Synthesis of Spirocyclic Pyrrolidine Compounds via Silver-Catalyzed Asymmetric [3 + 2] Cycloaddition Reaction of Imino Esters with α-Alkylidene Succinimides.

In this study, the AgOAc/ThioClickFerrophos (TCF) complex was used to successfully catalyze asymmetric [3 + 2] cycloaddition between glycine imino esters and CO2Me-appended α-alkylidene succinimides to afford spiropyrrolidines in good yields with high diastereo- and enantioselectivities (up to 95% ee). The silver/TCF afforded endo-(2,5-cis) cycloadducts in contrast to the previous exo'-(2,5-trans) selective reaction with ylidene-2,3-dioxopyrrolidine. A wide variety of imino esters bearing electron-donating and electron-withdrawing groups on the phenyl groups and heteroaryl substrates were utilized in this reaction. The scope of α-alkylidene succinimides was investigated, which revealed that substituents on α-benzylidene derivatives had negligible effect on the product yield and stereoselectivity, and α-alkylidene derivatives could be efficiently used as dipolarophiles.

Silver/ThioClickFerrophos-Catalyzed 1,3-Dipolar Cycloaddition and Tandem Addition-Elimination Reaction of Morita-Baylis-Hillman Adducts.

The asymmetric 1,3-dipolar cycloaddition of glycine imino esters to Morita-Baylis-Hillman (MBH) adducts or acetylated MBH adducts is described. The reaction was efficiently catalyzed by AgOAc/(R,Sp)-ThioClickFerrophos at room temperature to afford pyrrolidine derivatives bearing a quaternary carbon as a single diastereomer with excellent enantioselectivity. When a cyclic pyrroline ester was used as the nucleophile instead of a glycine imino ester, the enantioselective tandem addition-elimination reaction with an acetylated MBH adduct proceeded with an excellent yield and enantioselectivity, resulting in the formation of an exo-olefin. The wide substrate scope of these reactions and the transformability of the products enable expeditious access to divergent multifunctionalized pyrrolidines in an optically pure fashion.

Down-regulation of astrocytic sonic hedgehog by activation of endothelin ETB receptors: Involvement in traumatic brain injury-induced disruption of blood brain barrier in a mouse model.

In the adult brain, sonic hedgehog acts on cerebral microvascular endothelial cells to stabilize the blood-brain barrier. The expression of sonic hedgehog by astrocytes is altered during brain injury, and this change has been shown to affect permeability of blood-brain barrier. However, much remains unknown about the regulation of astrocytic sonic hedgehog production. Our results showed that endothelin-1 reduced sonic hedgehog mRNA expression and extracellular protein release in mouse cerebral cultured astrocytes, but had no effect in bEnd.3, a mouse brain microvascular endothelial-derived cell line. The effect of endothelin-1 on astrocyte sonic hedgehog expression was suppressed by an ETB antagonist BQ788, but was unchanged by the ETA antagonist FR139317. In cultured astrocytes and bEnd.3, endothelin-1 did not affect the expression of the sonic hedgehog receptor-related molecules, patched-1 and smoothened. In an animal model of traumatic brain injury, fluid percussion injury on the mouse cerebrum increased the expression of sonic hedgehog, patched-1, and smoothened. Repeated administration of BQ788 enhanced sonic hedgehog expression at 5 days after fluid percussion injury. Histochemical examination revealed sonic hedgehog expression in glial fibrillary acidic protein-positive astrocytes in the cerebrum after fluid percussion injury. Administration of exogenous sonic hedgehog and BQ788 suppressed Evans blue extravasation, an indicator of blood vessel permeability, induced by fluid percussion injury. The effects of BQ788 on fluid percussion injury-induced Evans blue extravasation were reduced by the administration of jervine, a sonic hedgehog inhibitor. Altogether, these results suggest that endothelin-1 down-regulates astrocytic sonic hedgehog to promote disruption of the blood-brain barrier during traumatic brain injury.

Endothelin receptor antagonists alleviate blood-brain barrier disruption and cerebral edema in a mouse model of traumatic brain injury: A comparison between bosentan and ambrisentan.

Traumatic brain injury (TBI) is induced by the immediate physical disruption of brain tissue. TBI causes disruption of the blood-brain barrier (BBB) and brain edema. In the cerebrospinal fluid (CSF) of TBI patients, endothelin-1 (ET-1) is increased, suggesting that ET-1 aggravates TBI-induced brain damage. In this study, the effect of bosentan (ETA/ETB antagonist) and ambrisentan (ETA antagonist) on BBB dysfunction and brain edema were examined in a mouse model of TBI using lateral fluid percussion injury (FPI). FPI to the mouse cerebrum increased the expression levels of ET-1 and ETB receptors. Administration of bosentan (3 or 15 mg/kg/day) and ambrisentan (0.1 or 0.5 mg/kg/day) at 6 and 24 h after FPI ameliorated BBB disruption and cerebral brain edema. Delayed administration of bosentan from 2 days after FPI also reduced BBB disruption and brain edema, while ambrisentan had no significant effects. FPI-induced expression levels of ET-1 and ETB receptors were reduced by bosentan, but not by ambrisentan. In cultured mouse astrocytes and brain microvessel endothelial cells, ET-1 (100 nM) increased prepro--ET-1 mRNA, which was inhibited by bosentan, but not by ambrisentan. FPI-induced alterations of the expression levels of matrix metalloproteinase-9, vascular endothelial growth factor-A, and angiopoietin-1 in the mouse cerebrum were reduced by delayed administration of bosentan, while ambrisentan had no significant effects. These results suggest that ET antagonists are effective in improving BBB disruption and cerebral edema in TBI patients and that an ETA/ETB non-selective type of antagonists is more effective.