Sheng Jiang

New ligands that promote cross-coupling reactions between aryl halides and unactivated arenes

Several ligands were designed to promote transition-metal-free cross-coupling reactions of aryl halides with benzene derivatives. Among the systems probed, quinoline-1-amino-2-carboxylic acid was found to serve as an excellent catalyst for cross-coupling between aryl halides and unactivated benzene. Reactions using this inexpensive catalytic system displayed a high functional group tolerance as well as excellent chemoselectivities.

Ligands for Copper-Catalyzed C−N Bond Forming Reactions with 1 Mol% CuBr as Catalyst

Several new ligands were designed to promote copper-catalyzed Ullman C-N coupling reactions. In this group, 8-hydroxyquinolin-N-oxide was found to serve as a superior ligand for CuBr-catalyzed coupling reactions of aryl iodides, bromides, and chlorides with aliphatic amines and N-heterocycles under a low catalyst loading (1% [Cu] mol). Reactions with the inexpensive catalytic system display a high functional group tolerance as well as excellent chemoselectivity.

Total synthesis and biological evaluation of largazole and derivatives with promising selectivity for cancers cells.

The efficient total synthesis of the natural substance largazole is described. Using this strategy, a small library of largazole analogs was developed. Structure-activity relationship studies suggested that the geometry of the alkene in the side chain is critical. While the largazoles analogues with trans-alkene are potent for the antiproliferative effect, those with cis-alkene are completely inactive. Most importantly, replacement of valine with tyrosine in largazole increased selectivity toward human cancer cells over human normal cells more than 100-fold.

Highly efficient synthesis of phenols by copper-catalyzed hydroxylation of aryl iodides, bromides, and chlorides.

8-Hydroxyquinolin-N-oxide was found to be a very efficient ligand for the copper-catalyzed hydroxylation of aryl iodides, aryl bromides, or aryl chlorides under mild reaction conditions. This methodology provides a direct transformation of aryl halides to phenols and to alkyl aryl ethers. The inexpensive catalytic system showed great functional group tolerance and excellent selectivity.

Interaction of a Cyclic, Bivalent Smac Mimetic with the X-Linked Inhibitor of Apoptosis Protein.

We have designed and synthesized a cyclic, bivalent Smac mimetic (compound 3) and characterized its interaction with the X-linked inhibitor of apoptosis protein (XIAP). Compound 3 binds to XIAP containing both BIR2 and BIR3 domains with a biphasic dose-response curve representing two binding sites with IC 50 values of 0.5 and 406 nM, respectively. Compound 3 binds to XIAPs containing the BIR3-only and BIR2-only domain with K i values of 4 nM and 4.4 microM, respectively. Gel filtration experiments using wild-type and mutated XIAPs showed that 3 forms a 1:2 stoichiometric complex with XIAP containing the BIR3-only domain. However, it forms a 1:1 stoichiometric complex with XIAP containing both BIR2 and BIR3 domains, and both BIR domains are involved in the binding. Compound 3 efficiently antagonizes inhibition of XIAP in a cell-free functional assay and is >200 times more potent than its corresponding monovalent compound 2. Determination of the crystal structure of 3 in complex with the XIAP BIR3 domain confirms that 3 induces homodimerization of the XIAP BIR3 domain and provides a structural basis for the cooperative binding of one molecule of compound 3 to two XIAP BIR3 molecules. On the basis of this crystal structure, a binding model of XIAP containing both BIR2 and BIR3 domains and 3 was constructed, which sheds light on the ability of 3 to relieve the inhibition of XIAP with not only caspase-9 but also caspase-3/-7. Compound 3 is cell-permeable, effectively activates caspases in whole cells, and potently inhibits cancer cell growth. Compound 3 is a useful biochemical and pharmacological tool for further elucidating the role of XIAP in regulation of apoptosis and represents a promising lead compound for the design of potent, cell-permeable Smac mimetics for cancer treatment.

Adsorption of Eu(III) on titanate nanotubes studied by a combination of batch and EXAFS technique

The effects of pH, contact time and natural organic ligands on radionuclide Eu(III) adsorption and mechanism on titanate nanotubes (TNTs) are studied by a combination of batch and extended X-ray absorption fine structure (EXAFS) techniques. Macroscopic measurements show that the adsorption is ionic strength dependent at pH < 6.0, but ionic strength independent at pH > 6.0. The presence of humic acid (HA) / fulvic acid (FA) increases Eu(III) adsorption on TNTs at low pH, but reduces Eu(III) adsorption at high pH. The results of EXAFS analysis indicate that Eu(III) adsorption on TNTs is dominated by outer-sphere surface complexation at pH < 6.0, whereas by inner-sphere surface complexation at pH > 6.0. At pH < 6.0, Eu(III) consists of ∼ 9 O atoms at REu-O ≈ 2.40 Å in the first coordination sphere, and a decrease in NEu-O with increasing pH indicates the introduction of more asymmetry in the first sphere of adsorbed Eu(III). At long contact time or high pH values, the Eu(III) consists of ∼2 Eu at REu-Eu ≈ 3.60 Å and ∼ 1 Ti at REu-Ti ≈ 4.40 Å, indicating the formation of inner-sphere surface complexation, surface precipitation or surface polymers. Surface adsorbed HA/FA on TNTs modifies the species of adsorbed Eu(III) as well as the local atomic structures of adsorbed Eu(III) on HA/FA-TNT hybrids. Adsorbed Eu(III) on HA/FA-TNT hybrids forms both ligand-bridging ternary surface complexes (Eu-HA/FA-TNTs) as well as surface complexes in which Eu(III) remains directly bound to TNT surface hydroxyl groups (i.e., binary Eu-TNTs or Eu-bridging ternary surface complexes (HA/FA-Eu-TNTs)). The findings in this work are important to describe Eu(III) interaction with nanomaterials at molecular level and will help to improve the understanding of Eu(III) physicochemical behavior in the natural environment.

Identification of an annonaceous acetogenin mimetic, AA005, as an AMPK activator and autophagy inducer in colon cancer cells.

Annonaceous acetogenins, a large family of naturally occurring polyketides isolated from various species of the plant genus Annonaceae, have been found to exhibit significant cytotoxicity against a variety of cancer cells. Previous studies showed that these compounds could act on the mitochondria complex-I and block the corresponding electron transport chain and terminate ATP production. However, more details of the mechanisms of action remain ambiguous. In this study we tested the effects of a set of mimetics of annonaceous acetogenin on some cancer cell lines, and report that among them AA005 exhibits the most potent antitumor activity. AA005 depletes ATP, activates AMP-activated protein kinase (AMPK) and inhibits mTOR complex 1 (mTORC1) signal pathway, leading to growth inhibition and autophagy of colon cancer cells. AMPK inhibitors compound C and inosine repress, while AMPK activator AICAR enhances, AA005-caused proliferation suppression and subsequent autophagy of colon cancer cells. AA005 enhances the ATP depletion and AMPK activation caused by 2-deoxyglucose, an inhibitor of mitochondrial respiration and glycolysis. AA005 also inhibits chemotherapeutic agent cisplatin-triggered up-regulation of mTOR and synergizes with this drug in suppression of proliferation and induction of apoptosis of colon cancer cells. These data indicate that AA005 is a new metabolic inhibitor which exhibits therapeutic potentials in colon cancer.

A Structure–Activity Guided Strategy for Fluorescent Labeling of Annonaceous Acetogenin Mimetics and their Application in Cell Biology

Annonaceous acetogenins are a large family of fatty acid-derived natural products with unique structures. Many members in this diverse family have a broad spectrum of biological activities, the most impressive of which is anticancer activity. 2] ccording to the literature, acetogenins are believed to act ACHTUNGTRENNUNGdirectly at the terminal electron-transfer step in complex I of mitochondria. 4] However, despite studies to pinpoint the binding sites of acetogenins, the precise locations of the sites remain unclear due to a lack of detailed structural information about complex I. 4] Significant efforts have been made to uncover the cytotoxic mechanism of the natural acetogenins and their analogues. Our interest in modifying the natural acetogenins (e.g. , bullatacin) stems from the potent anticancer activ-

Selective Histone Deacetylase Inhibitors with Anticancer Activity

HDAC inhibitors (HDACIs), which can be used to kill cancer cells through inhibiting histone deacetylase activity or altering the structure of chromatin, have emerged as efficacious agents in the treatment of cancer. With SAHA, FK228, belinostat and panobinostat approved by the FDA, displaying satisfying activity in both haematological and solid tumors of various tissues, efforts to create selective HDACIs have been attracted attention over the past several years. Herein, we mainly review the progress of selective HDAC inhibitors including class-selective and isoform-selective HDAC inhibitors.

Induction of Cell Death of Gastric Cancer Cells by a Modified Compound of the Annonaceous Acetogenin Family

Annonaceous acetogenins are a family of natural products with antitumor activities. The polyether mimic AA005 has been synthesized. The cytotoxic mechanism of AA005 was investigated. It was found that AA005 can induce the cell death of gastric tumor cells. Most AA005‐induced cell death is due to necrosis but partial and p53‐independent apoptosis is also detected. An expanded study with gastric tumor cells and a cell‐free system indicates that AA005 affects NADH:ubiquinone oxidoreductase (complex I; NADH=nicotinamide adenine dinucleotide, reduced form) in the mitochondrial electron transport system. These results show for the first time that the polyether mimic AA005 acts on the same biological target as the natural annonaceous acetogenins.