Kinase Inhibitors of Marine Origin

Kinase Inhibitors of Marine Origi

Cu–Mn Spinel Oxide Catalyzed Regioselective Halogenation of Phenols and <i>N</i>-Heteroarenes

A novel simple, mild chemo- and regioselective method has been developed for the halogenation of phenols using Cu–Mn spinel oxide as a catalyst and <i>N</i>-halosuccinimide as halogenating agent. In the presence of Cu–Mn spinel oxide B, both electron-withdrawing and electron-donating groups bearing phenols gave monohalogenated products in good to excellent yields with highest <i>para</i>-selectivity. The <i>para</i>-substituted phenol gave monohalogenated product with good yield and <i>ortho</i>-selectivity. <i>N</i>-Heteroarenes such as indoles and imidazoles also gave monohalogenated products with high selectivity. Unlike the copper-catalyzed halogenation, the present method works well with electron-withdrawing group bearing phenols and gives comparatively better yields and selectivity. The Cu–Mn spinel catalyst is robust and reused three times under optimized conditions without any loss in catalytic activity. Nonphenolics did not undergo this transformation

Table1_Flurbiprofen inhibits heme induced NLRP3 inflammasome in Berkeley sickle cell disease mice.DOCX

Sickle cell disease (SCD) is accompanied by several complications, which emanate from the sickling of erythrocytes due to a point mutation in the β-globin chain of hemoglobin. Sickled erythrocytes are unable to move smoothly through small blood capillaries and therefore, cause vaso occlusion and severe pain. Apart from pain, continuous lysis of fragile sickled erythrocytes leads to the release of heme, which is a strong activator of the NLRP3 inflammasome, thus producing chronic inflammation in sickle cell disease. In this study, we identified flurbiprofen among other COX-2 inhibitors to be a potent inhibitor of heme-induced NLRP3 inflammasome. We found that apart from being a nociceptive agent, flurbiprofen exerts a strong anti-inflammatory effect by suppressing NF-κB signaling, which was evidenced by reduced levels of TNF-α and IL-6 in wild-type and sickle cell disease Berkeley mice models. Our data further demonstrated the protective effect of flurbiprofen on liver, lungs, and spleen in Berkeley mice. The current sickle cell disease pain management regime relies mainly on opiate drugs, which is accompanied by several side effects without modifying the sickle cell disease-related pathology. Considering the potent role of flurbiprofen in inhibiting NLRP3 inflammasome and other inflammatory cytokines in sickle cell disease, our data suggests that it can be explored further for better sickle cell disease pain management along with the possibility of disease modification.</p