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At least 1,531 records · Page 85Linked to original sources
PubMed2000

Triterpenoids from Tripterygium wilfordii.

The extract (T(II)) of Tripterygium wilfordii Hook f. afforded four triterpenoids: wilforic acid D (3beta,24-epoxy-2alpha-hydroxy-24R*-ethoxy-29-friedelanoic acid); (E) 3beta,24-epoxy-2-oxo-3alpha-hydroxy-29-friedelanoic acid; (F) 2beta-hydroxy-3-oxo-friedelan-29-oic acid; 29-hydroxy-3-oxo-olean-12-en-28-oic acid and 17 known triterpenoids. Their structures were established on the basis of spectroscopic studies. In a bioactivity analysis, only the known dulcioic acid compound showed a significant inhibitory effect on cytokine production.

Immunosuppressive Agents↗
PubMed1999

Epitope mapping of secreted mouse leptin utilizing peripherally administered synthetic peptides.

We have recently reported that intraperitoneal (i.p.) administration of synthetic peptide amides corresponding to amino acids 106-140 of mouse leptin significantly reduced food intake and body weight gain in female C57BL/6J ob/ob mice. These results suggested that leptin activity was localized in domains toward its C-terminus between residues 106-140. In the present study, 14 overlapping peptides encompassing the complete sequence of secreted mouse leptin were synthesized, and their effects on body weight and food intake in female C57BL/6 J ob/ob mice were assessed. When given as seven daily 1-mg i.p. injections, only peptides corresponding to amino acids 106-120, 116-130 and 126-140 caused significant reductions in body weight and food intake. These results confirmed our earlier study and suggest that in contrast to the domain encompassed by amino acids 106-140, the N-terminal of mouse leptin between amino acids 21-105 may not contain functional epitopes that can be utilized as lead compounds in the development of peripherally administered bioactive peptide analogs or nonpeptide mimetics of leptin, which may have potential usefulness in treatment of the energy imbalance associated with obesity.

Amino Acid Sequence↗
PubMed1999

A highly convenient synthesis of hydroxytyrosol and its recovery from agricultural waste waters.

Hydroxytyrosol, a polyphenol with very interesting antioxidant properties, which naturally occurs in virgin olive oil and mainly in olive oil mill waste waters, was synthesized by reducing 3, 4-dihydroxyphenylacetic acid with LiAlH(4) in tetrahydrofuran under refluxing for 2 h. The yield of reaction was 82.8%. The spectroscopic and HPLC data of the synthesized compound proved to coincide fully with those of a pure sample obtained by the chromatographic recovery from olive oil mill waste waters (yield = 91 mg/L). This synthetic method appears to be the most convenient compared with those reported in the literature and is more convenient than the chromatographic recovery. The tri- and diacetyl derivatives of the synthetic compound were also prepared for structure-bioactivity relationship studies. A brief discussion is given on the economical and ecological aspects regarding the production of hydroxytyrosol.

Agriculture↗
PubMed2000

Development of peptide 3D structure mimetics: rational design of novel peptoid cholecystokinin receptor antagonists.

The two hormones cholecystokinin and gastrin share the same C-terminal sequence of amino acids, namely Gly(29)-Trp(30)-Met(31)-Asp(32)-Phe(33)-NH(2). Nevertheless, this congruence has not precluded using this structure to develop selective ligands for either CCK(1) or CCK(2) receptors. Manipulation of the hydrophobic residues at positions 31 and 33 gave a series of CCK(1) tripeptide antagonists, typified by N-t-BOC-Trp-2-Nal-Asp-2-(phenyl)ethylamide (pK(B) 6.8 +/- 0.3). Molecular modeling was used to identify the bioactive conformation of these CCK(1)-selective compounds and prompted the design of new peptoid structures. We aimed to maintain the conformation of the parent series by exploiting patterns of hydrogen-bonding and pi-stacking interactions present in the original molecule, rather than introducing additional covalent bonds. The prototype, N-(succinyl-D-Asp-2-phenylethylamido)-L-Trp-2-(2-naphthyl)ethylami de, was a potent and selective CCK(1) antagonist (pK(B) 7.2 +/- 0.3). Furthermore, the new series showed patterns of biological activity that mirrored those of the parent tripeptides. These compounds contain elements of both peptide primary and secondary structure and represent a novel approach to designing peptidomimetics. Interesting results were obtained from comparing models of a representative tripeptide CCK(1) antagonist with a conformation of CCK(30)(-)(33) that others have proposed to be responsible for its activity at the CCK(2) receptor. The results suggest that CCK(1) and CCK(2) receptors recognize enatiomeric dispositions of the Trp(30) indole, Asp(32) carboxylic acid, and C-terminal phenyl groups arrayed about a common backbone configuration. This "functional chirality" may underpin the mechanism by which these closely related receptor systems bind CCK(30)(-)(33) and explain patterns of selectivity observed with optical isomers of a number of peptoid and nonpeptide ligands.

Animals↗
PubMed2006

New 2',6'-dimethyl-L-tyrosine (Dmt) opioid peptidomimetics based on the Aba-Gly scaffold. Development of unique mu-opioid receptor ligands.

The Aba-Gly scaffold, incorporated into Dmt-Tic ligands (H-Dmt-Tic-Gly-NH-CH2-Ph, H-Dmt-Tic-Gly-NH-Ph, H-Dmt-Tic-NH-CH2-Bid), exhibited mixed micro/delta or delta opioid receptor activities with micro agonism. Substitution of Tic by Aba-Gly coupled to -NH-CH2-Ph (1), -NH-Ph (2), or -Bid (Bid=1H-benzimidazole-2-yl) (3) shifted affinity (Ki(micro)=0.46, 1.48, and 19.9 nM, respectively), selectivity, and bioactivity to micro-opioid receptors. These compounds represent templates for a new class of lead opioid agonists that are easily synthesized and suitable for therapeutic pain relief.

Analgesics, Opioid↗
PubMed1999

The presence of substituents on the aryl moiety of the aryl phosphoramidate derivative of d4T enhances anti-HIV efficacy in cell culture: A structure-activity relationship.

New substituted-aryl phosphoramidate derivatives of the anti-HIV drug d4T were synthesized as membrane-soluble intracellular prodrugs for the free bioactive phosphate to establish relationship(s) between compound structure and in vitro antiviral activity. The majority of compounds demonstrated an elevation of in vitro potency relative to that of the parent nucleoside, and unlike d4T, all retained full activity in thymidine kinase-deficient cells. The compound bearing a p-chloro aryl group (8e) expressed nanomolar activity in vitro, a 14-fold increase in activity relative to that of the unsubstituted phosphoramidate (100-fold compared to d4T). An assay using pig liver esterase was used to establish the stability of the compounds to enzymatic degradation. While there was no apparent correlation between in vitro activity and half-life of enzymatic degradation, there was a close correlation between compound lipophilicity, determined by octanol/water partition coefficient, and in vitro potency. We suggest that substitutions made to the aryl moiety of the aryl phosphoramidate of d4T that result in enhancing lipophilicity may serve to increase the cellular uptake of the prodrug by passive diffusion, leading to the expression of antiviral potency at reduced prodrug concentrations.

3T3 Cells↗
PubMed2002

A new triterpene saponin from Pittosporum viridiflorum from the Madagascar rainforest.

A novel triterpenoid saponin, pittoviridoside (1), which possesses an unusual 2,3,4-trisubstituted glycosidic linkage, has been isolated from Pittosporum viridiflorum using the engineered yeast strains 1138, 1140, 1353, and Sc-7 for bioactivity-guided fractionation. The structure of this compound was determined to be 3-O-[beta-D-glucopyranosyl(1-->2)]-[alpha-D-arabinopyranosyl(1-->3)],[alpha-l-arabinofuranosyl(1-->4)-beta-D-glucuronopyranosyl-21-angeloyl-22-senecioylolean-12-en-3beta,15alpha,16alpha,21beta,22alpha,28-hexol by spectral, chemical, and GC analyses. This compound showed weak cytotoxicity against the A2780 human ovarian cancer cell line.

Antineoplastic Agents, Phytogenic↗
PubMed1996

Squamotacin: an annonaceous acetogenin with cytotoxic selectivity for the human prostate tumor cell line (PC-3).

The bark extracts of Annona squamosa yielded a new bioactive acetogenin, squamotacin (1), and the known compound, molvizarin (2), which is new to this species. Compound 1 is identical to the potent acetogenin, bullatacin (3), except that the adjacent bistetrahydrofuran (THF) rings and their flanking hydroxyls are shifted two carbons toward the gamma-lactone ring. Compound 1 showed cytotoxic selectively for the human prostate tumor cell line (PC-3), with a potency of over 100 million times that of Adriamycin.

4-Butyrolactone↗
PubMed1999

1',2',3',4'-tetradehydrotubulosine, a cytotoxic alkaloid from Pogonopus speciosus.

Bioassay-guided phytochemical investigation of the stems of Pogonopus speciosus, using human oral epidermoid carcinoma (KB) cells as a monitor, led to the isolation of a novel alkaloid, 1',2', 3',4'-tetradehydrotubulosine (1), along with tubulosine (2) and psychotrine (3) as bioactive constituents. The structure of the novel compound was elucidated through 1D- and 2D-NMR spectroscopic methods. Alkaloids 1 and 3 showed weak cytotoxic activity against a panel of human cancer cell lines, with the potency of these compounds being markedly less than that of tubulosine (2).

Alkaloids↗
PubMed2003

Merging the potential of microbial genetics with biological and chemical diversity: an even brighter future for marine natural product drug discovery.

Marine invertebrates and a growing number of marine bacteria are the sources of novel, bioactive secondary metabolites. Structurally, many of these compounds appear to be biosynthesized by polyketide synthases (PKS) and/or nonribosomal peptide synthetases (NRPS) that have also been found in terrestrial microbes. This review highlights scientific advances from 1999-2003 in the emerging field of molecular genetics of polyketide and nonribosomal peptide natural products isolated from marine organisms. The implications of this research towards the development of marine secondary metabolites as a sustainable source of new drugs are discussed.

Biodiversity↗
PubMed2001

Inhibition of xanthine and monoamine oxidases by stilbenoids from Veratrum taliense.

The bioassay guided refractionation of the methanol extract of roots and rhizomes of Veratrum taliense (Liliaceae) yielded five stilbenoids: veraphenol, resveratrol, piceid, isorhapontin, and mulberroside E, all inhibiting xanthine oxidase (XO, EC 1.2.3.2.) in vitro in a dose-dependent manner with IC50 values of 11.0, 96.7, 66.1, 70.0, and 78.4 microM, respectively. Veraphenol and mulberroside E were found to be mixed XO inhibitors with the Ki and Ki data of the former being 32.8 and 239.3 microM, and those of latter 32.5 and 13.8 microM, respectively. However, the inhibition on the enzyme by resveratrol, isorhapontin, and piceid was shown to be competitive with their Ki values of 9.7, 19.1, and 14.3 microM, respectively. Among the five stilbenoids, veraphenol and resveratrol were also revealed to inhibit competitively monoamine oxidase A (MAO, EC 1.4.3.4) with IC50 values at 38.0 and 26.6 microM, and Ki data 36.4 and 47.3 microM, respectively. However, none of the stilbenoids was inhibitory on MAO B in our assay. The structure-activity relationship examination showed that glycosylation of the stilbenoids could reduce the inhibition on XO and diminish the activity against MAO A, indicating that the free phenolic hydroxy group of the compounds was most likely essential for these bioactivities.

Animals↗
PubMed1999

Inositol 1,4,5-trisphosphate-independent Ca(2+) mobilization triggered by a lipid factor isolated from vitreous body.

A complex phospholipid from bovine vitreous body with a strong Ca(2+)-mobilizing activity has been recently isolated to homogeneity by our group. In this work, a sequential analysis of its transmembrane signaling pathway has been undertaken to characterize the intracellular mechanisms responsible for the Ca(2+) rise. The results show that this phospholipid induces, in a dose-dependent manner (ED(50) of around 0.25 microgram/ml), a Ca(2+) mobilization from inositol 1,4,5-trisphosphate-insensitive intracellular stores, with no participation of extracellular Ca(2+). Upon repeated administration, it shows no signs of autologous desensitization, does not induce heterologous desensitization of the L-alpha-lysophosphatidic acid (LPA) receptor but is desensitized by the previous administration of LPA. The Ca(2+)-mobilizing activity requires a membrane protein, is blocked after preincubation of the cells with pertussis toxin and phorbol esters, as well as by U73122 (an inhibitor of phospholipases C/D), R59022 (a diacylglycerol kinase inhibitor), and D609 (which inhibits phosphatidylcholine-specific phospholipase C). Upon administration of this phospholipid, the intracellular levels of phosphatidic acid (PA) rise with a time course that parallels that of the Ca(2+) mobilization, suggesting that PA could be responsible for this Ca(2+) signal. Exposure to AACOCF(3) (a specific inhibitor of phospholipase A(2)) does not modify the Ca(2+) rise, ruling out the possibility that the PA generated could be further converted to LPA by the action of phospholipase A(2). Based on the experimental data obtained, a signaling pathway involving a phosphatidylcholine-specific phospholipase C coupled to diacylglycerol kinase is proposed. This compound may represent a new class of bioactive lipids with a putative role in the physiology of the vitreous body.

3T3 Cells↗
PubMed2006

Requirement of transmembrane transport for S-nitrosocysteine-dependent modification of intracellular thiols.

S-nitrosothiols have been implicated as intermediary transducers of nitric oxide bioactivity; however, the mechanisms by which these compounds affect cellular functions have not been fully established. In this study, we have examined the effect of S-nitrosothiol transport on intracellular thiol status and upon the activity of a target protein (caspase-3), in bovine aortic endothelial cells. We have previously demonstrated that the specific transport of amino acid-based S-nitrosothiols (S-nitroso-L-cysteine and S-nitrosohomocysteine) occurs via amino acid transport system L to generate high levels of intracellular protein S-nitrosothiols (Zhang, Y., and Hogg, N. (2004) Proc. Natl. Acad. Sci. U. S. A. 101, 7891-7896). In this study, we demonstrate that the transport of S-nitrosothiols is essential for these compounds to affect intracellular thiol levels and to modify intracellular protein activity. Importantly, the ability of these compounds to affect intracellular processes occurs independently of nitric oxide formation. These findings suggest that the major action of these compounds is not to liberate nitric oxide in the extracellular space but to be specifically transported into cells where they are able to modify cellular functions through nitric oxide-independent mechanisms.

Animals↗
PubMed1983

Pharmacokinetics of azlocillin in normal renal function: single and repetitive dosing studies.

Systemic and urinary pharmacokinetic studies of the disposition of azlocillin were performed in seven male and six female healthy volunteers. Four separate studies identified the kinetics of the drug following a single 2, 3 or 4 g administration and during the repetitive administrations of 3 g of the drug over a five-day period. Peak plasma concentrations were 174 +/- 19 mg/l, 214 +/- 17 mg/l and 286 +/- 11 mg/l in the 2, 3 and 4 g single dose studies respectively. Trough values at 4 h post-dosing were 6 +/- 1 mg/l, 10 +/- 1 mg/l and 26 +/- 3 mg/l respectively. The plasma half-life of azlocillin was approximately 60 min. A dose-dependent phenomenon was observed. This was characterized by a slight but significant progressive increase in the plasma half-life of the drug as increasing amounts of drug were given and as the same amount was given repeatedly. No significant systemic accumulation of azlocillin was noted during the repetitive dosing study. The urinary excretion of the compound was prompt with most of the bioactive drug being eliminated in the first 4-6 h following dosing. The apparent volume of distribution of azlocillin was slightly greater than the extracellular fluid compartment. For the therapy of systemic infections in adults with normal renal function a 4 h or 6 h dosing cycle would be appropriate.

Azlocillin↗
PubMed1998

NAD(P)H:quinone oxidoreductase: polymorphisms and allele frequencies in Caucasian, Chinese and Canadian Native Indian and Inuit populations.

NAD(P)H:quinone oxidoreductase (NQO1) catalyses the two-electron reduction of quinone compounds. NQO1 is involved in the reductive bioactivation of cytotoxic antitumour quinones such as mitomycin C, but also plays a protective role against the carcinogenicity and mutagenicity of quinones, their precursors and metabolites. Three alleles have been identified in the human population: the functional Arg139/Pro187 allele (which we have termed NQO1*1); the nonfunctional allele Arg139/Ser187 (NQO1*2) and the Trp139/Pro187 allele (NQO1*3), which is associated with a diminished activity. We applied polymerase chain reaction-based genotyping assays to characterize interethnic variability in the frequency of NQO1 alleles in Caucasian (n = 575), Canadian Native Indian (n = 110), Canadian Inuit (n = 83) and Chinese (n = 86) populations. The NQO1*2 allele was found at significantly higher frequencies in Chinese (0.49) and Native North American populations (Inuit 0.46; Canadian Native Indians 0.40) compared with Caucasians (0.16). The NQO1*3 allele was not observed in Inuit individuals, and occurred at a lower frequency than the NQO*2 allele in Caucasians (0.05), Chinese (0.04) and Canadian Native Indians (0.01). Our results predict that a greater proportion of Orientals and related ethnic groups lack, or have reduced, NQO activity relative to Caucasians. Affected individuals may not only exhibit resistance to quinone-based cancer therapy because of a decreased production of cytotoxic drug metabolites, but may also be more susceptible to toxicities associated with toxicants.

Alleles↗
PubMed2006

Absorption and metabolism of Astragali radix decoction: in silico, in vitro, and a case study in vivo.

To profile absorption of Astragali Radix decoction and identify its orally absorbable constituents and their metabolites, four complementary in silico, in vitro, and in vivo methods, i.e., a computational chemistry prediction method, a Caco-2 cell monolayer model experiment, an improved rat everted gut sac experiment, and a healthy human volunteer experiment, were used. According to the in silico computation result, 26 compounds of Astragali Radix could be regarded as orally available compounds, including 12 flavonoids. In the in vitro and in vivo experiments, 21 compounds were tentatively identified by high-performance liquid chromatography-diode array detection-electrospray ion trap tandem mass spectrometry data, which involved calycosin, formononetin, (6aR,11aR)-3-hydroxy-9,10-dimethoxypterocarpan, 7,2'-dihydroxy-3',4'-dimethoxyisoflavan, calycosin-7-O-beta-D-glucoside, formononetin-7-O-beta-D-glucoside, 7,2'-dihydroxy-3',4'-dimethoxyisoflavan-7-O-beta-D-glucoside-6''-O-malonate, (6aR,11aR)-3-hydroxy-9,10-dimethoxypterocarpan-3-O-beta-D-glucoside, and phase II metabolites calycosin-7-O-beta-D-glucuronide, formononetin-7-O-beta-D-glucuronide, (6aR,11aR)-3-hydroxy-9,10-dimethoxypterocarpan-3-O-beta-D-glucuronide, 7,2'-dihydroxy-3',4'-dimethoxyisoflavan-7-O-beta-D-glucuronide, and calycosin sulfate. Calycosin and formononetin were proved absorbable by four methods; (6aR,11aR)-3-hydroxy-9,10-dimethoxypterocarpan and 7,2'-dihydroxy-3',4'-dimethoxyisoflavan were proved absorbable by three methods; formononetin-7-O-beta-D-glucoside and (6aR,11aR)-3-hydroxy-9,10-dimethoxypterocarpan-3-O-beta-D-glucoside were proved absorbable by two methods. The existence of calycosin-7-O-beta-D-glucuronide, formononetin-7-O-beta-D-glucuronide, (6aR,11aR)-3-hydroxy-9,10-dimethoxypterocarpan-3-O-beta-D-glucuronide, 7,2'-dihydroxy-3',4'-dimethoxyisoflavan-7-O-beta-D-glucuronide, and calycosin sulfate was proved by two or three methods. We found that besides isoflavones, pterocarpans and isoflavans also could be metabolized by the intestine during absorption, and the major metabolites were glucuronides. In conclusion, the present study demonstrated that the flavonoids in Astragali Radix decoction, including isoflavones, pterocarpans, and isoflavans, could be absorbed and metabolized by the intestine. These absorbable compounds, which were reported to have various bioactivities related to the curative effects of Astragali Radix decoction, could be regarded as an important component of the effective constituents of Astragali Radix decoction.

Adult↗
PubMed1996

Comparative cytotoxicity of 14 novel selenocysteine se-conjugates in rat renal proximal tubular cells.

Recently, Se-substituted selenocysteine conjugates were proposed as potential prodrugs to target biologically active selenol compounds to tissues containing high activities of cysteine conjugate beta-lyases, such as the kidneys. However, several selenium compounds are known to be relatively toxic compounds. In the present study, the cytotoxicity of 14 selenocysteine Se-conjugates was determined in freshly isolated rat renal proximal tubular cells (RPTC). The results of this study show that four selenocysteine Se-conjugates with alkyl substituents (methyl, ethyl, n-propyl, and n-butyl) did not cause significant cytotoxicity to RPTC up to concentrations of 500 microM after 90 min of incubation. Also, no effect was observed on mitochondrial functioning as indicated by the unaffected mitochondrial membrane potential (delta psi). Se-(i-Propyl)-selenocysteine, however, appeared to be a cytotoxic compound, causing time- and dose-dependent cytotoxicity, and caused a decrease of delta psi in remaining viable cells. Aminooxyacetic acid (AOAA) provided significant protection against cell death of Se-(i-propyl)-selenocysteine, pointing to involvement of cysteine conjugate beta-lyase. AOAA, however, did not prevent the decrease of delta psi. Differentially substituted Se-(phenyl)-L-selenocysteine and Se-(benzyl)-L-selenocysteine conjugates appeared to be cytotoxic to RPTC at a concentration of 200 microM, as indicated by increased cell death and a decreased delta psi in remaining viable cells. Within the Se-benzyl-series, Se-(4-methoxybenzyl)-L-selenocysteine was the most toxic conjugate, whereas Se-(4-chlorophenyl)-L-selenocysteine was the most toxic conjugate of the Se-phenyl compounds. The selenocysteine Se-conjugates with nonsubstituted phenyl and benzyl substituents were nontoxic at 200 microM, but caused significant cell death at a concentration of 500 microM. Preincubation with AOAA, an inhibitor of cysteine conjugate beta-lyase, provided only partial protection against the cytotoxicity of Se-(phenyl)-L-selenocysteine (500 microM) and Se-(4-methoxybenzyl)-L-selenocysteine (200 microM). AOAA did not protect against cytotoxicity of the other conjugates, suggesting direct effects of these compounds or involvement of alternative routes of bioactivation. This study demonstrates that cytotoxicity of selenocysteine Se-conjugates is strongly dependent on the nature of the Se-bound substituent. The nontoxic Se-(alkyl)-Se-conjugates may be promising candidates for further evaluation for chemopreventive activities.

Aminooxyacetic Acid↗