Antitumor Active Protein-containing Glycans from the Body of Ganoderma tsugae

To explore the effects of traditional herbal medicine Ganoderma tsugae(G. tsugae) on immunomodulatory and antitumor activities, the crude polysaccharides of G. tsugae were purified by filtration, diethylaminoethyl(DEAE) sepharose-fast flow chromatography and sephadex G-100 size-exclusion chromatography. Two main fractions, protein- containing glycans CSSLP-1 and CSSLP-2, were obtained via the gradient elution. The protein content, molecular weight, and monosaccharide composition of the two fractions were analyzed. Furthermore, the influence of the protein-containing glycans from G. tsugae on the activation of human acute monocytic leukemia cell line(THP-1) and their antitumor activities to the human hepatocellular liver carcinoma cell(HepG-2) in vitro were evaluated. The results indicate that CSSLP-1 and CSSLP-2 could increase the pinocytic activity of THP-1 cells and induce THP-1 cells to produce the cytokines of TNFα and IL-2, significantly. CSSLP-1 and CSSLP-2 also played an inhibiting effect on the cancer cell(HepG-2). Moreover, the anti-proliferation activity of CSSLP-1 and CSSLP-2 increased with the participation of TNFα and IL-2 or other antitumor factors induced from THP-1 cells by G. tsugae protein-containing glycan fractions.     

Heteropolymolybdate–amino acid complexes: synthesis,characterization and biological activity

Three Keggin-type polyoxometalates functionalized by amino acids, (C₅H₁₃N₂O₂)₂(H₃O)PMo₁₂O₄₀·8H₂O 1, (C₅H₁₄N₂O₂)₂SiMo₁₂O₄₀·12H₂O 2 and (C₅H₁₄N₂O₂)₂GeMo₁₂O₄₀·12H₂O 3, were synthesized and characterized by elemental analysis, IR and ¹H?NMR spectra and single-crystal X-ray diffraction. The X-ray crystallographic study showed that the structures of the three compounds involved N–H···O and O–H···O hydrogen bonds among the protonated ornithine cations, water molecules and the heteropolyanion cluster, and thus represent a model interaction between polyoxometalates and proteins. These complexes display inhibitory actions to the human cancer cells Hela and PC-3?m in vitro.     

The introduction of antibacterial drug pipemidic acid into the POM field: Syntheses, characterization and antitumor activity

Two new compounds based on polyoxometalates (POMs) and the quinolone antibacterial drug pipemidic acid (HPPA), {[Ni(PPA)₂]H₄[SiW₁₂O₄₀]}·HPPA·3H₂O (1), and {[Zn(PPA)₂]₂H₄[SiW₁₂O₄₀]}·3H₂O (2), have been synthesized under hydrothermal conditions and structurally characterized by routine technique. Single-crystal X-Ray diffraction analysis shows that compound 1 is constructed by Keggin clusters grafted by binuclear nickel clusters, isolated HPPA and water molecules, while compound 2 consists of Keggin clusters grafted by binuclear zinc clusters and water molecules. Due to the selection of different transition metal (TM) ions, compounds 1 and 2 exhibit different structures and antitumor activities. Compound 1 possesses 0D structure and shows no antitumor activities. However, compound 2 possesses 1D structure and exhibits higher antitumor activities than its parent compound. The results show that introduction of different TM-PPA moieties onto the polyoxoanion surface can affect not only the final structures but also their antitumor activities.     

Asymmetric synthesis of 3(S),17-dihydroxytanshinone

The first synthesis of 3(S),17-dihydroxytanshinone was achieved by ultrasound promoted Diels-Alder reaction of the protected 3-hydroxymethyl-4,5-benzofurandione with a vinylcyclohexene derivative. Bioassay showed that the synthetic 3(S),17-dihydroxytanshinone was active in vitro against HL-60 tumor cell line by MTT method.     

A stereocontrolled total synthesis of (±)-saframycin A

A thirteen-step total synthesis of (±)-saframycin A from a tricyclic lactam intermediate is described. The key step of this total synthesis is the stereocontrolled construction of a pentacyclic saframycin framework via a modified Pictet-Spengler type cyclization generating a bis-carboxylic acid ester derivative, followed by decarboxylation. The cytotoxicity profiles are also presented.     

Synthesis,Cytotoxicity, and Structure-Activity Relationships of New Oxaliplatin Derivatives

Summary. In order to setup structure-activity relationships and to explore the possibilities of improving the anticancer activity of oxaliplatin, which was recently approved for combination chemotherapy of metastatic colorectal cancer, new oxaliplatin analogues have been synthesized. The cytotoxicity was determined in nine human tumor cell lines and revealed a comparable or even higher cytotoxic potency in leukemia, ovarian and colon cancer cell lines in the case of small substituents at position 4 of the cyclohexane-1,2-diamine ligand. Introduction of bigger substituents at this position and thereby increasing the steric demand of the diamine ligands and the lipophilicity of the oxaliplatin derivatives resulted in platinum complexes with reduced cytotoxic properties.     

Synthesis and in vitro antitumor activity of substituted anthracene-1,4-diones

Based on a rational approach, 6-substituted 1,4-anthracenediones were synthesized and found to exhibit potent cytotoxic activity against murine and human leukemic cells. The synthetic sequence includes a double Friedel-Crafts reaction, reductive quinone formation, and selective bromination of the alkyl side chain. A key intermediate, 6-bromomethyl-1,4-anthracenedione (10), was synthesized and converted to various active antitumor agents, including a water-soluble phosphate ester pro-drug. The interconversion reactions include displacement of the bromide with various nucleophiles and basic hydrolysis to the alcohol and subsequent oxidation to provide the aldehyde. Based on their ability to decrease L1210 and HL-60 tumor cell viability, 1,4-dihydroxyanthraquinones are inactive but 1,4-anthracenediones have interesting antitumor activity, which may be abolished by modification of the A-ring and improved by substitution of the C-ring. The cytostatic and cytotoxic activity of the representative compound 10 was verified at the National Cancer Institute in studies on the 60-human tumor cell line panel in the in vitro antitumor screening. A wide spectrum of tumor cells are sensitive to 10 inhibition, and concentrations required to inhibit tumor cell growth by 50% (GI₅₀) at 48 h are <10 nM in HL-60 and MOLT-4 and 37.1 nM in SR leukemia. Preliminary studies suggest that the molecular targets and mechanisms of action of 10 may be different from those of daunomycin.     

Synthesis of a staurosporine analogue possessing a 7-azaindole unit instead of an indole moiety

The synthesis of a new staurosporine analogue possessing a 7-azaindole unit instead of an indole moiety is described. This synthesis could be achieved by coupling a sugar moiety previously tosylated in 2′ position to the azaindolocarbazole aglycone. Nucleophilic substitution on the carbon bearing the tosyl group yielded to the key cyclization leading to a compound in which the carbohydrate part is linked to both indole and azaindole nitrogens.     

Chemical Basis of the Action of Glyoxalase I,an Anticancer Target Enzyme

Although glyoxalase I was discovered in 1913 the physiological role of this ubiquitous enzyme is still far from clear. It catalyzes the reaction of α-ketoaldehydes and glutathione to produce S-D-lactoylglutathione, from which D-lactate and glutathione are produced by glyoxalase II. Argument raged for many decades about the nature of the natural substrate. Was it methylglyoxal? Was methylglyoxal ever formed metabolically or was it purely artifactual? Some of these questions have been resolved in that a number of metabolic processes which produce α-ketoaldehydes have now been recognized. Equally unsuccessful have been attempts to ascribe a physiological role to glyoxalase. This is clearly an important question since glyoxalase I occurs in cells at all levels of evolution. Time and time again glyoxalase I has been claimed to be linked to cancer, and a number of research groups worldwide are using it as a model for designing potential anticancer drugs. In this review article the mechanism of action of the enzyme is discussed, knowledge of which enables stronger inhibitors to be synthesized. Until roughly ten years ago when powerful NMR techniques were used to study it for the first time, it was assumed that the key step in the mechanism was a hydride ion transfer. Today, the mechanism is envisaged as a proton transfer.     

Synthesis of 7- and 10-spermine conjugates of paclitaxel and 10-deacetyl-paclitaxel as potential prodrugs

Efficient syntheses of two taxol analogs bearing the linear polyamine spermine at 7- and 10-positions of paclitaxel and 10-deacetyl-paclitaxel have been developed. These polyamine-taxol-conjugates were isolated as water soluble difluoride salts. The aim of the present work was to introduce a chemical modification into taxol skeleton in order to increase drug selectivity toward tumor cells. The cytotoxic activity of these conjugates was evaluated in MCF7 and MCF7-R cell lines. The observed low cytotoxicity suggests that these conjugates could act as potential prodrugs.