Synthesis and biological evaluation of N-(arylsulfanyl)carbonyl analogues of paclitaxel (taxol)

Four new N-(arylsufanyl)carbonyl paclitaxel analogues (2a-d) were prepared from 7-(triethylsilyl)-protected baccatin III (5). Their cytotoxicities against human ovarian (A2780) and prostate cancer (PC3) cell lines, as well as their tubulin-assembly activities, were determined. In these assays, the new compounds showed rather weak activities, one two orders of magnitude below those of paclitaxel (taxol; 1). The known 3'-N-[(thiophen-2-yl)carbonyl] paclitaxel analogue 3 was also prepared. As previously reported, 3 exhibited strongly improved cytotoxicities and tubulin-assembly activities as compared to paclitaxel (1).     

Hepatic biotransformation in the buzzard (Buteo buteo) and the Japanese quail (Coturnix coturnix): effect of PCBs

Hepatic biotransformation was studied in microsomal (cytochrome P-450-dependent monooxygenase activities) and cytosolic (glutathione S-transferase activities) fractions from Japanese quail (Coturnix coturnix) and buzzard (Buteo buteo). Monooxygenase activities were not very different apart from a high 7-ethoxycoumarin de-ethylase activity in quail as compared to buzzard. Glutathione S-transferase activities were higher in quail than in buzzard. DP5 (a commercial mixture of PCBs containing 50% chlorine) produced a marked increase in monooxygenase activity from quail liver. In contrast, no induction was found in buzzard under the same conditions. Glutathione S-transferase activities were not modified in both species.     

Antitumor activity of phenylene bridged binuclear bis(imino-quinolyl)palladium(II) and platinum(II) complexes

Antitumor effects of a known bis(imino-quinolyl)palladium(II) complex 1 and its newly synthesized platinum(II) analogue 2 were evaluated against human breast (MCF-7) and human colon (HT-29) cancer cell lines. The complexes gave cytotoxicity profiles that were better than the reference drug cisplatin. The highest cytotoxic activities were pronounced in complex 2 across the two examined cancer cell lines. Both compounds represent potential active drugs based on bimetallic complexes.     

Heat shock protein-90 and the catalytic activities of the 20 S proteasome (multicatalytic proteinase complex)

The effect of heat shock protein 90 (Hsp-90) and several other proteins on the catalytic activities of the 20 S proteasome (MPC) was examined. The chymotrypsin-like (ChT-L) and peptidylglutamyl-peptide hydrolyzing (PGPH) activities of the pituitary MPC were inhibited by Hsp-90 with IC50 values of 8 and 28 nM, respectively. Bovine serum albumin and two other proteins tested inhibited the same activities with much higher IC50 values. The trypsin-like and branched-chain amino-acid-preferring activities were not affected by any of the proteins. None of the activities of the bovine spleen MPC, an enzyme form in which the X, Y, and Z subunits are virtually completely replaced by the LMP2, LMP7, and LMP10 subunits, was affected by either Hsp-90 or the other proteins tested. Hsp-90 inhibited the degradation of the oxidized B-chain of insulin by the pituitary MPC but not by its spleen counterpart. The PA28 activator (11 S regulator; REG) of the proteasome abolished the inhibitory effect of Hsp-90 and other proteins on the ChT-L and PGPH activities of the pituitary MPC. It is suggested that Hsp-90 induces conformational changes that affect the ChT-L and PGPH activities expressed by the X and Y subunits, respectively, but does not affect the activities expressed by LMP subunits.     

Synthesis and evaluation of bi-functional 7-hydroxycoumarin platinum(IV) complexes as antitumor agents

A series of bi-functional 7-hydroxycoumarin platinum(IV) complexes were synthesized, characterized, and evaluated for antitumor activities. The 7-hydroxycoumarin platinum(IV) complexes display moderate to effective antitumor activities toward the tested cell lines and show much potential in overcoming drug resistance of platinum(II) drugs. In reducing microenvironment, the title compounds could be reduced to platinum(II) complex accompanied with two equivalents of coumarin units. By a unique mechanism, the 7-hydroxycoumarin platinum(IV) complex attacks DNA via the released platinum(II) compound, meanwhile it also inhibits the activities of cyclooxygenase by coumarin fragment. This action mechanism might be of much benefit for reducing tumor-related inflammation in the progress of inhibiting tumor proliferation and overcoming cisplatin resistance. The incorporation of 7-hydroxycoumarin leads to significantly enhanced platinum accumulation in both whole tumor cells and DNA. The HSA interaction investigation reveals that the tested coumarin platinum(IV) compound could effectively combine with HSA via van der Waals force and hydrogen bond.     

Effect of triterpenoids and limonoids isolated from Cabralea canjerana and Carapa guianensis (Meliaceae) against Spodoptera frugiperda (J. E. Smith)

The activities of two triterpenoids, ocotillone and cabraleadiol, and four limonoids, methyl angolensate, 3-beta-deacetylfissinolide, 7-deacetoxy-7-oxogedunin, and beta-photogedunin, isolated from arillus of Carapa guianensis and fruits and seeds of Cabralea canjerana (Meliaceae), were evaluated against the fall armyworm Spodoptera frugiperda. Gedunin was used as a positive control. 7-Deacetoxy-7-oxogedunin and beta-photogedunin reduced the pupal weight as occurred with gedunin. Cabraleadiol, 3-beta-deacetylfissinolide, and 7-deacetoxy-7-oxogedunin prolonged the larval phase similar to the control (gedunin) of approximately 1.2 days at 50.0 mg kg(-1). The highest insecticidal activity was obtained for beta-photogedunin.     

Angiotensin-(1-7) stimulates oxidative stress in rat kidney

The effect of two different doses of angiotensin-(1-7) and angiotensin II on the oxidative stress generation was analyzed in rat kidney. Animals were injected intraperitoneally with a single dose of angiotensin-(1-7) or angiotensin II (20 or 50 nmol/kg body weight) and killed 3 h after injection. Production of thiobarbituric acid reactive substances (TBARS), measured as indicator of oxidative stress induction, was significantly increased in rat kidney after Ang-(1-7) administration up to 30% and 50% over controls, at 20 and 50 nmol/kg, respectively. Reduced glutathione (GSH), the most important soluble antioxidant defense in mammalian cells, showed a significant decrease of 13% and 20% at 20 and 50 nmol/kg of angiotensin-(1-7), respectively. When the antioxidant enzyme activities were determined, it was found that catalase activity was not altered by the assayed angiotensin-(1-7) doses while superoxide dismutase and glutathione peroxidase activities were significantly reduced by injection of 20 nmol/kg (34% and 13%, with respect to controls) and 50 nmol/kg of angiotensin-(1-7) (54% and 22%, respectively). In contrast, angiotensin II injections did not produce significant changes neither in TBARS levels nor in soluble and enzymatic defense parameters at the two doses used in this work. These results suggest that angiotensin-(1-7) is undoubtedly related to oxidative stress induction.     

Structure-based de novo design, synthesis, and biological evaluation of the indole-based PPARgamma ligands (I)

MCSS and LeapFrog, two de novo drug design programs, were used for the novel indole-based PPARgamma ligands' study. The designed compounds were synthesized and tested for the PPARgamma protein binding activities in vitro. Out of the compounds that were synthesized, two molecules (compounds 14d and 7d) possessed potent PPARgamma protein binding activity close to rosiglitazone in vitro.     

alpha-Glucosidase inhibitory constituents from stem bark of Terminalia superba (Combretaceae)

The CH(2)Cl(2)/CH(3)OH (1/1) extract of the dried stem bark of Terminalia superba afforded two compounds, (7S,8R,7'R,8'S)-4'-hydroxy-4-methoxy-7,7'-epoxylignan and meso-(rel 7S,8R,7'R,8'S)-4,4'-dimethoxy-7,7'-epoxylignan along with 11 known compounds. The structures of the compounds were established by analysing the spectroscopic data and also comparing it with the data of previously known analogues. All the isolated compounds were evaluated for their glycosidase inhibition activities. Gallic acid and methyl gallate showed significant alpha-glucosidase inhibition activity.     

Purification of mRNA guanylyltransferase and mRNA (guanine-7-) methyltransferase from vaccinia virions.

The sequences m7G(5')pppGm-and m7G(5')pppAm-are located at the 5' termini of vaccinia mRNAs. Two novel enzymatic activities have been purified from vaccinia virus cores which modify the 5' terminus of unmethylated mRNA. One activity transfers GMP from GTP to mRNA and is designated a GTP: mRNA guanylyltransferase. The second activity transfers a methyl group from S-adenosylmethionine to position 7 of the added guanosine and is designated a S-adenosylmethionine: mRNA (guanine-7-)methyltransferase. Advantage was taken of the selective binding of these activities to homopolyribonucleotides relative to DNA to achieve a 200-fold increase in specific activity. The guanylyl- and methyltransferase remained inseparable during chromatography on DNA-agarose, poly(U)-Sepharose, poly(A)-Sepharose, and Sephadex G-200 and during sedimentation through sucrose density gradients suggesting they were associated. A Stokes radius of 5.0 nm, an S20,w of 6.0 and a molecular weight of 127,000 were obtained by gel filtration on Sephadex G-200 and sedimentation in sucrose density gradients. Under denaturing conditions of sodium dodecyl sulfate-polyacrylamide gel electrophoresis two major polypeptides were detected in purified enzyme preparations. Their molecular weights of 95,000 and 31,400 suggested they were polypeptide components of the 127,000 molecular weight enzyme system.     

Antifungal activity of tetra-substituted tetrahydrofuran lignan, (-)-virgatusin, and its structure-activity relationship

Antifungal activities of the optically pure (>99%ee) (-)- and (+)-virgatusin, a tetra-substituted tetrahydrofuran lignan, were tested. (-)-Virgatusin, which is a natural product, showed highest antifungal activity against Colletotrichum lagenarium. Research on its structure-activity relationship was also performed. It was shown that two methoxy groups on 9 and 9' positions and a 3,4-methylenedioxyphenyl group on the 7 position of virgatusin were essential for high fungal growth inhibition. The part on 7'-phenyl group was not essential for activity. The 7'-(4-methoxyphenyl) derivative showed higher activity than that of (-)-virgatusin.     

Biomonitoring of polybrominated diphenyl ether (PBDE) pollution: a field study

Polybrominated diphenyl ethers (PBDEs) and cytochrome P450 enzyme activities were investigated in European eels (Anguilla anguilla) collected from seven sites in a coastal lagoon in the north-western Mediterranean Sea, Orbetello lagoon (Italy). Twelve PBDE congeners were measured in muscle and two CYP1A enzyme activities, 7-ethoxyresorufin-O-deethylase (EROD) and benzo(a)pyrene monooxygenase (BP(a)PMO), were investigated in liver microsomal fraction in order to obtain insights into the health of the lagoon environment. PBDE muscle levels were low and the most abundant congeners were 2,2',4,4'-tetrabromodiphenylether (BDE-47), 2,2',4,4',5,5'-hexaBDE (BDE-153) and 2,2',4,5'-tetraBDE (BDE-49). EROD and B(a)PMO activities were also low and no differences were observed between eels from different sites. Multivariate analysis (PCA) did not indicate correlations between PBDEs and either P450 activities.     

Effect of ivermectin on activities of cytochrome P450 isoenzymes in mouflon (Ovis musimon) and fallow deer (Dama dama)

Ivermectin is an antiparasitic drug widely used in veterinary and human medicine. We have found earlier that repeated treatments of rats with high doses of this drug led to significant increase of cytochrome P450-dependent 7-methoxyresorufin O-demethylase (MROD) and 7-ethoxyresorufin O-deethylase (EROD) activities in hepatic microsomes. In the present study, the effects of ivermectin on cytochrome P450 (CYP) activities were investigated in mouflon (Ovis musimon) and fallow deer (Dama dama). This study was conducted also to point out general lack of information on both basal levels of CYP enzymes and their inducibilities by veterinary drugs in wild ruminants. Liver microsomes were prepared from control animals, mouflons, after single or repeated (six doses in six consecutive days) treatments with therapeutic doses of ivermectin (0.5 mg kg(-1) of body weight), and fallow deer exposed to repeated doses of ivermectin under the same conditions. Alkyloxyresorufins, testosterone and chlorzoxazone were used as the specific substrate probes of activities of the CYP isoenzymes. A single therapeutic dose of ivermectin significantly induced (300-400% of the control group) the activities of all alkyloxyresorufin dealkylases tested in mouflon liver microsomes. Repeated doses of ivermectin also caused an increase of these activities, but due to fair inter-individual differences, this increase was not significant. The administration of ivermectin led to an induction (170-210% of the control) of the testosterone 6beta- and 16alpha-hydroxylase activities in mouflon liver but no significant modulation of chlorzoxazone hydroxylase (CZXOH) activity was found in mouflon liver. CYP-dependent activities in hepatic microsomes were generally higher in fallow deer than in mouflons. However, with the exception of slight increase in the 7-benzyloxyresorufin O-dealkylase (BROD) activities, no significant modulation of the other activities was observed. The induction of CYP3A-like isoenzyme was confirmed by immunoblotting only in the microsomes from mouflons administered with repeated doses of ivermectin; however, no significant increase of CYP1A isoenzymes was observed due to a weak cross-reactivity of anti-rat CYP1A1/2 polyclonal antibodies used in the study. The results indicate that ivermectin should be considered as an inducer of several cytochrome P450 isoenzymes, including CYP1A, 2B and 3A subfamilies, in mouflons. The comparison of induction effect of ivermectin in rat, mouflon and fallow deer also demonstrates the inter-species differences in inducibility of CYP enzymes.     

Ontogeny of catabolic and morphological properties of skeletal muscle of the red-winged blackbird (Agelaius phoeniceus)

Thermogenic capabilities of red-winged blackbirds improve markedly during their 10-12-day nestling period, especially between day 5 and day 8. The time course of improvements may be determined by the maturation of skeletal muscles involved in shivering thermogenesis, particularly the pectoralis muscles. To test this hypothesis, morphological and biochemical changes in pectoral and leg muscles were measured in young and adult blackbirds. Both muscles grew disproportionately relative to body mass. The pectoralis consisted entirely of fast-twitch fibers, predominantly fast oxidative glycolytic. In contrast, the gastrocnemius muscle consisted of a mixture of slow and fast fibers (predominantly fast glycolytic). Although fiber composition was constant, both cross-sectional area and density of fibers increased with age in both muscles. Catabolic capacities of the pectoralis increased significantly (approximately 7-8-fold) throughout the nestling period, most abruptly after day 3 (citrate synthase, CS) or day 4 (3-hydroxacyl-CoA-dehydrogenase, HOAD). Myofibrillar ATPase activities in the pectoralis were initially low, but increased after day 5. Further increases in CS and myofibrillar ATPase activities occurred in the pectoralis after fledging. CS and HOAD activities in the leg were much lower, but myofibrillar ATPase activities were remarkably similar in the two muscles, differing only in adults. These results are consistent with the hypothesis that the development of endothermy is dependent on the morphological and biochemical maturation of skeletal muscles important in thermogenesis.     

沙棘木蠹蛾(鳞翅目：木蠹蛾科)性信息素组分鉴定及其生物活性

报道了沙棘木蠹蛾性信息素的结构及组分,并报道了不同组分：顺-3-十四碳烯醇;反-3-十四碳烯醇;顺-3-十四碳乙酸酯;反-3-十四碳乙酸酯;顺-7-十四碳烯醇;顺-7-十四碳乙酸酯;顺-9-十四碳乙酸酯的室内触角电位反应和林间诱捕试验。林间诱蛾结果表明2组分和5组分的诱蛾活性高于其它组合。     

Synthesis and structural characterization of silver(I), aluminium(III) and cobalt(II) complexes with 4-isopropyltropolone (hinokitiol) showing noteworthy biological activities. Action of silver(I)-oxygen bonding complexes on the antimicrobial activities

Through two unequivalent oxygen donor atoms of the hinokitiol (Hhino; C10H12O2; 4-isopropyltropolone) ligand that showed noteworthy biological activities, the dimeric, silver(I)-oxygen bonding complex [Ag(hino)]2 1, the monomeric aluminium(III) complex [Al(hino)3].0.5H2O 4 and the cobalt(II) complex "[Co(hino)2]2.H2O" 6 were synthesized and characterized with elemental analysis, thermogravimetric and differential thermal analysis (TG/DTA), FTIR and solution (1H and 13C) NMR spectroscopy. The crystal structure of 1 was determined by Rietveld analysis based on X-ray powder diffraction (XPD) data and those of [Al(hino)3].MeOH 4a and [Co(hino)2(EtOH)]2 6a, being obtained as yellow block crystals and red platelet crystals, respectively, by crystallization of 4 and 6, were determined by single-crystal X-ray analysis. The antimicrobial activities of 1, 4 and 6, evaluated with minimum inhibitory concentration (MIC; microg ml(-1)), were compared with those of other metal complexes (M=Na, Li, Cs, Ca, V, Zn) with the hino- ligand. The antimicrobial activities observed in the alkali-metal salts strongly suggested that they were attributed to the effect of the anionic hino- species. The antimicrobial activities of 1 were significantly enhanced, whereas those of other metal complexes were suppressed, compared with those of the neutral Hhino and anionic hino- molecules. The antimicrobial activities observed in 1 were comparable with those of other recently found silver(I)-oxygen bonding complexes, the ligands of which had no activity. Thus, it is proposed that the antimicrobial activities of the silver(I)-oxygen bonding complexes are due to a direct interaction or complexation of the silver(I) ion with biological ligands such as protein, enzyme and membrane, and the coordinating ligands of the silver(I) complexes play the role of a carrier of the silver(I) ion to the biological system.     

Importance of the Chiral Centers of Jasmonic Acid in the Responses of Plants (Activities and Antagonism between Natural and Synthetic Analogs)

The importance of the two chiral centers at C-3 and C-7 in the molecular structure of jasmonic acid in plant responses was investigated. We separated methyl jasmonate (MeJA) into (3R)- and (3S)-isomers with a fixed stereochemistry at C-3, but epimerization at C-7 is possible. The four isomers of the nonepimerizable analog 7-methyl MeJA were synthesized. These six esters and their corresponding acids were tested in three bioassays: (a) senescence in sunflower (Helianthus annuus) cotyledons; (b) proteinase inhibitor II gene expression in transgenic tobacco (Nicotiana tabacum) with [beta]-glucuronidase as a biochemical reporter; and (c) seed germination in Brassica napus and wheat (Triticum aestivum). The esters and acids had similar activities in the three assays, with the ester being more effective than its acid. The (3R)-stereochemistry was critical for jasmonate activity. Although activity was reduced after substituting the C-7 proton with a methyl group, the analogs with (3R,7R)- or (3R,7S)-stereochemistry were active in some of the assays. Although the four isomers of 7-methyl MeJA were inactive or only weakly active in the senescence assay, they could overcome the senescence-promoting effect of (3R)-MeJA. The strongest antagonistic effect was observed with the (3R,7S)-isomer.     

Synthesis, structural characterization and antimicrobial activities of 4- and 6-coordinate nickel(II) complexes with three thiosemicarbazones and semicarbazone ligands

To investigate the relationship between antimicrobial activities and the molecular structures of nickel(II) complexes with thiosemicarbazone and semicarbazone ligands, nickel(II) complexes with ligands Hmtsc, Hatsc, Hasc and H2dmtsc, were prepared and characterized by elemental analysis, FT-IR, 1H and 13C NMR spectroscopies, magnetic susceptibility measurements, UV-Vis absorption spectra, TG/DTA and single-crystal X-ray analysis. Their antimicrobial activities were evaluated by the MIC against four bacteria (B. subtilis, S. aureus, E. coli and P. aeruginosa), two yeasts (C. albicans and S. cerevisiae) and two molds (A. niger and P. citrinum). The 4-coordinate, diamagnetic nickel(II) complexes showed antimicrobial activities which were different from those of free ligands or the starting nickel(II) compounds; [Ni(mtsc)(OAc)] 1 showed selective and effective antimicrobial activities against two Gram-positive bacteria (B. subtilis and S. aureus) and modest activities against a yeast (S. cerevisiae), [Ni(mtsc)Cl] 3 exhibited moderate activities against a Gram-positive bacterium (S. aureus), and [Ni(atsc)(OAc)] 5 showed modest activities against two Gram-positive bacteria (B. subtilis and S. aureus). On the other hand, the 6-coordinate, paramagnetic nickel(II) complexes with two protonated or deprotonated ligands ([Ni(mtsc)2] 2, [Ni(atsc)(mtsc)] 4, [Ni(atsc)2] 6, [Ni(Hatsc)2](NO3)(2)7, [Ni(Hatsc)2]Cl(2)8 and [Ni(Hasc)2](OAc)(2)9) and the sterically crowded 4-coordinate, diamagnetic nickel(II) complex ([Ni(dmtsc)] 10) did not inhibit the growth of the test organisms. The structure-activity correlation in this series of nickel(II) complexes was discussed based on their ligand-replacement abilities.     

Syntheses, crystal structures and antimicrobial activities of 6-coordinate antimony(III) complexes with tridentate 2-acetylpyridine thiosemicarbazone, bis(thiosemicarbazone) and semicarbazone ligands

Five novel antimony(III) complexes with the mono- and bis(thiosemicarbazone) ligands of 2N1S or 4N2S donor atoms, N'-[1-(2-pyridyl)ethylidene]morpholine-4-carbothiohydrazide (Hmtsc, L1) and bis[N'-[1-(2-pyridyl)ethylidene]]-1,4-piperazinedicarbothiohydrazide (H(2)ptsc, L7), and the tridentate semicarbazone ligand of 2N1O donor atoms, 2-acetylpyridine semicarbazone (Hasc, L2b), were prepared by reactions of SbCl(3) or SbBr(3), and characterized by elemental analysis, TG/DTA, FT-IR and (1)H NMR spectroscopy. The crystal and molecular structures of five antimony(III) complexes were determined by single-crystal X-ray structure analysis. The neutral, 6-coordinate antimony(III) complexes ([Sb(mtsc)Cl(2)] 1, [Sb(mtsc)Br(2)] 2, [Sb(asc)Cl(2)] 3 and [Sb(asc)Br(2)] 4) are depicted with one electron pair (5s(2)) of the antimony(III) atom, deprotonated forms of multidentate thiosemicarbazone or semicarbazone ligands, and two monodentate halogen ligands, respectively. In the dimer complex 5 ([Sb(2)(ptsc)Cl(4)]) with the ligand in which two tridentate thiosemicarbazone moieties are connected by the piperazine moiety, each antimony(III) was also described as a neutral 6-coordinate structure. These antimony(III) complexes were thermally stable around 200 degrees C. Water-soluble antimony(III) complexes 1 and 2 showed moderate antimicrobial activities against Gram-positive (Bacillus subtilis and Staphylococcus aureus) and -negative bacteria (Escherichia coli and Pseudomonas aeruginosa), yeasts (Candida albicans and Saccharomyces cerevisiae) and molds (Aspergillus niger and Penicillium citrinum). Complex 5 showed moderate antimicrobial activities against four bacteria, and two molds, while the ligand itself showed only modest antimicrobial activities against selected bacteria (B. subtilis, E. coli and S. aureus). The molecular structures and antimicrobial activities of antimony(III) complexes were compared with those of bismuth(III) complexes in the same 15 group in the periodic table.     

Functionalized 3-benzylidene-indolin-2-ones: Inducers of NAD(P)H-quinone oxidoreductase 1 (NQO1) with antiproliferative activity

Functionalized benzylidene-indolin-2-ones are widely associated with antiproliferative activity. The scaffold is not normally associated with chemoprevention in spite of the presence of a nitrogen-linked Michael acceptor moiety that may predispose members to induction of NQO1, a widely used biomarker of chemopreventive potential. To investigate this possibility, we have synthesized and evaluated a series of functionalized 3-benzylidene-indolin-2-ones for induction of NQO1 in murine Hepa1c1c7 cells as well as antiproliferative activity against two human cancer cell lines (MCF-7, HCT116). The benzylideneindolinones were found to be good inducers of NQO1 activity, with 85% of test compounds able to increase basal NQO1 activity by more than twofold at concentrations of ?10 μM. By contrast, fewer compounds (11%) tested at the same concentration were able to reduce cell viability by more than 50%. Structure activity relationships showed that the nitrogen linked Michael acceptor moiety was an essential requirement for both activities. This common feature notwithstanding, substitution of the 3-benzylidene-indolin-2-one core structure affected NQO1 induction and antiproliferative activities in dissimilar ways, underscoring different structural requirements for these two activities. Nonetheless, promising compounds (10, 42, 45–48) were identified that combine selective induction of NQO1 with potent antiproliferative activity. A potential advantage of such agents would be the ability to provide added protection to normal cells by the up-regulation of NQO1 and other phase II enzymes while simultaneously targeting neoplastic cells.