Relay Annulation of Ammonium Ylides with Oxindole-Derived α,ß-Unsaturated Ketimines: Catalytic Construction of Spiro-polycyclic Oxindoles.

An ammonium ylide-based relay annulation was disclosed, which uses DABCO as the catalyst and oxindole-derived α,ß-unsaturated ketimines and γ-bromo-crotonates as the starting materials. This method enables the rapid assembly of a series of structurally novel spiro-polycyclic oxindoles containing a bicyclo[4.1.0]heptane moiety through simultaneous generation of three new bonds and two rings in one step under mild reaction conditions.

1,5-Hydrogen atom transfer of α-iminyl radical cations: a new platform for relay annulation for pyridine derivatives and axially chiral heterobiaryls.

The exploitation of new reactive species and novel transformation modes for their synthetic applications have significantly promoted the development of synthetic organic methodology, drug discovery, and advanced functional materials. α-Iminyl radical cations, a class of distonic ions, exhibit great synthetic potential for the synthesis of valuable molecules. For their generation, radical conjugate addition to α,ß-unsaturated iminium ions represents a concise yet highly challenging route, because the in situ generated species are short-lived and highly reactive and they have a high tendency to cause radical elimination (ß-scission) to regenerate the more stable iminium ions. Herein, we report a new transformation mode of the α-iminyl radical cation, that is to say, 1,5-hydrogen atom transfer (1,5-HAT). Such a strategy can generate a species bearing multiple reactive sites, which serves as a platform to realize (asymmetric) relay annulations. The present iron/secondary amine synergistic catalysis causes a modular assembly of a broad spectrum of new structurally fused pyridines including axially chiral heterobiaryls, and exhibits good functional group tolerance. A series of mechanistic experiments support the α-iminyl radical cation-induced 1,5-HAT, and the formation of several radical species in the relay annulations. Various synthetic transformations of the reaction products demonstrate the usefulness of this relay annulation protocol for the synthesis of significant molecules.

Rapid isolation of a potent human antibody against H7N9 influenza virus from an infected patient.

Influenza virus A H7N9 remains a serious threat to public health due to the lack of effective vaccines and drugs. In this study, a neutralizing human antibody named 3L11 was rapidly isolated from the switched memory B cells of a patient infected with H7N9. The antibody 3L11 was encoded by the heavy-chain VH1-8 gene and the light-chain VL2-13 gene that had undergone somatic mutations, and conferred high affinity binding to H7N9 hemagglutinins (HAs). It promoted killing of infected cells by antibody-dependent cell-mediated cytotoxicity (ADCC). Epitope mapping by mass spectroscopy (MS) indicated that 3L11 bound to the peptide 149-175 of HAs that contained the 150-loop of the receptor-binding site (RBS). Additionally, the 3L11 escape strains had G151R (Gly151→Arg151) and S152P (Ser152→Pro152) mutations within a conserved antigenic site A near the RBS that were not observed in field strains. Importantly, 3L11 fully protected mice against a lethal H7N9 virus challenge, in both pre- and postexposure administration regimens. Altogether, this work demonstrates the feasibility of rapid isolation of neutralizing H7N9 antibodies from infected patients and provides a potential prophylactic and therapeutic agent against H7N9 viruses.

Vaccination with a DNA vaccine encoding CD317-targeting HBs antigen elicits enhanced immunity in mice.

BACKGROUND: Conventional hepatitis B virus (HBV) vaccines fail to induce protective antibody titers in 5-10% of immune-competent vaccines. Therefore, safe and effective HBV vaccines are still clinically needed. METHODS: In this study, we developed a plasmid DNA vaccine encoding CD317 single-chain fragment variable (α317scFv) linked with the hepatitis B surface antigen (HBsAg) and detected the humoral and cellular immune responses elicited by this vaccine in BALB/c mice. RESULTS: Vaccination with this fusion DNA vaccine in BALB/c mice induced more robust antiviral T cell and antibody immunity against HBsAg. Compared with mice vaccinated with control vaccine encoding HBsAg, the level of serum-circulating anti-HBsAg antibody (HBsAb) was nearly double in fusion DNA-vaccinated mice. More interesting, splenic lymphocytes isolated from fusion DNA-vaccinated mice showed more potent proliferation and IFN-γ production after being re-stimulated with recombinant HBsAg in vitro. And not only that, the cytotoxicity of fusion DNA vaccine-sensitized splenocytes was ∼3-fold higher than that of controls. CONCLUSION: Taken together, our results reveal that the fusion DNA vaccine can induce more effective immunological protection against HBV, and is a promising candidate for preventing HBV infection.

DcR3 combined with hematological traits serves as a valuable biomarker for the diagnosis of cancer metastasis.

Decoy receptor 3 (DcR3) is abnormally up-regulated in many cancer cells. It may help cancer cells to escape from immune surveillance and establish metastatic lesions. However, whether DcR3 can be used as a biomarker for the diagnosis of cancer metastasis is unclear. In this study, sera from healthy controls and patients with different cancers were collected, and tested for their DcR3 levels by ELISA. Significantly elevated DcR3 levels were observed in the sera of patients with gastric cancer (2.04 ± 1.01, P = 0.0061), lymphoma (1.62 ± 0.75, P = 0.041), and breast cancer (1.53 ± 0.51, P = 0.023). DcR3 was found to be a suitable biomarker for identifying gastric cancer patients. Importantly, DcR3 was positively associated with platelet distribution width (PDW) (P = 2.45 × 10-6, R = 0.63) in metastatic cancers but negatively associated with hemoglobin (HGB) (P = 0.002, R = -0.59) and hematocrit (HCT) (P = 0.001, R = -0.62) in non-metastatic cancers. Combined with PDW, HGB and HCT, serum DcR3 could be used to predict the occurrence of cancer metastasis. These findings indicate that DcR3 could be used as a biomarker for the diagnosis of gastric cancer, and for cancer metastasis in combination with hematological traits.