Cobalt-Catalyzed Effective Access to Quinoxalines with Insights in Annulation of Terminal Alkynes and o-Phenylenediamines.

A novel methodology for the annulation of terminal alkynes and o-phenylenediamines by using a combination of a cobalt catalyst and oxygen as a terminal oxidant is reported. This method shows wide substrate scope and good functional group tolerance and provides a wide range of quinoxalines in good to high yields. The method is demonstrated by its gram-scale and broad potential applications. Furthermore, this protocol serves as a powerful tool for the late-stage functionalization of various complex bioactive molecules and drugs to provide a new class of molecules containing two distinct bioactive molecules directly linked. Detailed mechanistic studies reveal that the current reaction goes through a novel mechanism different from the previously reported glyoxal mechanism.

Cytoplasm protein GFAP magnetic beads construction and application as cell separation target for brain tumors.

BACKGROUND: It is very important to develop a highly efficient cerebrospinal fluid (CSF) detection system with diagnosis and prediction function, for which the detection of circulating tumor cells (CTCs) in CSF is a good choice. In contrast to the past use of epithelial EpCAM as CTCs separation target, a cytoplasm protein of GFAP antibody was first selected to construct highly-sensitive immunomagnetic liposome beads (IMLs). The validation and efficiency of this system in capturing CTCs for brain tumors were measured both in vitro and in vivo. The associations between the numbers of CTCs in patients with their clinical characteristics were further analyzed. RESULTS: Our data show that CTCs can be successfully isolated from CSF and blood samples from 32 children with brain tumors. The numbers of CTCs in CSF were significantly higher than those in blood. The level of CTCs in CSF was related to the type and location of the tumor rather than its stage. The higher the CTCs number is, the more possibly the patient will suffer from poor prognosis. Genetic testing in GFAP CTC-DNA by sanger sequencing, q-PCR and NGS methods indicated that the isolated CTCs (GFAP+/EGFR+) are the related tumor cell. For example, the high expression of NPR3 gene in CSF CTCs was consistent with that of tumor tissue. CONCLUSIONS: The results indicated that GFAP-IML CTCs isolation system, combined with an EGFR immunofluorescence assay of antitumor marker, can serve as a brand-new method for the identification of CTCs for brain tumors. Via lumbar puncture, a minimally invasive procedure, this technique may play a significant role in the clinical diagnosis and drug evaluation of brain tumors.

Pd-Catalyzed Intramolecular Chemoselective C(sp2)-H and C(sp3)-H Activation of N-Alkyl- N-arylanthranilic Acids.

A controllable palladium-catalyzed intramolecular C-H activation of N-alkyl- N-arylanthranilic acids has been developed. The methodology allows selective synthesis of 1,2-dihydro-(4 H)-3,1-benzoxazin-4-ones and carbazoles from the same starting materials and palladium catalyst. The selectivity is controlled by the oxidant. Silver oxide promotes C(sp3)-H activation/C-O cyclization to provide 1,2-dihydro-(4 H)-3,1-benzoxazin-4-ones, while copper acetate contributes to C(sp2)-H activation/decarboxylative arylation to afford carbazoles. This protocol is demonstrated by its wide substrate scope and good functional group tolerance.

Discovery of a Bioactive Inhibitor with a New Scaffold for Cystathionine γ-Lyase.

We identify three submicromolar inhibitors with new chemical scaffolds for cystathionine γ-lyase (CSE) by a tandem-well-based high-throughput assay. NSC4056, the most potent inhibitor with an IC50 of 0.6 µM, which is also known as aurintricarboxylic acid, selectively binds to Arg and Tyr residues of CSE active site and preferably inhibits the CSE activity in cells rather than cystathionine ß-synthase (CBS), the other H2S-generating enzyme. Moreover, NSC4056 effectively rescues hypotension in hemorrhagic shock rats.

Enantioselective Synthesis of 3-Alkynyl-3-hydroxyindolin-2-ones by Copper-Catalyzed Asymmetric Addition of Terminal Alkynes to Isatins.

A highly efficient copper-catalyzed asymmetric addition of terminal alkynes to isatins has been developed. In the presence of a catalytic amount of copper iodide and a chiral phosphine ligand, the reaction gave the corresponding chiral 3-alkynyl-3-hydroxyindolin-2-ones in high yields with high enantioselectivity. This methodology has a broad substrate scope, and the synthetic utility of the present protocol was further demonstrated by the transformation of chiral alkynylation products.

Copper-catalyzed annulation of heteroaromatic ß-halo-α,ß-unsaturated carboxylic acids with alkynes for the synthesis of indolo[2,3-c]pyrane-1-ones and thieno[2,3-c]pyrane-7-ones.

The annulation of heteroaromatic ß-halo-α,ß-unsaturated carboxylic acids with alkynes proceeds efficiently in the presence of Cu(OAc)2·H2O as a catalyst to afford the corresponding indolo[2,3-c]pyrane-1-ones and thieno[2,3-c]pyrane-7-ones in moderate to good yields. This strategy offers a simple and efficient route for the synthesis of indolo[2,3-c]pyrane-1-ones and thieno[2,3-c]pyrane-7-ones with good tolerance to a variety of functional groups from easily available heteroaromatic ß-halo-α,ß-unsaturated carboxylic acids.

Synthesis of isocoumarin derivatives by copper-catalyzed addition of o-halobenzoic acids to active internal alkynes.

The addition of o-halobenzoic acids to active internal alkynes proceeds efficiently in the presence of CuCl(2) as a catalyst to give the corresponding isocoumarin derivatives in moderate to good yields. This strategy offers a simple, efficient route to synthesis of the isocoumarin derivatives.

Chiral silver amides as effective catalysts for enantioselective [3+2] cycloaddition reactions.

Asymmetric [3+2] cycloaddition of α-aminoester Schiff bases with substituted olefins is one of the most efficient methods for the preparation of chiral pyrrolidine derivatives in optically pure form. In spite of its potential utility, applicable substrates for this method have been limited to Schiff bases that bear relatively acidic α-hydrogen atoms. Here we report a chiral silver amide complex for asymmetric [3+2] cycloaddition reactions. A silver complex prepared from silver bis(trimethylsilyl)amide (AgHMDS) and (R)-DTBM-SEGPHOS worked well in asymmetric [3+2] cycloaddition reactions of α-aminoester Schiff bases with several olefins to afford the corresponding pyrrolidine derivatives in high yields with remarkable exo- and enantioselectivities. Furthermore, α-aminophosphonate Schiff bases, which have less acidic α-hydrogen atoms, also reacted with olefins with high exo- and enantioselectivities. The stereoselectivities of the [3+2] cycloadditions with maleate and fumarate suggested that the reaction proceeded by means of a concerted mechanism. An NMR spectroscopic study indicated that complexation of AgHMDS with the bisphosphine ligand was not complete, and that free AgHMDS, which did not show any significant catalytic activity, existed in the catalyst solution. This means that significant ligand acceleration occurred in the current reaction system.

Radiosynthesis, biodistribution and micro-SPECT imaging study of dendrimer-avidin conjugate.

Partially acetylated generation five polyamidoamine (PAMAM) dendrimer (G5-Ac) was reacted with biotin and 2-(p-isothiocyanatobenzyl)-6-methyl-diethylenetria minepentaacetic acid (1B4M-DTPA), respectively to form the complex Bt-G5-Ac-1B4M which was further conjugated with avidin to give the conjugate Av-G5-Ac-1B4M. Then both of the conjugates were radiolabeled with technetium-99m ((99m)Tc), respectively. Their in vitro cellular uptake study shows that the conjugate of Av-G5-Ac-1B4M-(99m)Tc exhibits much higher cellular uptake in HeLa cells than that of Bt-G5-Ac-1B4M-(99m)Tc. Accordingly the following evaluation such as in vitro/in vivo stability, biodistribution and micro-SPECT imaging was observed only for the conjugate of Av-G5-Ac-1B4M-(99m)Tc.

Chiral silver amide-catalyzed enantioselective [3 + 2] cycloaddition of alpha-aminophosphonates with olefins.

The first catalytic asymmetric [3 + 2] cycloadditions of Schiff bases of alpha-aminophosphonates with olefins have been developed. Chiral silver amide complexes bearing (R)-DTBM-SEGPHOS worked well as catalysts for the first time, and proline phosphonic analogues were obtained in high yields with excellent exo- and enantioselectivities.

Rhodium-catalyzed asymmetric hydroalkoxylation and hydrosulfenylation of diphenylphosphinylallenes.

The rhodium-catalyzed intermolecular asymmetric hydroalkoxylation and hydrosulfenylation of diphenylphosphinylallenes gave chiral allylic phosphine oxides substituted with vinyl ether and thioether moieties in high yields with high enantioselectivities.

Rhodium-catalyzed asymmetric ring-opening alkynylation of azabenzonorbornadienes.

Asymmetric ring-opening alkynylation of meso-azabenzonorbornadienes with (triisopropylsilyl)acetylene giving 2-alkynyl-1-aminodihydronaphthalenes took place in high yields with high enantioselectivity in the presence of a rhodium/(R)-DTBM-segphos catalyst.

Rhodium-catalyzed asymmetric addition of terminal alkynes to diarylphosphinylallenes.

The presence of an acid was found to be essential in the rhodium-catalyzed asymmetric addition of terminal alkynes to diarylphosphinylallenes giving exo-enynes in high yields with high regio- and enantioselectivity. The stereochemical outcome is determined at the protonolysis of the pi-allylrhodium(I) intermediate involved in the catalytic cycle.

Rhodium-catalyzed asymmetric hydrogenation of functionalized olefins using monodentate spiro phosphoramidite ligands.

Novel chiral monodentate phosphorus ligands, SIPHOS, were conveniently synthesized from 1,1'-spirobiindane-7,7'-diol. The Rh complexes of SIPHOS can catalyze the hydrogenation of alpha-dehydroamino esters in mild conditions, providing alpha-amino acid derivatives in up to 99% ee. Enamides and beta-dehydroamino esters can also be hydrogenated in good to excellent enantioselectivities (up to 99% and 94% ee, respectively). The SIPHOS ligand with smaller alkyl groups on the N-atom afforded higher enantioselectivity. The X-ray analysis of single crystal showed that the structure of Rh/SIPHOS catalyst is [Rh(COD)((S)-SIPHOS-Me)(2)](+), which clarified the configuration of the catalyst with the monodentate chiral phosphorus ligand in Rh-catalyzed asymmetric hydrogenation. A positive nonlinear effect in the relationship of the optical purities of ligand and product was observed in the hydrogenation of dehydroamino acid derivatives. The kinetic study of hydrogenation showed that the reaction is zero order in the concentration of substrate and first order in the concentration of Rh catalyst and the hydrogenation pressure. The rate of hydrogenation decreased when the Rh/L ratio changed from 1:1 to 1:4.