; IC₅₀ (<b>30</b>) = 2.4 μM), rat brain monoacylglycerol hydrolysis (IC₅₀ (<b>8</b>) = 1.8 μM; IC₅₀ (<b>30</b>) = 0.68 μM), and rat brain FAAH (IC₅₀ (<b>8</b>) = 5.1 μM; IC₅₀ (<b>30</b>) = 0.29 μM). Importantly, and in contrast to the other previously described MAGL inhibitors, these compounds behave as reversible inhibitors either of competitive (<b>8</b>) or noncompetitive nature (<b>30</b>). Hence, they could be useful to explore the therapeutic potential of reversible MAGL inhibitors

New Synthetic Inhibitors of Fatty Acid Synthase with Anticancer Activity

Fatty acid synthase (FASN) is a lipogenic enzyme that is highly expressed in different human cancers. Here we report the development of a new series of polyphenolic compounds <b>5</b>–<b>30</b> that have been evaluated for their cytotoxic capacity in SK-Br3 cells, a human breast cancer cell line with high FASN expression. The compounds with an IC₅₀ < 50 μM have been tested for their ability to inhibit FASN activity. Among them, derivative <b>30</b> blocks the 90% of FASN activity at low concentration (4 μM), is highly cytotoxic in a broad panel of tumor cells, induces apoptosis, and blocks the activation of HER2, AKT, and ERK pathways. Remarkably, <b>30</b> does not activate carnitine palmitoyltransferase-1 (CPT-1) nor induces in mice weight loss, which are the main drawbacks of other previously described FASN inhibitors. Thus, FASN inhibitor <b>30</b> may aid the validation of this enzyme as a therapeutic target for the treatment of cancer

Development of a Fluorescent Bodipy Probe for Visualization of the Serotonin 5‑HT_1A Receptor in Native Cells of the Immune System

Serotonin (5-HT) modulates key aspects of the immune system. However, its precise function and the receptors involved in the observed effects have remained elusive. Among the different serotonin receptors, 5-HT_1A plays an important role in the immune system given its presence in cells involved in both the innate and adaptive immune responses, but its actual levels of expression under different conditions have not been comprehensively studied due to the lack of suitable tools. To further clarify the role of 5-HT_1A receptor in the immune system, we have developed a fluorescent small molecule probe that enables the direct study of the receptor levels in native cells. This probe allows direct profiling of the receptor expression in immune cells using flow cytometry. Our results show that important subsets of immune cells including human monocytes and dendritic cells express functional 5-HT_1A and that its activation is associated with anti-inflammatory signaling. Furthermore, application of the probe to the experimental autoimmune encephalomyelitis model of multiple sclerosis demonstrates its potential to detect the specific overexpression of the 5-HT_1A receptor in CD4+ T cells. Accordingly, the probe reported herein represents a useful tool whose use can be extended to study the levels of 5-HT_1A receptor in ex vivo samples of different immune system conditions

New Inhibitors of Angiogenesis with Antitumor Activity in Vivo

Angiogenesis is a requirement for the sustained growth and proliferation of solid tumors, and the development of new compounds that induce a sustained inhibition of the proangiogenic signaling generated by tumor hypoxia still remains as an important unmet need. In this work, we describe a new antiangiogenic compound (<b>22</b>) that inhibits proangiogenic signaling under hypoxic conditions in breast cancer cells. Compound <b>22</b> blocks the MAPK pathway, impairs cellular migration under hypoxic conditions, and regulates a set of genes related to angiogenesis. These responses are mediated by HIF-1α, since the effects of compound <b>22</b> mostly disappear when its expression is knocked-down. Furthermore, administration of compound <b>22</b> in a xenograft model of breast cancer produced tumor growth reductions ranging from 46 to 55% in 38% of the treated animals without causing any toxic side effects. Importantly, in the responding tumors, a significant reduction in the number of blood vessels was observed, further supporting the mechanism of action of the compound. These findings provide a rationale for the development of new antiangiogenic compounds that could eventually lead to new drugs suitable for the treatment of some types of tumors either alone or in combination with other agents

Search for scalar leptoquarks in pp\mathit{pp} collisions at s=13\sqrt{s}=13 TeV with the ATLAS experiment

An inclusive search for a new-physics signature of lepton-jet resonances has been performed by the ATLAS experiment. Scalar leptoquarks, pair-produced in pp collisions at s√ = 13 TeV at the large hadron collider, have been considered. An integrated luminosity of 3.2 fb(−)(1), corresponding to the full 2015 dataset was used. First (second) generation leptoquarks were sought in events with two electrons (muons) and two or more jets. The observed event yield in each channel is consistent with Standard Model background expectations. The observed (expected) lower limits on the leptoquark mass at 95% confidence level are 1100 and 1050 GeV (1160 and 1040 GeV) for first and second generation leptoquarks, respectively, assuming a branching ratio into a charged lepton and a quark of 100%. Upper limits on the aforementioned branching ratio are also given as a function of leptoquark mass. Compared with the results of earlier ATLAS searches, the sensitivity is increased for leptoquark masses above 860 GeV, and the observed exclusion limits confirm and extend the published results