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