Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “bioactive compound”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,261 records · Page 70Linked to original sources
PubMed2006

[Separation and identification of active constituents of Paris vietnamensis].

AIM: To study the anti-tumor bioactive steroid saponins of Paris vietnamensis (Takht.). METHODS: The constituents were isolated and purified by chromatography and their structures were identified by spectral analysis and physicochemical properties. The cytotoxic bioactivities of the constituents were determined by MTT. RESULTS: Eleven compounds were obtained and identified as 3beta, 5alpha,6alpha-trihydroxy-7(8)-en-isospirostanol-3-O-beta-D-glucopyranosyl(1-->3) [alpha-L-rhamnopyranosyl(1-->2)]-beta-D-glucopyranoside (1), which was named as parisvietnaside A, 25 (R) diosgenin-3-O-alpha-L-arabinofuranosyl(1-->4)-beta-D-glucopyranoside (2), 25(R) diosgenin-3-O-alpha-L-rhamnopyranosyl(1-->2)-beta-D-glucopyranoside (3), 25 (R) diosgenin-3-O-alpha-L-arabinofuranosyl (1-->4) [alpha-L-rhamnopyranosyl (1-->2)]-beta-D-glucopyranoside (4), 25 (R) diosgenin-3-O-beta-D-glucopyranosyl (1-->3) [alpha-L-rhamnopyranosyl (1-->2)]-beta-D-glucopyranoside (5), 25 (R) diosgenin-3-O-alpha-L-rhamnopyranosyl (1-->4)-alpha-L-rhamnopyranosyl(1-->4) [alpha-L-rhamnopyranosyl-(1-->2)]-beta-D-glucopyranoside (6), 25 (R) pennogenin-3-O-alpha-L-arabinofuranosyl(1-->4)-beta-D-glucopyranoside (7), 25 (R) pennogenin-3-O-alpha-L-rhamnopyranosyl (1-->2)-beta-D-glucopyranoside (8), 25 (R) pennogenin-3-O-alpha-L-arabinofuranosyl (1-->4) [alpha-L-rhamnopyranosyl-(1-->2)]-beta-D-glucopyranoside (9), 25 (R) pennogenin-3-O-beta-D-glycopyranosyl (1-->3) [alpha-L-rhamnopyranosyl(1-->2)-beta-D-glucopyranoside (10) and 25 (R) pennogenin-3-O-alpha-L-rhamnopyranosyl (1-->4)-alpha-L-rhamnopyranosyl(1-->4) [alpha-L-rhamnopyranosyl-(1-->2)]-beta-D-glucopyranoside (11). Some constituents had cytotoxic bioactivities. CONCLUSION: Compound 1 is a new spirostanol saponin, and compounds 2, 3, 6-11 were obtained from Paris vietnamensis (Takht.) for the first time. Compounds 3, 4, 6, 8 had cytotoxic bioactivities against tumor cells HepG2 and SGC-7901.

Adenocarcinoma↗
PubMed1997

New anti-HIV-1, antimalarial, and antifungal compounds from Terminalia bellerica.

A bioactivity-guided fractionation of an extract of Terminalia bellerica fruit rind led to the isolation of two new lignans named termilignan (1) and thannilignan (2), together with 7-hydroxy-3',4'-(methylenedioxy)flavan (3) and anolignan B (4). All four compounds possessed demonstrable anti-HIV-1, antimalarial, and antifungal activity in vitro.

Anti-HIV Agents↗
PubMed2006

Preparative isolation and purification of chemical constituents from the root of Polygonum multiflorum by high-speed counter-current chromatography.

High-speed counter-current chromatography methods, combined with solvent partition, were applied to the systematic separation and purification of chemical components from Chinese medicinal herb Polygonum multiflorum extract. The aim of this paper is summing up the rules of solvent system selection for diverse fractions of herbal extract, and establishing the systematic pattern to screen the bioactive constituents rapidly. Nine compounds including emodin, chrysophanol, rhein, 6-OH-emodin, emodin-8-beta-D-glucoside, polygonimitin B, 2,3,5,4'-tetrahydroxystilbene-2-beta-D-glucoside, gallic acid and an unknown glycoside, which differed in quantity and polarity remarkably, were obtained. The purities of them were all above 97% as determined by high-performance liquid chromatography (HPLC), and their structures were identified by 1H NMR and electrospray ionization mass spectrometry (ESI-MS). The results demonstrated that HSCCC is a speedy and efficient technique for systematic isolation of bioactive components from traditional medicinal herbs.

Anthraquinones↗
PubMed2000

Salivary glands in ixodid ticks: control and mechanism of secretion.

The salivary glands are vital to the biological success of ixodid ticks and the major route for pathogen transmission. Important functions include the absorption of water vapor from unsaturated air by free-living ticks, excretion of excess fluid for blood meal concentration, and the secretion of bioactive protein and lipid compounds during tick feeding. Fluid secretion is controlled by nerves. Dopamine is the neurotransmitter at the neuroeffector junction regulating secretion via adenylate cyclase and an increase in cellular cAMP. Dopamine also affects the release of arachidonic acid which is subsequently converted to prostaglandins. Prostaglandin E(2) (PGE(2)) is secreted at extremely high levels into tick saliva for export to the host where it impacts the host physiology. Additionally, PGE(2) has an autocrine or paracrine role within the salivary gland itself where it interacts with a PGE(2) receptor to induce secretion (exocytosis) of bioactive saliva proteins via a phosphoinositide signalling pathway and an increase in cellular Ca(2+). Regulation of fluid secretion has been extensively studied, but little is known about the mechanism of fluid secretion. Continuing advances in tick salivary gland physiology will be made as key regulatory and secretory gland proteins are purified and/or their genes cloned and sequenced.

Journal Article↗
PubMedDate not supplied

3,3',5'-Tri-O-methylpiceatannol and 4,3',5'-tri-O-methylpiceatannol: improvements over piceatannol in bioactivity.

Piceatannol (3,4,3',5'-tetrahydroxy-trans-stilbene) (NSC 365798) has recently been isolated and was subsequently synthesized for NCI tumor panel testing as a new antileukemic natural product from the seeds of Euphorbia lagascae. During the synthesis, a bioactive reaction mixture of several partially O-methylated piceatannol analogues was obtained. This mixture has now been maximized and subjected to bioactivity-directed fractionation, using brine shrimp lethality, to yield 3,3',5'-tri-O-methylpiceatannol (NSC 381281); this new compound has improved stability and better bioactivity in several systems than piceatannol itself. To confirm the structure, 5 was synthesized from vanillin. In addition, the isovanillin analogue, 4,3',5'-tri-O-methylpiceatannol (NSC 381864), another new compound, was synthesized and found to be bioactive.

Animals↗
PubMed2005

The use of biodiversity as source of new chemical entities against defined molecular targets for treatment of malaria, tuberculosis, and T-cell mediated diseases--a review.

The modern approach to the development of new chemical entities against complex diseases, especially the neglected endemic diseases such as tuberculosis and malaria, is based on the use of defined molecular targets. Among the advantages, this approach allows (i) the search and identification of lead compounds with defined molecular mechanisms against a defined target (e.g. enzymes from defined pathways), (ii) the analysis of a great number of compounds with a favorable cost/benefit ratio, (iii) the development even in the initial stages of compounds with selective toxicity (the fundamental principle of chemotherapy), (iv) the evaluation of plant extracts as well as of pure substances. The current use of such technology, unfortunately, is concentrated in developed countries, especially in the big pharma. This fact contributes in a significant way to hamper the development of innovative new compounds to treat neglected diseases. The large biodiversity within the territory of Brazil puts the country in a strategic position to develop the rational and sustained exploration of new metabolites of therapeutic value. The extension of the country covers a wide range of climates, soil types, and altitudes, providing a unique set of selective pressures for the adaptation of plant life in these scenarios. Chemical diversity is also driven by these forces, in an attempt to best fit the plant communities to the particular abiotic stresses, fauna, and microbes that co-exist with them. Certain areas of vegetation (Amazonian Forest, Atlantic Forest, Araucaria Forest, Cerrado-Brazilian Savanna, and Caatinga) are rich in species and types of environments to be used to search for natural compounds active against tuberculosis, malaria, and chronic-degenerative diseases. The present review describes some strategies to search for natural compounds, whose choice can be based on ethnobotanical and chemotaxonomical studies, and screen for their ability to bind to immobilized drug targets and to inhibit their activities. Molecular cloning, gene knockout, protein expression and purification, N-terminal sequencing, and mass spectrometry are the methods of choice to provide homogeneous drug targets for immobilization by optimized chemical reactions. Plant extract preparations, fractionation of promising plant extracts, propagation protocols and definition of in planta studies to maximize product yield of plant species producing active compounds have to be performed to provide a continuing supply of bioactive materials. Chemical characterization of natural compounds, determination of mode of action by kinetics and other spectroscopic methods (MS, X-ray, NMR), as well as in vitro and in vivo biological assays, chemical derivatization, and structure-activity relationships have to be carried out to provide a thorough knowledge on which to base the search for natural compounds or their derivatives with biological activity.

Anti-Bacterial Agents↗
PubMed1998

Cytotoxicity of a series of mono- and di-substituted thiourea in freshly isolated rat hepatocytes: a preliminary structure-toxicity relationship study.

The cytotoxicity of a series of 12 mono- and 4 di-substituted thiourea containing compounds in freshly isolated rat hepatocytes was investigated. It was found that thiourea toxicity, as evidenced by an increase in LDH-leakage from the cells, was accompanied by a depletion of intracellular glutathione (GSH). No increase in lipid peroxidation was observed with any of the thiourea. Burimamide and thioperamide, thiourea-containing histamine receptor ligands, were also found to deplete intracellular GSH. A clear structure-toxicity relationship was uncovered among a homologous series of N-phenylalkylthiourea. N-benzylthiourea (BTU) and N-phenylethylthiourea (PETU) were found to be non-toxic at a concentration of 1 mM, while N-phenylpropylthiourea (PPTU) and N-phenylbutylthiourea (PBTU) were found to cause significant LDH-leakage from the cells, accompanied by a depletion of intracellular GSH. This structure-toxicity relationship was further investigated using hepatocytes of differentially induced rats, however, no significantly different results were obtained when using hepatocytes of rats induced with phenobarbital (PB) or beta-naphthoflavone (BNF). Oxidation of the thiourea moiety is thought to be the first step in the bioactivation of thiourea containing compounds. The oxidation of thiocholine sulfenic acids, produced by FMO-mediated oxidation of the thiourea moiety, was used to determine whether the compounds examined are substrates for the FMO enzymes in rat liver. No clear relationship was found between cytotoxicity of the mono-substituted thiourea and lipophilicity of the N-substituent, nor with the FMO-mediated oxidation of the thionosulfur atom of the mono-substituted thiourea. It is concluded from this study, that thiourea toxicity in rat hepatocytes is structure-dependent and manifests itself as LDH-leakage and as a depletion of intracellular non-protein sulfhydryls, notably GSH, most likely followed by alkylation of vital macromolecular structures.

Animals↗
PubMed2006

Dynamics of progestogenic activity in serum following administration of Ligusticum chuanxiong.

Many women are using botanical alternatives for menopausal hormone replacement therapy (HRT) because current progestins, compounds with progesterone activity, have adverse risk profiles. However the development of phyto-progestins for HRT is hampered by the absence of basic pharmacokinetic/pharmacodynamic (PK/PD) data due to the lack of methods to capture summated effects of the numerous compounds that contribute to bioactivity in vivo. In this study, we explored the utility of progesterone receptor (PR)-driven bioassays to track changes in serum progestogenic activity following administration of traditional Chinese medicinal herb, Ligusticum chuanxiong, with potent progestogenic activity. Sensitive and specific (>300-fold) increases in progestogenic activity were observed when HeLa cells transfected with PR and a PR-driven promoter were exposed to the progestogenic drug, medroxy-progesterone acetate (MPA), suggesting the utility of the bioassay to measure progestogenic effects for PK/PD studies. Progestogens were administered to male Sprague-Dawley rats and serum extracted for measurement of progestogenic activity. Effect-time studies indicate that injection of MPA and L. chuanxiong extract raised area-under-curve of progestogenic activity in sera by 8.2-fold (p<0.001) and 4.5-fold (p<0.01) respectively, compared to sera from rats administered vehicle only. Administration of MPA and L. chuanxiong extract by the oral route resulted in a 5.4 (p<0.001) and 2.3-fold (p=0.07) increase respectively. Our data suggest that PR-responsive reporter gene bioassays can measure bioavailability of compounds, known and unknown, of complex botanicals for hormone replacement therapy. L. chuanxiong extracts exert progestogenic activity in vivo, and may have utility for progesterone-replacement therapy.

Animals↗
PubMed2000

Bioactive beta-bend structures for the antagonist halpha CGRP(8 - 37) at the CGRP(1) receptor of the rat pulmonary artery.

The aim of this study was to determine beta-bend structures and the role of the N- and C-terminus in the antagonist halpha CGRP(8 - 37) at the rat pulmonary artery CGRP receptor mediating halpha CGRP relaxation. Halpha CGRP(8 - 37) Pro(16) (10(-6) M), with a bend-biasing residue (proline) at position 16, did not antagonize halpha CGRP responses, while a structure-conserving amino acid (alanine(16)) at the same position retained antagonist activity (apparent pK(B) 6.6+/-0.1; 10(-6) M). Halpha CGRP(8 - 37) Pro(19) (10(-6) M), with proline at position 19 was an antagonist (apparent pK(B) 6.9+/-0.1). Incorporation of a beta-bend forcing residue, BTD (beta-turn dipeptide), at positions 19 and 20 in halpha CGRP(8 - 37) (10(-6) M) antagonized halpha CGRP responses (apparent pK(B) 7.2+/-0.2); and BTD at positions 19,20 and 33,34 within halpha CGRP(8 - 37) was a competitive antagonist (pA(2) 7.2; Schild plot slope 1.0+/-0.1). Halpha CGRP(8 - 37) analogues, substituted at the N-terminus by either glycine(8) or des-NH(2) valine(8) or proline(8) were all antagonists (apparent pK(B) 6.9+/-0.1; (10(-6) M), 7.0+/-0.1 (10(-6) M), and pA(2) 7.0 (slope 1.0+/-0.2), respectively); while replacements by proline(8) together with glutamic acid(10,14) in halpha CGRP(8 - 37) (10(-6) M) or alanine amide(37) at the C-terminus of halpha CGRP(8 - 37) (10(-5) M) were both inactive compounds. In conclusion, possible bioactive structures of halpha CGRP(8 - 37) include two beta-bends (at 18 - 21 and 32 - 35), which were mimicked by BTD incorporation. Within halpha CGRP(8 - 37), the N-terminus is not essential for antagonism while the C-terminus may interact directly with CGRP(1) receptors in the rat pulmonary artery.

Alanine↗
PubMed2005

Contents and bioactivities of lunasin, bowman-birk inhibitor, and isoflavones in soybean seed.

It has been previously demonstrated that lunasin is a novel and promising cancer preventive peptide from soybean. The Bowman-Birk protease inhibitor (BBI) and isoflavones are well-studied substances from soy. This study evaluated the levels and bioactivities of these three compounds as affected by stages of seed development and sprouting under light and dark conditions. BBI and lunasin appear at 7 and 6 weeks, respectively, after flowering and increase as the seed matures. Daidzein and genistein both decrease during seed maturation. During sprouting under light, BBI increases up to the 6th day and decreases thereafter, disappearing at the 9th day after soaking. Under dark conditions, BBI increases up to the 7th day after soaking and decreases thereafter, disappearing at the 10th day. Lunasin starts to decrease at 2 days after soaking and disappears completely at 7 days under light and dark conditions. Daidzein and genistein increase continuously during the 10 days of soaking, and both increase more in the dark than under light conditions. Protein extracts from early seed development (2-5 weeks after flowering) suppress cell viability to a greater degree than those from later stages (6-9 weeks). Inhibition of foci formation by protein extracts from later stages is greater than those from earlier stages. Lunasin and BBI suppress foci formation more than the isoflavones. Sprouting decreases lunasin and BBI contents but increases isoflavones. Protein extracts from early soaking times inhibit foci formation more and suppress cell viability less than those from later soaking times. Light and dark conditions have no influence on the bioactivities of protein extracts. These data are useful in the preparation of soy fractions enriched in lunasin, BBI, and isoflavones and in making dietary recommendations.

Animals↗
PubMed1992

Foreign compound metabolism capacity in man measured from metabolites of dietary caffeine.

Caffeine is sequentially metabolized by cytochrome P4501A2 (CYP1A2), N-acetyltransferase (NAT) and/or xanthine oxidase (XO). In the present study the activity of these three enzymes was estimated from ratios of the metabolites formed from dietary caffeine and excreted into the urine collected as spot samples. In the urine samples from 10 out of 377 subjects concentrations of caffeine metabolites were too low to allow reliable measurements of the ratios. In 335 healthy subjects the NAT activity showed a typically bimodal distribution with 47% fast acetylators and 53% slow acetylators, consistent with a Danish population. The ratios reflecting CYP1A2 and XO activities were log normal and normal distributed, respectively. In 103 non-smoking men and 90 non-smoking women the ratio of caffeine metabolites expressing CYP1A2 activity was 4.7 +/- 1.6 and 4.3 +/- 1.9 as compared to 7.8 +/- 2.5 and 7.3 +/- 3.0 in 31 male and 25 female subjects smoking 10 cigarettes/day or more respectively, verifying induction of CYP1A2 by tobacco (P less than 0.05), but minimal sex-related differences. In 12 non-smoking pregnant women and in 28 women using oral contraceptives the CYP1A2 ratio was 29 and 20% reduced respectively (P less than 0.05). In a multivariate analysis the only significant predictor of the XO ratio was the consumption of caffeine with an increase of 2% per cup of coffee or equivalent (P less than 0.05). In 23 healthy male subjects 30 days of vigorous exercise increased the CYP1A2 ratio by 70% and the XO ratio by 42% (P less than 0.05), but left the NAT ratio unchanged. In nine healthy volunteers daily ingestion of 500 g of broccoli for 10 days increased the CYP1A2 ratio by an average of 12% (P less than 0.05), compared to a control period with ingestion of an equivalent weight of non-cruciferous green vegetables. The ratios of metabolites from dietary caffeine in spot urine samples offer ethical, non-invasive and reliable estimates of CYP1A2, NAT and XO. These enzymes are highly relevant for the bioactivation of potentially toxic compounds and the formation of oxygen radicals. The method is applicable in large-scale epidemiological studies, allowing, for example, prospective testing of the relationship between these enzyme activities and the development of disease. Exercise may increase CYP1A2 activity to a magnitude corresponding to heavy smoking, as well as XO by mechanisms that remain to be clarified.

Acetylation↗
PubMed1996

Reductase enzyme expression across the National Cancer Institute Tumor cell line panel: correlation with sensitivity to mitomycin C and EO9.

BACKGROUND: Many antitumor drugs require metabolic activation to exert their cytotoxic or cytostatic effects. The so-called bioreductive compounds, whose conversion into active antitumor agents is catalyzed by reductase enzymes, are examples of such drugs. The identification of specific enzymes involved in the activation of these compounds is important in understanding cellular factors that may influence drug antitumor activity. PURPOSE: We measured expression levels of three different reductase enzymes-DT-diaphorase [NAD(P)H (i.e., reduced nicotinamide adenine dinucleotide, with or without phosphate): quinone oxidoreductase]; NADPH:cytochrome P-450 reductase; and NADH (i.e., reduced nicotinamide adenine dinucleotide): cytochrome-b5 reductase- in 69 cell lines (most of the National Cancer Institute [NCI] human tumor cell panel) to see if relationships could be established between the activities of these enzymes and cellular sensitivities to the bioreductive compounds mitomycin C and EO9. METHODS: For all 69 cell lines, the activity of each enzyme was determined using cellular extracts and photometric assays involving the reduction of cytochrome c. Western blot analysis was used to measure the relative amount of DT-diaphorase protein in each extract, and coupled reverse transcription and polymerase chain reactions were employed to assess DT-diaphorase and NADPH:cytochrome P-450 reductase messenger RNA (mRNA) levels in a subset of the cell lines. The cytotoxic and/or cytostatic activities of mitomycin C and EO9 toward the cell lines were determined under aerobic conditions. Relationships between enzyme activity levels and drug sensitivities were assessed by use of the COMPARE program and Pearson correlation coefficients. RESULTS: In general, DT-diaphorase activity levels were higher than those observed for the other two reductases across the entire cell line panel. Measured activities for all three enzymes varied among cell lines derived from the same tissue as well as between lines derived from different tissues; however, tissue-specific patterns of expression could be discerned. Differences in the activity levels of individual enzymes appeared to reflect differences in corresponding enzyme protein and/or mRNA levels. A relationship between enzyme activity and chemosensitivities to mitomycin C and EO9 was observed only for DT-diaphorase (Pearson correlation coefficient = .424 [two-sided P<.0005] for mitomycin C and .446 [two-sided P< or = to .0013] for EO9). CONCLUSIONS: Reductase enzyme expression is heterogeneous across human tumor cell lines, and tissue-specific patterns of expression are apparent. DT-diaphorase activity levels correlate with sensitivities to mitomycin C and EO9, supporting a role for this enzyme in the bioactivation of these anticancer compounds. IMPLICATIONS: Comparison of biochemical, molecular biological, and chemosensitivity data obtained from screening a large number of cell lines (e.g., the NCI tumor cell line panel) may facilitate investigation of factors influencing drug antitumor activity. The knowledge gained may be of value in the development of new anticancer agents or in the selection of patients to receive specific therapies.

Antineoplastic Agents↗
PubMed1989

Antithrombogenic surfaces: characterization and bioactivity of surface immobilized PGE1-heparin conjugate.

A covalently bonded conjugate of commercial grade heparin and prostaglandin E1 (PGE1) was synthesized to prevent both fibrin formation and platelet aggregation during thrombus formation. The PGE1-heparin conjugate was immobilized on an imidazole carbamate derivatized sepharose bead surface through hydrophilic spacer groups (diamino-terminated polyethylene oxides). One end of the spacer group was coupled to the derivatized surface through a urethane bond between the amine group of the spacer and the derivatized surface. The free amine group of the immobilized spacers was coupled to a carboxylic group of the PGE1-heparin conjugate through an amide bond. Bioactivity of the immobilized conjugate (heparin activity) was measured in terms of increased clotting times (thrombin time assay) and for the inactivation of Factor Xa. Bioactivity of the immobilized compound (PGE1 activity) was analyzed by platelet adhesion and platelet release reactions using C14-5-hydroxytryptamine (5-HT). The conjugate immobilized via the C2 spacer showed the highest incidence of platelet adhesion, 5-HT released and the lowest activity for coagulation factors. In contrast, the 1000 and 4000 immobilized systems showed a significant reduction in platelet activation, while having the greatest effect on coagulation factors. The results of these experiments imply that the immobilized conjugate is active in preventing both pathways of thrombus formation, and the efficacy is improved through the use of long-chain hydrophilic spacer groups.

Alprostadil↗
PubMed1995

Studies on structure-activity relationship of seiridins, phytotoxins, produced by three species of Seiridium.

The phytotoxins seiridin (SEI) and iso-seiridin (ISE), two delta alpha,beta-butenolides produced in vitro by Seiridium cardinale, S. cupressi, and S. unicorne, as well as their derivatives obtained by chemical modification of each toxin, were analyzed for their bioactivity. The effects each compound on host and non-host plants and their antimicrobial activity on bacteria were investigated. The toxicity of both seiridins (SEIs) decreased in the derivatives with modifications of the gamma-lactone ring or with acetylation of the hydroxy group of the aliphatic side chain at C-4. Shoot tissues of Cupressus macrocarpa artificially infected by S. cardinale leached electrolytes more than those of C. sempervirens and C. arizonica. Electrolyte loss from shoot tissues of cypress plants treated with each derivative also decreased for most of them. Seed germination was not affected by SEI and ISE derivatives. Inhibition of root growth of three herbaceous test plants was studied. SEI and 3,4-dihydro SEI were active to germlings of lettuce. No ISE derivative affected root growth of lettuce and oat germlings. Reduction was observed on roots of radish germlings treated with acetyl ISE or 3,4-dihydro ISE. No derivative of SEI or ISE elicited hormone-like activity as SEI did. Antibacterial activity shown by SEI and ISE at 150 microM accounted for both hydrogenated derivatives of SEI. The integrity of the delta alpha,beta-unsaturated-gamma-lactone ring and the location of the hydroxy group in the heptyl side chain are features of importance in biological activity of the two butenolides.

Bacteria↗
PubMed2003

Soy isoflavonoid equol modulates the growth of benign and malignant prostatic epithelial cells in vitro.

BACKGROUND: The dietary consumption of high levels of soy has been linked to reduced risks for prostate cancer (PC) in Asians and vegetarians. In vitro studies have focused on the two most abundant isoflavones in soy, genistein and daidzein. However, daidzein is differentially metabolized by gut microflora in humans, yielding compounds with very different bioactivities and half-lives. Asians are significantly more likely to produce the metabolite equol than Caucasians, suggesting its role in the prevention of PC. We hypothesize that equol is a bioactive metabolite that exerts direct antiproliferative effects on prostatic epithelial cells. METHODS: Benign and malignant prostatic epithelial cells were treated in vitro with equol, genistein, and daidzein by using the range of concentrations found in the prostatic fluids of Asians consuming soy. Growth and cell cycle distribution were analyzed over time. RESULTS: After 9 days of treatment, equol inhibited growth of benign human prostatic epithelial cells (PrEC) by 37% at 10(-6) M and 80% at 10(-5) M. Although genistein also had profound effects, daidzein appeared only one tenth as potent as equol. Equol and daidzein caused an accumulation of cells in G0/G1, whereas genistein arrested cells in G2/M. The isoflavonoids demonstrated differential effects on the established PC cell lines 22Rv1, LNCaP, LAPC-4, PC-3, and DU 145. PC-3 cells showed the greatest resistance. CONCLUSION: Equol is a biologically active metabolite of daidzein that has potent antiproliferative effects on benign and malignant prostatic epithelial cells at concentrations that can be obtained naturally through dietary soy consumption.

Apoptosis↗
PubMed1998

Comparison of formation of D2/E2-isoprostanes and F2-isoprostanes in vitro and in vivo--effects of oxygen tension and glutathione.

The isoprostanes (IsoPs) are bioactive prostaglandin-like compounds derived from the free-radical-catalyzed peroxidation of arachidonic acid in vitro and in vivo. IsoPs possessing either an F-type prostane ring (F2-IsoPs) or D/E-type prostane rings (D2/E2-IsoPs) are formed depending on whether IsoP endoperoxide intermediates undergo reduction or isomerization, respectively. Little, however, is known regarding factors influencing the formation of various classes of IsoPs, particularly D2/E2-IsoPs. Thus, studies were undertaken to examine the formation of D2/E2-IsoPs in relation to F2-Isops both in vitro and in vivo. In peroxidizing rat liver microsomes, the formation of D2/E2-IsoPs increased in a time- and oxygen-dependent manner and correlated with F2-IsoP generation and loss of precursor arachidonic acid, although the absolute amount of D2/E2-IsoPs formed exceeded by over 5-fold the levels of F2-IsoPs formed. Surprisingly, however, in liver tissue from rats exposed to an oxidant stress, levels of F2-IsoPs were up to 10-fold greater than those of D2/E2-IsoPs, suggesting that an endogenous process causes IsoP endoperoxide reduction in vivo. Addition of glutathione (GSH) to peroxidizing microsomes at concentrations from 0.01 to 5 mM increased the formation of F2-IsoPs at the expense of D2/E2-IsoPs. Boiling of microsomes did not alter the effect of GSH. Formation of D2/E2-IsoPs in liver tissue in vivo was greatly enhanced compared to F2-IsoPs in rats depleted of GSH. Thus, GSH modulates the formation of different classes of IsoPs in vitro and in vivo. Other thiols, including beta-mercaptoethanol, dithiothreitol, and cysteine, were able to substitute for GSH. These studies indicate that GSH promotes F2-IsoP formation and diminishes D2/E2-IsoP levels in vitro and in vivo by causing reduction of IsoP endoperoxides.

Adenosine Diphosphate↗
PubMed1996

Determination of receptor-bound drug conformations by QSAR using flexible fitting to derive a molecular similarity index.

Results are presented for a QSAR analysis of bisamidines, using a similarity index as descriptor. The method allows for differences in conformation of bisamidines at the receptor site to be taken into consideration. In particular, it has been suggested by others that pentamidine binds in the minor groove of DNA in a so-called isohelical conformation, and our QSAR supports this suggestion. The molecular similarity index for comparison of molecules can be used as a parameter for correlating and hence rationalising the activity as well as suggesting the design of bioactive molecules. The studied compounds had been evaluated for potency against Leishmania mexicana amazonensis, and this potency was used as a dependent variable in a series of QSAR analyses. For the calculation of similarity indexes, each analogue was in turn superimposed on a chosen lead compound in a reference conformation, either extended or isohelical, maximising overlap and hence similarity by flexible fitting.

Animals↗
PubMedDate not supplied

Anticancer drug design based on plant-derived natural products.

This review article focuses on recent research in my laboratory on various classes of compounds that possess potent antitumor activity. These compounds were obtained by bioactivity- and mechanism of action-directed isolation and characterization coupled with rational drug design-based modification and analog synthesis. Structural modification, structure-activity relationship, and mechanism of action studies will be discussed.

Animals↗