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PubMed1985

In vitro mutagenicity of valepotriates.

Valepotriates are epoxide-bearing triesters of the monoterpene alcohol 4,7-dimethylcyclopenta-(c)-pyrane isolated from the roots of several Valerianacae species. They are regarded as the main tranquilizing constituents of these drugs. Although the valepotriates valtrate/isovaltrate (VAL) and dihydrovaltrate (DH-VAL) showed a strong alkylating activity against the nucleophilic agent 4-(p-nitrobenzyl)-pyridine (NBP), they were not clearly mutagenic for the strains TA98, TA100, TA1535, and TA1537 of Salmonella typhimurium or for the strains WP2 and WP2 uvrA- of Escherichia coli in the absence of a metabolic activation system (S9-mix). However, the valepotriates were mutagenic for TA100, WP2 and WP2 uvrA- at concentrations up to about 1.0 mumole/plate when S9-mix was added to the test system. With more than 1 mumole/plate the valepotriates were toxic in the presence of a metabolic activation system for all strains tested. The mutagenicity of the valepotriates was inversely related to the protein content of the S9-mix used. The mutagenicity and toxicity of the valepotriates could be inhibited when the S9-mix was preincubated with the esterase inhibitor paraoxon (1 mM) for 5 min before the test compounds and bacteria were added. Therefore, bioactivation of the valepotriates by an enzymatic hydrolysis of their ester groups is considered. This could be proven by activating the valepotriates with purified esterase.

Animals↗
PubMedDate not supplied

Spinal plasticity of acute opioid tolerance.

Spinal acute opioid tolerance remains mechanistically undercharacterized. Expanded clinical use of direct spinal administration of opioids and other analgesics indicates that studies to further understand spinal mechanisms of analgesic tolerance are warranted. Rodent models of spinal administration facilitate this objective. Specifically, acute spinal opioid tolerance in mice presents a plasticity-dependent, rapid, and efficient opportunity for evaluation of novel clinical agents. Similarities between the pharmacology of acute and chronic spinal opioid tolerance, neuropathic pain, and learning and memory suggest that this model may serve as a high through-put predictor of bioactivity of novel plasticity-modifying compounds.

Animals↗
PubMed1997

Synthesis and molecular modeling: related approaches to progress in brassinosteroid research.

In the field of brassinosteroids, which are potent plant growth regulators, we have developed a quantitative structure-activity relationship study to develop knowledge from a structural point of view and to find out new requirement definitions. This will help identify other suitable active brassinosteroid derivatives with a good activity/synthetic cost ratio for further application in agriculture. The methodology used to achieve this goal represents a multidisciplinary study involving synthesis, molecular modeling calculations, and bioactivity evaluation. The influence of different molecular properties in the bioactivity of a set of synthetic compounds (i.e., molecular electrostatic potential and the ability to form H bonds) is discussed. The molecular electrostatic potential is expressed in terms of the electrostatic Carbó similarity index (CI) between brassinolide (1) and other brassinosteroids. We have found that the electrostatic charges of the functional groups play an important role in the description of the activity, as evidenced by its good correlation with the CI in most cases. Deviation from this rule could be explained by the H bonding abilities of some of these compounds, which we believe may play an essential role in binding to the natural receptors.

Brassinosteroids↗
PubMed1988

Role for monoamine oxidase-A (MAO-A) in the bioactivation and nigrostriatal dopaminergic neurotoxicity of the MPTP analog, 2'Me-MPTP.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration leads to the selective destruction of the dopaminergic neurons of the nigrostriatal pathway in experimental animals including monkeys and mice. The neurotoxicity of MPTP is dependent upon its monoamine oxidase-B (MAO-B)-catalyzed conversion to the 1-methyl-4-phenylpyridinium species (MPP+). A methylated analog of MPTP. A methylated analog of MPTP, namely 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'Me-MPTP), is a more potent dopaminergic neurotoxin than MPTP in mice. Although the selective inhibition of MAO-B is sufficient to protect mice against MPTP-induced neurotoxicity, it is reported here that complete inhibition of MAO-B failed to prevent 2'Me-MPTP-induced dopaminergic neurotoxicity. However, the neurotoxicity of 2'Me-MPTP was completely prevented and 2'Me-MPP+ formation was markedly attenuated in mice in which both MAO-A and MAO-B were almost totally inhibited. This information about the role of MAO-A in the bioactivation of 2'Me-MPTP may be of relevance to those who speculate that the MAO-B catalyzed bioactivation of MPTP or a similar compound may be the cause of idiopathic Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1986

A new vitamin E analogue more active than alpha-tocopherol in the rat curative myopathy bioassay.

Vitamin E owes its biological effects to its antioxidant activity. Kinetic and mechanistic studies on phenolic antioxidants in vitro have led us to design and synthesize all-rac-2,4,6,7-tetramethyl-2-(4',8',12'-trimethyltridecyl) -5-hydroxy-3,4-dihydrobenzofuran, 3. In the rat curative myopathy bioassay the acetate of this compound has 1.5-1.9 times the bioactivity of all-rac-alpha-tocopherol acetate. This represents the first time that a rationally designed synthetic 'vitamin' has been found to have more activity in vivo than the corresponding natural vitamin.

Animals↗
PubMed1995

The expanding role of quantitative structure-activity relationships (QSAR) in toxicology.

Quantitative structure-activity relationships (QSAR) have found wide use in correlating the bioactivity of all kinds of organic compounds with all kinds of biological entities. So many QSAR have been published that it is time for a new phase of study, that of comparative QSAR. From our current database of about 6000 QSAR illustrative examples are discussed.

Structure-Activity Relationship↗
PubMed2004

Analogues of FAUC 73 revealing new insights into the structural requirements of nonaromatic dopamine D3 receptor agonists.

Employing the nonaromatic D3 agonist FAUC 73 as a lead compound, the dopaminergic enynes 1a,b and the diene 2 (FAUC 206) were synthesized via palladium-catalyzed cross-coupling. FAUC 206 showed remarkable D3 affinity and enhanced selectivity over D4 when compared to the lead compound. To learn more about the bioactive structure of the diene moiety, computational studies including DFT-based conformational analysis and calculations of the magnetic shielding properties were performed. The electrostatic properties of the pharmacophoric pi-systems were visualized by diagnostic MEP maps.

Alkynes↗
PubMed2006

3D QSAR for GSK-3beta inhibition by indirubin analogues.

Glycogen synthase kinase 3 (GSK-3) plays an important role in a diverse number of regulatory pathways by phosphorylation of several different cellular targets and its inhibitors have been evaluated as promising drug candidates. Indirubin analogues show favorable inhibitory activity targeting GSK-3beta, which is closely related to the property and position of substituents. Two methods were used to build 3D-QSAR models for indirubin derivatives. The conventional 3D-QSAR (ligand-based) studies were performed based on the lower energy conformations employing atom fit alignment rule. The receptor-based 3D-QSAR models were also derived using bioactive conformations obtained by docking the compounds to the active site of GSK-3. Conclusions of models based on two methods are similar and reliable. The results indicate that both ligand-based and receptor-based are feasible tools to build 3D-QSAR models. Contour maps of the receptor-based CoMSIA model (q(2) = 0.766, r(2) = 0.908, N (number of components) = 5) including the steric, electronic and hydrophobic fields were taken as representative to explain factors affecting activities of inhibitors.

Antibiotics, Antineoplastic↗
PubMed2006

Comparative aromatic hydroxylation and N-demethylation of MPTP neurotoxin and its analogs, N-methylated beta-carboline and isoquinoline alkaloids, by human cytochrome P450 2D6.

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin is a chemical inducer of Parkinson's disease (PD) whereas N-methylated beta-carbolines and isoquinolines are naturally occurring analogues of MPTP involved in PD. This research has studied the oxidation of MPTP by human CYP2D6 (CYP2D6*1 and CYP2D6*10 allelic variants) as well as by a mixture of cytochrome P450s-resembling HLM, and the products generated compared with those afforded by human monoamine oxidase (MAO-B). MPTP was efficiently oxidized by CYP2D6 to two main products: MPTP-OH (p-hydroxylation) and PTP (N-demethylation), with turnover numbers of 10.09 min-1 and Km of 79.36+/-3 microM (formation of MPTP-OH) and 18.95 min-1 and Km 69.6+/-2.2 microM (PTP). Small amounts of dehydrogenated toxins MPDP+ and MPP+ were also detected. CYP2D6 competed with MAO-B for the oxidation of MPTP. MPTP oxidation by MAO-B to MPDP+ and MPP+ toxins (bioactivation) was up to 3-fold higher than CYP2D6 detoxification to PTP and MPTP-OH. Several N-methylated beta-carbolines and isoquinolines were screened for N-demethylation (detoxification) that was not significantly catalyzed by CYP2D6 or the P450s mixture. In contrast, various beta-carbolines were efficiently hydroxylated to hydroxy-beta-carbolines by CYP2D6. Thus, N(2)-methyl-1,2,3,4-tetrahydro-beta-carboline (a close MPTP analog) was highly hydroxylated to 6-hydroxy-N(2)-methyl-1,2,3,4-tetrahydro-beta-carboline and a corresponding 7-hydroxy-derivative. Thus, CYP2D6 could participate in the bioactivation and/or detoxification of these neuroactive compounds by an active hydroxylation pathway. The CYP2D6*1 enzymatic variant exhibited much higher metabolism of both MPTP and N(2)-methyl-1,2,3,4-tetrahydro-beta-carboline than the CYP2D6*10 variant, highlighting the importance of CYP2D6 polymorphism in the oxidation of these toxins. Altogether, these results suggest that CYP2D6 can play an important role in the metabolic outcome of both MPTP and beta-carbolines.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1999

Evidence for the formation of a novel cyclopentenone isoprostane, 15-A2t-isoprostane (8-iso-prostaglandin A2) in vivo.

A2/J2-Isoprostanes (IsoPs) are prostaglandin (PG) A2/J2-like compounds that are produced in vivo as dehydration products of D2/E2-IsoPs. One A2-IsoP that should be formed is 15-A2t-IsoP (8-iso-PGA2). Analogous to cyclopentenone PGs, 15-A2t-IsoP readily undergoes nucleophilic addition to various biomolecules suggesting the compound is capable of exerting potent bioactivity. However, proof that it is definitively formed in vivo is lacking. Evidence is now presented that 15-A2t-IsoP, in fact, is generated in vivo by demonstrating that an endogenous A2-IsoP with a retention time on capillary GC identical with that 15-A2t-IsoP co-chromatographs through four high resolving HPLC purification procedures with authentic radiolabeled 15-A2t-IsoP.

Animals↗
PubMed2001

Mechanisms of estradiol inactivation in primate endometrium.

In uterine endometrium, the level of estradiol is controlled by oxidative 17beta-hydroxysteroid dehydrogenase (17HSD) activity which converts the bioactive hormone to the less active compound estrone. At least three different types of 17HSD (types 2, 4 and 8) use estradiol as their preferred substrate and may contribute to the overall rate of estradiol-inactivation in the uterus. In this study the marmoset monkey (Callithrix jacchus) was used for the investigation of the particular contribution of each type of 17HSD. Northern Blots revealed essentially the same tissue distribution as in the human. Likewise, uterine 17HSD enzyme activity increases in the secretory phase of the reproductive cycle, in parallel to the rise in circulating progesterone levels. Northern analysis of uteri from defined time points of the reproductive cycle showed that only the level of 17HSD2 expression is strongly upregulated in the secretory phase, whereas 17HSD4 and 17HSD8 seem to be expressed constitutively.

17-Hydroxysteroid Dehydrogenases↗
PubMed2003

Kinetic study of the riboflavin-sensitised photooxygenation of two hydroxyquinolines of biological interest.

4-Hydroxyquinoline (4-OHQ) and 8-hydroxyquinoline (8-OHQ), two compounds of interest because of their bioactivity and their structural relation with bioactive products, are effectively photooxygenated when irradiated with visible light in the presence of riboflavin (Rf) (vitamin B2) in solution in air-saturated water-methanol (9:1). Rf behaves as a dye-sensitiser, since both quinolines are transparent to visible light. 8-OHQ degrades about five times faster than 4-OHQ. Kinetic data obtained through time-resolved and stationary detection of Rf-electronically excited states indicate that a superoxide radical anion-mediated mechanism exclusively operates for 4-OHQ, whereas singlet molecular oxygen--mainly--plus superoxide radical anion is the species that reacts with 8-OHQ. The sensitiser Rf, which is known to photodegrade under visible-light aerobic irradiation, is regenerated in the presence of any of the quinolines through an electron transfer process that produces superoxide radical anion. The overall picture indicates that both quinolines act as sacrificial scavengers of the photogenerated oxygen species, thus preventing the photodegradation of Rf.

Hydroxyquinolines↗
PubMed1996

Bioactive ent-kaurene diterpenoids from Annona senegalensis.

Activity-guided fractionation of the stem bark of Annona senegalensis gave four bioactive ent-kaurenoids (1-4). Compound 2 showed selective and significant cytotoxicity for MCF-7 (breast cancer) cells (ED50 1.0 microgram/mL), and 3 and 4 exhibited cytotoxic selectivity for PC-3 (prostate cancer) cells but with weaker potencies (ED50 17-18 micrograms/mL). The structure of the new compound, 3, was deduced from spectral evidence.

Africa↗
PubMed1999

Annocherin and (2,4)-cis- and trans-annocherinones, monotetrahydrofuran Annonaceous acetogenins with a C-7 carbonyl group from Annona cherimolia seeds.

The new cytotoxic monotetrahydrofuran Annonaceous acetogenins, annocherin (1) and a mixture of (2,4)-cis- and trans-annocherinones (2 and 3), were isolated from the bioactive methanolic extract of Annonacherimolia seeds. Compounds 1-3 each possess an unusual 7-carbonyl group. Their structures were established on the basis of chemical and spectral evidence. Compounds 1-3 showed significant toxicity in the brine shrimp lethality test and cytotoxicity for six human solid tumor cell lines, with selectivity for the renal cell line (A-498) at potencies equivalent to Adriamycin.

Antineoplastic Agents, Phytogenic↗
PubMed2005

A cytotoxic triketone-phloroglucinol-bullatenone hybrid from Lophomyrtus bullata.

Cytotoxic activity against the P388 cell line was seen in a crude extract of the New Zealand shrub Lophomyrtus bullata(Myrtaceae). Bioactivity-guided isolation led to a compound with NMR spectra complicated by the presence of two isomers. These crystallised together and an X-ray structure showed them to be stereoisomeric hybrids of triketone, phloroglucinol and bullatenone units. NMR measurements on the mixed isomers, as well as a cyclic ether produced from them by acid catalysed dehydration, were consistent with these structures. The natural products, named bullataketals A and B, have cytotoxic activity against the P388 cell line (IC(50) 1 microg ml(-1)), and antimicrobial activity against Bacillus subtilis.

Animals↗
PubMed2001

Biocatalytic potential of Fusarium globulosum lipase in selective acetylation/deacetylation reactions and in ester synthesis.

AIMS: The present study was carried out to assess the potential of Fusarium globulosum lipase (FGL) for chemoselective and regioselective biotransformations for the synthesis of industrially important organic compounds. METHODS AND RESULTS: Different acetylation/deacetylation reactions and ester synthesis reactions were carried out in organic media. Fusarium globulosum lipase showed exclusive selectivity for the acetylation of the alcoholic hydroxyl group over the phenolic hydroxyl group of the hydroxymethylated phenols and aryl alkyl ketones. This also led to the enantiomeric resolution of the aryl alkyl ketone. In contrast, the lipase showed reversed selectivity in deacetylation where it preferred the phenolic acetoxy group over the alcoholic acetoxy moiety of the peracetates of hydroxymethylated compounds. The enzyme also exhibited strict regioselection for deacetylation at the para position of the peracetate of an aryl alkyl ketone. In addition, the lipase also synthesized a variety of industrially important fatty acid esters of sugars, sugar alcohols, alcohols and ascorbic acid with high preference for middle-chain fatty acids. CONCLUSION: Fusarium globulosum lipase shows versatile catalytic potential in terms of chemo-, enantio- and regioselectivity and fatty acid specificity in carrying out a variety of industrially important biotransformations. SIGNIFICANCE AND IMPACT OF THE STUDY: The biocatalytic potential of FGL can thus be utilized for the synthesis and modification of different types of polyphenolic compounds and esters. These compounds find widespread uses as surfactants, bioactive analogues, antioxidants and flavour components in the food, detergent, pharmaceutical and cosmetic industries.

Acetylation↗
PubMed2001

Inhibition of trypsin and chymotrypsin by anti-inflammatory triterpenoids from Compositae flowers.

Taraxastane, oleanane, ursane, lupane, taraxane, cycloartane, dammarane and tirucallane triterpenoids isolated from flowers of Compositae plants have been previously reported to exhibit anti-inflammatory effects and are variously competitive and non-competitive inhibitors of the serine proteases trypsin and chymotrypsin. The general features of those triterpenoids found to be protease inhibitors are having a hydroxy group and an appropriate side chain in the region of the molecule distal to the 3-hydroxy group. However, fatty acid esterification of the triterpenoid 3-hydroxy group can have a marked effect on inhibitor effectiveness. This suggests a possible means of rapid alteration of the plant defensive complement in vivo and of the bioactivity of these anti-inflammatory compounds.

Anti-Inflammatory Agents, Non-Steroidal↗