Xianghui Zeng

Oxidative carbon-carbon bond formation in the synthesis of bioactive spiro beta-lactams.

New oxidative dearomatization procedures leading to spiro beta-lactams and oxindoles were developed. By a variation of the oxidative reaction conditions, the usefulness of phenolic amides, derived from 4-aminophenol, in the synthesis of structurally different types of molecules was demonstrated.

pH-triggered self-assembly of biocompatible histamine-functionalized triblock copolymers

Histamine functionalized poly(allyl glycidyl ether)-b-poly(ethylene glycol)-b-poly(allyl glycidyl ether) (PAGE-PEO-PAGE) triblock copolymers represent a new class of physically cross-linked, pH-responsive hydrogels with significant potential for biomedical applications. These telechelic triblock copolymers exhibited abrupt and reversible hydrogelation above pH 7.0 due to a hudrophilic/hydrophobic transition of the histamine units to form a network of hydrophobic domains bridged by a hydrophilic PEO matrix. These hydrophobic domains displayed improved ordering upon increasing pH and self-assembled into a body centered cubic lattice at pH 8.0, while at lower concentrations formed well-defined micelles. Significantly, all materials were found to be non-toxic when evaluated on three different cell lines and suggests a range of medical and biomedical applications.

Biological evaluation of polyhalo 1,3-diazaheterocycle fused isoquinolin-1 (2H)-imine derivatives

A series of polyhalo 1,3-diazaheterocycle fused isoquinolin-1(2H)-imines were evaluated in vitro against human tumour cell lines including A431, K562, HL60, HepG2 and Skov-3. As a result, some of the target compounds such as 5b, 5c, 5i, 5o, 6c, 6h and 7f showed stronger cytotoxicity against K562, H562 and Skov-3 cells in comparison with cisplatin, and the others displayed moderate cytotoxicity to A431 and HepG2. Biological investigations using the representative compounds 5c, 6c and 6h were also performed in mice bearing S(180) and H(22) tumours. The results indicated that these three compounds inhibit S(180) and H(22) growth. In addition, compounds 6c and 6h have very low acute toxicities. The preliminary analysis of structure-activity relationships is also discussed.

Endocytic Uptake and Intracellular Trafficking of Bis-MPA-Based Hyperbranched Copolymer Micelles in Breast Cancer Cells

Dendrimers and their less well-defined cousins, hyperbranched polymers, are widely investigated as scaffold materials in tissue engineering, as drug delivery agents, and in diagnostic imaging applications. Despite the large interest of using these unique materials as polymer-based nanoparticles in biomedical applications, a clear understanding of the cellular uptake and transport of these polyester-based nanoparticles is still lacking. The objective of this study is to evaluate the cellular uptake profiles and intracellular trafficking of polymer micelles built from the hyperbranched polyester Boltorn, fitted with poly(ethylene glycol) and fluorescent groups in MDA-MB468 breast cancer cells. Results show that the uptake of these nanoparticles correlated positively to both time and concentration, and that the uptake of the nanoparticles was energy dependent. These polyesterbased nanoparticles appear to translocate across cells via clathrin- and macropinocytosis-mediated endocytosis. Observations of the intracellular trafficking of the nanoparticles indicate that particles could be released from early endosomes after being internalized, and the particles exhibit perinuclear localization. The uptake behavior of the nanoparticles was further evaluated in a range of cell lines. These results allow the generation of the knowledge base required to design polyester-based nanocarriers that can be used efficiently and specifically for drug delivery applications and imaging applications.

Solvent-free, microwave assisted synthesis of polyhalo heterocyclic ketene aminals as novel anti-cancer agents.

A series of polyhalo heterocyclic ketene aminals (polyhalo-HKAs) were synthesized under solvent-free conditions and evaluated in vitro against a panel of human tumor cell lines. Trifluoro-HKAs were the most cytotoxic compounds, followed by difluoro-HKAs and trichloro-HKAs. Trichloro-HKAs were more potent against the tumor cell lines Skov-3, Hep-2, K562, and A431 than difluoro-HKAs. An ethoxycarbonyl at the 2-position of the polyhalo HKAs gave the highest activity. Ethoxycarbonyl substituted 5o, bearing three fluorine atoms on the isophthalonitrile ring, was found to be the most potent derivative with IC(50) values lower than 3.7microg/mL against five human tumor cell lines making it more active than cisplatin (DDP).

Synthesis and cytotoxic activities of novel phenacylimidazolium bromides

A series of novel phenacylimidazolium derivatives, bearing an aryl or alkyl substituent at position-1 and a phenacyl substituent at position-3 of the imidazole ring, has been prepared and evaluated in vitro against a panel of human tumor cell lines. Phenacylimidazolium bromides bearing a highly sterically hindered aryl group at position-1 and an electron-rich phenacyl or naphthylacyl substituent at position-3 of imidazole ring proved to be more active than imidazolium bromides with other substituted groups. In particular, compound 5j was found to be the most potent compounds with IC(50) values lower than 5.0 microM against 8 strains human tumor cell lines and more active than cisplatin (DDP).

Synthesis and cytotoxic activities of novel hybrid compounds of imidazole scaffold-based 2-substituted benzofurans

A series of novel hybrid compounds between 2-substituted benzofuran and imidazole have been prepared and evaluated in vitro against a panel of human tumor cell lines. The results show that the hybrid compounds were more selective towards an ovarian carcinoma cell line (Skov-3) and suggest that hybrid compounds bearing 2-substituted benzofuran and benzimidazole moieties, as well as imidazolium salts, were vital for modulating cytotoxic activity. The 2-substituted benzofuran imidazole hybrids 24 and 8 can serve as valuable leads for further structural modifications.

Synthesis and antitumor activity of 1-mesityl-3-(2-naphthoylmethano)-1H-imidazolium bromide

An imidazolium salt, 1-mesityl-3-(2-naphthoylmethano)-1H-imidazolium bromide (MNIB), has been investigated for its antitumor properties. In vitro studies demonstrate that MNIB is active against K562, SMMC-7721, EJ, AGZY, HEP-2, A549, HepG2, and Raji tumor cells, and can induce the G1 phase cell cycle arrest and apoptosis in K562 cells. Moreover, administration of MNIB significantly inhibited tumor growth in human non-small lung tumor (A549) xenografts.

Silica Gel-Mediated Amide Bond Formation: An Environmentally Benign Method for Liquid-Phase Synthesis and Cytotoxic Activities of Amides

An efficient, functional group tolerable, and environmentally benign process for the synthesis of amides was developed. No activation reagents or scavengers are required in this process. Purification of desired compounds is easy, rapid, and cost-effective. This protocol provides an alternative for the combinatorial liquid-phase synthesis of amide libraries for drug discovery. By this method, a number of amides were prepared and evaluated in vitro against a panel of human tumor cell lines. Cinnamic amide IV-4 was found to be the most potent compound synthesized against four human tumor cell lines.

Neurochemical effects of exercise and neuromuscular electrical stimulation on brain after stroke: A microdialysis study using rat model

Treadmill exercise and neuromuscular electrical stimulation are common clinical approaches for stroke rehabilitation. Both animal and clinical studies have shown the functional improvements after these interventions. However, the neurochemical effects on the ischemic brain had not been well studied. This study aimed at evaluating the effects of treadmill exercise and neuromuscular electrical stimulation (NMES), and studying their effects during a 2-week training, on the levels of common neurotransmitters (aspartate, glutamate, taurine and gamma-aminobutyric acid (GABA)) in the hippocampus following transient focal cerebral ischemia. Either treadmill exercise or neuromuscular electrical stimulation was prescribed to the rats 24 h after cerebral ischemia whereas Control group remained in cages for 2 weeks. Microdialysis technique was used to collect dialysates from ipsilesional hippocampus in vivo. It was found that the glutamate level was increased significantly during treadmill exercise and then returned to baseline level. Both interventions did not trigger significant effects on aspartate and glutamate basal levels during the 2 weeks. The relatively high taurine level in Control groups may suggest that the interventions might suppress the taurine release in hippocampus. GABA and aspartate levels did not showed significant changes over the 2 weeks in all groups. These results provide insights to explain the neurochemical effects on the ischemic injured brain during the course of rehabilitation.