Nickel-Catalyzed α-selective Hydroalkylation of Vinylarenes.

C(sp3) centers adjacent to (hetero) aryl groups are widely present in physiologically active molecules. Metal-hydride-catalyzed hydroalkylation of alkenes represents an efficient means of forging C(sp3)-C(sp3) bonds, boasting advantages as a wide source of substrates, mild reaction conditions, and facile selectivity manipulation. Nevertheless, the hydroalkylation of vinylarenes encounters constraints in terms of substrate scope, necessitating the employment of activated alkyl halides or alkenes containing chelating groups, remains a challenge. In this context, we report a general nickel-hydride-catalyzed hydroalkylation protocol for vinylarenes. Remarkably, this system enables α-selective hydroalkylation of both aryl and heteroaryl alkenes under an extra ligand-free condition, demonstrating excellent coupling efficiency and selectivity. Furthermore, through the incorporation of chiral bisoxazoline ligands, we have achieved regio- and enantioselective hydroalkylation of vinylpyrroles, thereby facilitating the synthesis of α-branched alkylated pyrrole derivatives.

Nickel-Catalyzed Remote Asymmetric Hydroalkylation of Alkenyl Ethers to Access Ethers of Chiral Dialkyl Carbinols.

Site- and enantio-selective alkyl-alkyl bond formation is privileged in the retrosynthetic analysis due to the universality of sp3-hybridized carbon atoms in organic molecules. Herein, we report a nickel-catalyzed remote asymmetric hydroalkylation of alkenyl ethers via synchronous implementation of alkene isomerization and enantioselective C(sp3)-C(sp3) bond formation. Regression analysis of catalyst structure-activity relationships accelerates the rational ligand modification through modular regulation. This reaction has several advantages for synthesizing chiral dialkyl carbinols and their ether derivatives, including the broad substrate scope, good functional group tolerance, excellent regioselectivity (>20:1 regioisomeric ratio), and high enantioselectivity (up to 95% enantiomeric excess).

Nickel-Catalyzed Switchable Site-Selective Alkene Hydroalkylation by Temperature Regulation.

Regiodivergent alkene functionalization that produces either regioisomer starting from the same raw materials is desirable. Herein, we report a nickel-catalyzed switchable site-selective alkene hydroalkylation. The selection of reaction temperatures leads to protocols that provide regiodivergent hydroalkylated products starting from a single alkene substrate. This protocol allows the convenient synthesis of α- and ß-branched protected amines, both of which are important to the fields of pharmaceutical chemistry and biochemistry. In addition, enantioenriched ß-branched alkylamines can be accessed in a catalytic asymmetric variant. Preliminary mechanistic studies indicate that the formation of a more stable nickelacycle provides the driving force of migration. The thermodynamic and kinetic properties of different reduction elimination intermediates are responsible for the switchable site-selectivity.

Nickel-Catalyzed Enantioconvergent Reductive Hydroalkylation of Olefins with α-Heteroatom Phosphorus or Sulfur Alkyl Electrophiles.

Substantial advances in enantioconvergent C(sp3)-C(sp3) bond formation reactions have been made in recent years through the use of transition-metal-catalyzed cross-coupling reactions of racemic secondary alkyl electrophiles with organometallic reagents. Herein, we report a general process for the asymmetric construction of alkyl-alkyl bonds adjacent to heteroatoms, namely, a nickel-catalyzed enantioconvergent reductive hydroalkylation of olefins with α-heteroatom phosphorus or sulfur alkyl electrophiles. Including the use of readily available olefins, this reaction has considerable advantages, such as mild reaction conditions, a broad substrate scope, and good functional group compatibility, making it a desirable alternative to traditional electrophile-nucleophile cross-coupling reactions.

LRBA is Essential for Allogeneic Responses in Bone Marrow Transplantation.

The PH-BEACH-WD40 (PBW) protein family members play a role in coordinating receptor signaling and intracellular vesicle trafficking. LPS-Responsive-Beige-like Anchor (LRBA) is a PBW protein whose immune function remains elusive. Here we show that LRBA-null mice are viable, but exhibit compromised rejection of allogeneic, xenogeneic and missing self bone-marrow grafts. Further, we demonstrate that LRBA-null Natural Killer (NK) cells exhibit impaired signaling by the key NK activating receptors, NKp46 and NKG2D. However, induction of IFN-γ by cytokines remains intact, indicating LRBA selectively facilitates signals by receptors for ligands expressed on the surface of NK targets. Surprisingly, LRBA limits immunoregulatory cell numbers in tissues where GvHD is primed or initiated, and consistent with this LRBA-null mice also demonstrate resistance to lethal GvHD. These findings demonstrate that LRBA is redundant for host longevity while being essential for both host and donor-mediated immune responses and thus represents a unique and novel molecular target in transplant immunology.

Zanthoxylum bungeanum essential oil induces apoptosis of HaCaT human keratinocytes.

ETHNOPHARMACOLOGICAL RELEVANCE: Zanthoxylum bungeanum (ZB), a Chinese herb medicine, has been shown to possess a wide range of biological activities including anti-tumor, anti-inflammatory, and anti-microbial activity and has long been used to treat a variety of skin diseases including psoriasis. However, the underlying mechanism of action has not been systematically elucidated. AIM OF THE STUDY: to analyze the chemical composition of the hydro-distilled Zanthoxylum bungeanum essential oil (ZBEO), and to investigate its anti-proliferative activity on HaCaT cells as well as the underlying anti-psoriasis mechanisms. MATERIALS AND METHODS: The chemical composition of ZBEO was analyzed with gas chromatography coupled to mass spectrometry (GC-MS). HaCaT cells was exposed to different dose of ZBEO added in medium prior to morphologic features analysis as well as cell cycle arrest examination with Flow cytometry. Western blot analysis was employed to estimate the expression level of proteins including caspase-8/9/3, PARP, Bax and Bcl-2. RESULTS: Thirty-nine compounds of the ZBEO were identified GC-MS. ZBEO-treated HaCaT cells showed typical apoptotic morphologic features by DAPI staining assay. The ZBEO significantly inhibited proliferation of HaCaT cells in a dose- and time-dependent manner and induced S phase arrest apoptosis in HaCaT cells. Furthermore, western blot analysis revealed that the ZBEO increased expression of cleaved caspase-8/9/3, PARP, and Bax, decreased Bcl-2 levels. CONCLUSION: ZBEO inhibits the proliferation of HaCaT cells, resulting from the induction of cellular apoptosis through both intrinsic and extrinsic pathways. ZBEO is a potential candidate that may be considered for development into an anti-psoriasis drug.

Anti-VEGF Therapy with Bevacizumab--limited cardiovascular toxicity.

PURPOSE: This analysis was conducted to evaluate cardiovascular toxicity of commonly used anti-VEGF therapeutic agent, bevacizumab, in treating patients with cancer. METHODS: Clinical studies evaluating the efficacy and safety of bevacizumab-based regimens on response and safety for patients with cancer were identified using a predefined search strategy, allowing cardiovascular toxicity and other side effects of treatment to be estimated. RESULTS: In bevacizumab based regimens, 4 clinical studies including 282 patients with advanced cancer (including gliomas, cervical, breast and ovarian cancer) were considered eligible for inclusion. These bevacizumab-based regimens included docetaxel, irinitecan and carboplatin. Systematic analysis suggested that, of 282 patients treated by bevacizumab based regimens, hypertension and thrombo-embolism occurred in 2.5% (7/282), while only 3 patients reported cardiovascular events (1.1%). No treatment related death occurred in bevacizumab based treatment. CONCLUSION: This systemic analysis suggests that bevacizumab based regimens are associated with reasonable and accepted cardiovascular toxicity when treating patients with gliomas, cervical, breast and ovarian cancer.

Expansion of myeloid suppressor cells in SHIP-deficient mice represses allogeneic T cell responses.

Previously we demonstrated that SHIP(-/-) mice accept allogeneic bone marrow transplants (BMT) without significant acute graft-vs-host disease (GvHD). In this study we show that SHIP(-/-) splenocytes and lymph node cells are poor stimulators of allogeneic T cell responses that cause GvHD. Intriguingly, SHIP(-/-) splenocytes prime naive T cell responses to peptide epitopes, but, conversely, are partially impaired for priming T cell responses to whole Ag. However, dendritic cells (DC) purified from SHIP(-/-) splenocytes prime T cell responses to allogeneic targets, peptide epitopes, and whole Ag as effectively as SHIP(+/+) DC. These findings point to an extrinsic effect on SHIP(-/-) DC that impairs priming of allogeneic T cell responses. Consistent with this extrinsic effect, we found that a dramatic expansion of myeloid suppressor cells in SHIP(-/-) mice impairs priming of allogeneic T cells. These findings suggest that SHIP expression or its activity could be targeted to selectively compromise T cell responses that mediate GvHD and graft rejection.

Deregulated expression of LRBA facilitates cancer cell growth.

LRBA expression is induced by mitogens in lymphoid and myeloid cells. The Drosophila LRBA orthologue rugose/DAKAP550 is involved in Notch, Ras and EGFR pathways. These findings suggest that LRBA could play a role in cell types that have increased proliferative and survival capacity. Here, we show by microarray and real-time PCR analyses that LRBA is overexpressed in several different cancers relative to their normal tissue controls. We also show that LRBA promoter activity and endogenous LRBA mRNA levels are reduced by p53 and increased by E2F1, indicating that mutations in the tumor suppressors p53 and Rb could contribute to the deregulation of LRBA. Furthermore, inhibition of LRBA expression by RNA interference, or inhibition of its function by a dominant-negative mutant, leads to significant growth inhibition of cancer cells, demonstrating that deregulated expression of LRBA contributes to the altered growth properties of a cancer cell. Finally, we show that the phosphorylation of EGFR is affected by the dominant-negative mutant, suggesting LRBA plays a role in the mammalian EGFR pathway. These findings demonstrate that LRBA facilitates cancer cell growth and thus LRBA may represent a novel molecular target for cancer therapy.

Influence of SHIP on the NK repertoire and allogeneic bone marrow transplantation.

Natural killer cell (NK) receptors for major histocompatibility complex (MHC) class I influence engraftment and graft-versus-tumor effects after allogeneic bone marrow transplantation. We find that SH2-containing inositol phosphatase (SHIP) influences the repertoire of NK receptors. In adult SHIP-/- mice, the NK compartment is dominated by cells that express two inhibitory receptors capable of binding either self or allogeneic MHC ligands. This promiscuous repertoire has significant functional consequences, because SHIP-/- mice fail to reject fully mismatched allogeneic marrow grafts and show enhanced survival after such transplants. Thus, SHIP plays an important role in two processes that limit the success of allogeneic marrow transplantation: graft rejection and graft-versus-host disease.