Antitumor activity of methylan polysaccharide derivatives

Methylan polysaccharide derivatives were prepared by dialkylaminoalkylation and reductive amination followed by quaternization. Their antitumor activity was investigated and a relationship between structure and activity is suggested. For quaternized DEAE-methylan at only 75 μg ml^?1, tumor cell proliferation was suppressed by 58–84% in three cell lines tested in the order Colo < Hela < HepG2.     

Darpones and water-soluble aminobutoxylated darpone derivatives are distinguished by matrix COMPARE analysis

Darpones are a class of compounds with antiproliferative activity for cancer cells in vitro and in mouse models. In order to improve the solubility of the compounds, darpones with aminobutoxy side chains were synthesized. The new derivatives showed retained antiproliferative activity for cultured cancer cell lines. However, a change of the selectivity pattern in the in vitro cell line screening project of the American National Cancer Institute indicates that the solubilized derivatives might act through a different biological mechanism. A matrix COMPARE analysis of the cancer cell line screening data clearly distinguished darpones with and without solubilizing aminobutoxy side chains.     

Antitumor activity of diethynylfluorene derivatives of gold(I)

A list of diethynylfluorenes and their gold(I) derivatives have been studied for their antitumor activity as a function of their structure–activity relationships. End-capping the fluoren-9-one unit with gold(I) moieties could significantly strengthen the cytotoxic activity in vitro on three human cancer cell lines with induction of reactive oxygen species generation on Hep3B hepatocellular carcinoma cells and exhibit attractive antitumor activity from in vivo nude mice Hep3B xenograft model with limited adverse effects on vital organs including liver and kidney.     

Antitumor activity of fatty acid derivatives isolated from protozoa]

Water-soluble monoethers of sucrose and fatty acids were obtained from Trypanosoma lewisi and Astasia longa. The maximum tolerated dose of the preparations on their single intraperitoneal administration was more than 25 g/kg. The doses of 10--40 mg/kg were used repeatedly in therapy. Carcinoma 755, Lewis carcinoma, sarcoma 45, sarcoma 37 and sarcoma 180 were sensitive to the preparations. The preparations were inactive against experimental leukemia.     

Antitumor and antioxidant activity of spin labeled derivatives of podophyllotoxin (GP-1) and congeners

The spin labeled derivative of podophyllotoxin, i.e. podophyllic acid-[4-(2,2,6,6,-tetramethyl-1-piperidyloxy)] hydrazone (GP-1,2) and its congeners (GP-1-OH,3, GP-1-H, 4) were synthesized. The inhibition activity to the transplanted tumor S180 and HepA and the LD50 values of these compounds in mice were tested. Their partition coefficients and pKa values were measured. The results showed that the anticancer activity of these compounds followed the order GP-1 >GP-1-OH> GP-1-H. It can be attributed to the influence of their partition coefficients and ionization constants to the compounds properties. Meanwhile, the antilipoperoxidative activities of GP-1, GP-1-OH and GP-1-H to MDA formation of liver homogenate of rat induced by Fe2+-ascorbic acid were measured. Electrochemical studies were carried out to measure the redox midpoint potentials. The relationship between the redox midpoint potentials and the antilipoperoxidative activity followed the same order as the antitumor activity. The EPR (Electron Paramagnetic Resonance) spectroscopy of the blood from carotid artery of anesthetized Wistar rat in vivo was measured. The results indicated that there is an equilibration between GP-1 and GP-1-OH, furthermore, GP-1-H can be oxidized partly to GP-1 and equilibrated with GP-1-OH in vivo. The EPR signal intensity of GP-1 is stronger than GP-1-OH and GP-1-H. It can be concluded that the oxidative state of nitroxide in compounds play a key role to the antioxidant activity.     

Synthesis of novel mono and bis-indole conduritol derivatives and their α/β-glycosidase inhibitory effects

Here we synthesized four novel indole conduritol derivatives 1–4 for the first time in the literature and probed their biological activities with the α and β-glucosidases. The compounds showed quite effective glucosidase inhibitory action. IC₅₀ values of the compounds were compared with the known glucosidase inhibitor acarbose and it was determined that newly synthesized indole conduritols had more powerful effect against β-glucosidase in addition to exhibiting moderate influence against α-glucosidase. Our molecules thus constitute an important starting point for the design and exploitation of novel glucosidase inhibitors since glucosidase inhibitors have widespread applications in the treatment of diabetes, viral infections, lysosomal storage diseases and cancers.     

Antitumor activity of some natural flavonoids and synthetic derivatives on various human and murine cancer cell lines

The effect of various natural flavonoids, cinnamic acid derivatives, and a series of synthetic flavones on cell proliferation was evaluated in vitro in a panel of established human and murine tumor cell lines. The most potent antiproliferative agents were caffeic acid n-butyl ester (12) > 2'-nitroflavone (26) > caffeic acid ethyl ester (11) approximately = 2',6-dinitroflavone (27) > apigenin (3) > 3'-bromoflavone (20) approximately = 2'-fluoro-6-bromoflavone (31). Some compounds showed a moderate effect, the order of cytotoxic activities being chrysin (2) > 2'-fluoro-6-chloroflavone (30) approximately = 2'-chlorochrysin (32) > alpha-naphthoflavone (7) > beta-naphthoflavone (8) approximately = 6-chloroflavone (14) approximately = 6-bromoflavone (15) approximately = 4'-nitroflavone (23). A structure-activity relationship analysis of each group of compounds was performed. None of the natural or synthetic compounds tested affected the proliferation of epithelial cells derived from normal mammary gland of mice or fibroblastic cells from mouse embryo, suggesting a selective action against tumor cells.     

Antitumor activity of marine algae

Powdered tissue from 46 species of air-dried marine algae (four green, 21 brown and 21 red algae) were screened for antitumor activity. Significant activity against Ehrlich carcinoma was found in the brown algae Scytosiphon lomentaria (69.8% inhibition), Lessonia nigrescens (60.0%), Laminaria japonica (57.6%), Sargassum ringgoldianum (46.5%), the red algae Porphyra yezoensis (53.2%) and Eucheuma gelatinae (52.1%) and the green alga Enteromorpha prolifera (51.7%). Five brown and four red algae showed appreciable antitumor activity against Meth-A fibrosarcoma. To identify specific molecules with antitumor activity, 15 kinds of polysaccharide preparations of seaweed origin and 24 kinds of lipid fractions extracted from various seaweeds were tested. Appreciable inhibition of Ehrlich carcinoma was found for fucoidan preparations from Undaria pinnatifida and Sargassum ringgoldianum, for carrageenans and for porphyran. Several glycolipid and phospholipid fractions from brown and red algae were effective against Meth-A fibrosarcoma.     

Antitumor activity of equinatoxin.

Equinatoxin, a highly basic protein extracted from Actinia equina, causes an increase in the survival time of mice bearing the ascitic form of Ehrlich carcinoma, whereas it has no effect on L1210 leukaemia. When tested for in vitro cytotoxicity by the dye exclusion test, it shows a potent activity on both tumour cell lines, with ED50 of a few ng/ml. Higher concentrations produce an extensive lysis of the cells. The cytotoxic effects of Equinatoxin are inhibited by phospholipids, thus suggesting that its mechanism of action may be related to interactions with lipids or other charged components of cell membrane. The observed lack of in vivo activity against L1210 leukaemia presumably is due to poor systemic absorption of the protein and/or neutralization by serum factors.     

Antitumor and antimetastatic activity of IL-23

The structure and T cell stimulatory effects of the recently discovered cytokine IL-23 are similar to, but distinct from, those of IL-12. Although the antitumor activities of IL-12 are well characterized, the effect of IL-23 on tumor growth is not known. In this study, murine CT26 colon adenocarcinoma and B16F1 melanoma cells were engineered using retroviral vectors to release single-chain IL-23 (scIL-23) to evaluate its antitumor activity. In BALB/c mice, scIL-23-transduced CT26 cells grew progressively until day 26 to an average size of 521 +/- 333 mm(3), then the tumors started to regress in most animals, resulting in a final 70% rate of complete tumor rejection. scIL-23 transduction also significantly suppressed lung metastases of CT26 and B16F1 tumor cells. In addition, mice that rejected scIL-23-transduced tumors developed a memory response against subsequent wild-type tumor challenge. Compared with scIL-12-expressing CT26 cells, scIL-23-transduced tumors lacked the early response, but achieved comparable antitumor and antimetastatic activity. These results demonstrated that IL-23, like IL-12, provided effective protection against malignant diseases, but it probably acted by different antitumor mechanisms. As a first step in identifying these antitumor mechanisms, tumor challenge studies were performed in immunocompromised hosts and in animals selectively depleted of various lymphocyte populations. The results showed that CD8(+) T cells, but not CD4(+) T cells or NK cells, were crucial for the antitumor activity of IL-23.     

Antitumor activity of bent metallocenes: electronic structure analysis using DFT computations

The antitumor activities of bent metallocenes [Cp–M–Cp]²⁺ (M = Ti, V, Nb, Mo) and complexes of them with guanine, adenine, thymine and cytosine nucleotides have been probed using electronic structure calculations. DFT/BP86 calculations have revealed that the bent metallocene–nucleotide interaction strongly depends on the stability of the hydrolyzed form of the bent metallocene dichloride [Cp₂M]²⁺ species, and in turn the stability of the [Cp₂M]²⁺ species strongly depends on the electronic structure of [Cp₂M]²⁺. Detailed electronic structure and Walsh energy analyses have been carried out for the hydrolyzed forms of four [Cp–M–Cp]²⁺ (M = Ti, V, Nb, Mo) species to find out why the bent structure is unusually stable. Energy changes that occur during the bending process in frontier molecular orbitals as well as the p(π)–d(π) overlap have been invoked to account for the anticipated antitumor activities of these species. The bonding situation and the interactions in bent metallocene–nucleotide adducts were elucidated by fragment analysis. Of the four nucleotides complexed with the four bent metallocenes, adenine and guanine show better binding abilities than the other two nucleotides. Metallocenes of second-row transition metals exhibit better binding with pyrimidine-base nucleotides. In particular, the Lewis acidic bent metallocenes interact strongly with nucleotides. The antitumor activity is directly related to the binding strength of the bent metallocene with nucleotide adducts, and the computed interaction energy values correlate very well with the experimentally observed antitumor activities.     

Antitumor agents 243. Syntheses and cytotoxicity of desmosdumotin C derivatives

New analogs of desmosdumotin C (1), in which other aromatic rings replaced the terminal phenyl group and the A-ring was modified, were synthesized. Compounds 2-9, 13, and 16 were evaluated in vitro against human tumor cell replication. The 4-bromophenyl analog (2) showed potent cytotoxic activity in four different tumor cell lines.     

QSAR analysis of antibacterial activity of some 4-aminodiphenylsulfone derivatives

QSAR studies on a set of 36 congeners of 4-aminodiphenylsulfone derivatives with measured inhibition potencies of dihydropterate synthase were made using multiple regression analysis. Conformational entropy in combination with indicator parameters gave excellent results.     

Antitumor activity of titanocene amino acid complexes

Seven ionic titanocene -amino acid (aa) complexes [(C₅H₅)₂Ti(aa)₂]²⁺[X]₂ ^– with aa = glycine,l-alanine, 2-methylalanine,d-l-phenylalanine,d,l-4-fluorophenylalanine and X = Cl or AsF₆, were investigated for antitumor activity against fluid Ehrlich ascites tumor growing in CF1 mice. These complexes are the first stable model compounds of titanocene units with protein components, synthesized from a water-like, methanolic medium. All titanocene amino acid complexes induced antitumor activity which was manifested by maximum cure rates ranging from 30 to 70% and increases in life span from 78 to 276% in comparison with untreated control animals. The complexes containing chloride as anion X were more effective than the hexafluoroarsenate derivatives, which surprisingly showed a low substance toxicity. In all cases, the antitumor activity of the ionic titanocene amino acid complexes tested was less pronounced than that of the neutral parent compound [(C₅H₅)₂TiCl₂].     

Antitumor activity of L-asparaginase from Yersinia pseudotuberculosis

The cytotoxic activity of L-asparaginases from Yersinia pseudotuberculosis and from Erwinia carotovora were investigated in vitro using human T-lymphoblastic leukemia (Jurkat and Molt-4) and also solid tumor cell lines MCF-7 (human breast adenocarcinoma), LnCap (human prostate carcinoma), NGUK1 (rat Gasser node neurinoma). E.coli L-asparaginase produced by Medak (Germany) was used as a reference preparation. The data obtained indicate that Y. pseudotuberculosis L-asparaginase significantly inhibits growth of leukemic and solid tumor cells. Its antitumor activity is comparable to that of the reference preparation of L-asparaginase (Medak). These results suggest that the recombinant L-asparaginase can be used for the development of new preparations for the therapy of different types of tumors.     

Antitumor and immunomodulating activity of polysaccharides from Enteromorpha intestinalis

Two polysaccharides (WEA and WEB) were isolated from Enteromorpha intestinalis by hot water extraction, anion-exchange, and gel-permeation chromatography. The average molecular weights (Mw) of the two fractions were 72.03 kDa (WEA) and 60.12 kDa (WEB). WEA was composed of Rha, Xyl, Man, and Glc in a molar ratio of 1.39:1.00:0.13:3.23. WEB consisted of Rha, Xyl, Gal, and GlcA (glucuronic acid) in a molar ratio of 7.32:1.00:0.51:1.28. Both polysaccharides could inhibit tumor growth in S180 tumor-bearing mice, and increased the relative spleen and thymus weight. They also increased the expression of tumor necrosis factor-alpha (TNF-α) in serum. WEA and WEB induced lymphocyte proliferation, increased the production of TNF-α in macrophages, and stimulated macrophages to produce nitric oxide dose-dependently through the up-regulation of inducible NO synthase activity. However, no direct cytotoxicity against Sarcoma 180 was investigated in vitro. These results indicate that the antitumor effects of these polysaccharides are associated with immunostimulation.     

Antitumor and hepatoprotective activity of natural and synthetic neo steroids

In this review, steroids with a tertiary butyl group, which are usually called neo steroids, are a small group of natural lipids isolated from higher plants, fungi, marine sponges, and yeast. In addition, steroids with a tertiary butyl group have been synthesized in some laboratories in Canada, USA, Europe, and Japan and their biological activity was studied. Some natural neo steroids demonstrate antitumor or hepatoprotective activities. In addition, synthetic neo steroids exhibit anticancer and neuroprotective properties. However, to confirm the above data, both practical and clinical experimental studies are necessary. Nevertheless, the results may be useful for pharmacologists, chemists, biochemists, and the pharmaceutical industry.     

Antitumor activity of lipopolysaccharide and radio-detoxified lipopolysaccharide of Vibrio parahaemolyticus

The antitumor activity of lipopolysaccharide (LPS) and radio-detoxified LPS of Vibrio parahaemolyticus was tested against S180 cells in Swiss mice. The toxicity of the LPS was 200 times less than that of Salmonella typhimurium LPS. The V. parahaemolyticus LPS could be detoxified by exposure to gamma radiation. Both LPS and the irradiated LPS exhibited antitumor activity, though the irradiated LPS was less effective than the native LPS. These observations indicated that exposure to gamma radiation caused significant detoxification of V. parahaemolyticus LPS and the detoxified LPS still possessed considerable antitumor activity.