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PubMed1992

Bioactivation of halogenated hydrocarbons by rabbit pulmonary cells.

1,1-Dichloro-2,2-bis (4'-chlorophenyl)ethane (DDD), 1,2-dibromoethane (DBE) and trichloroethylene are three halogenated hydrocarbons that selectively bind to pulmonary epithelial cells and that may be pneumotoxic. The susceptibility of pulmonary cells and the mechanisms of cytotoxicity of these compounds were evaluated using enriched subpopulations of isolated rabbit lung cells incubated with DDD, DBE, and trichloroethylene. These chlorinated and brominated hydrocarbons were studied to evaluate their ability to induce selective pneumotoxicity by their bioactivation in three cell types, i.e. Clara cells, alveolar type II cells, and alveolar macrophages. Evidence of cytochrome P-450 bioactivation was assessed by utilizing the suicide inhibitor, 1-aminobenzotriazole (ABT) to ameliorate cytotoxicity. DDD, DBE and trichloroethylene were cytotoxic to Clara cells, type II cells and alveolar macrophages and the order of cell susceptibility to DDD was Clara > type II > macrophages. DBE and trichloroethylene were nonselectively cytotoxic. ABT reduced the cytotoxic effects of DDD and DBE in Clara cells. These studies indicated that all three compounds were toxic to isolated lung cells and that bioactivation of DDD and DBE in rabbit Clara cells to a cytotoxic intermediate was mediated, at least in part, by cytochrome P-450 oxidation.

Animals↗
PubMed2003

Addressing the metabolic activation potential of new leads in drug discovery: a case study using ion trap mass spectrometry and tritium labeling techniques.

Metabolic activation of drug candidates to electrophilic reactive metabolites that can covalently modify cellular macromolecules may result in acute and/or idiosyncratic immune system-mediated toxicities in humans. This presents a significant potential liability for the future development of these compounds as safe therapeutic agents. We present here an example of an approach where sites of metabolic activation within a new drug candidate series were rapidly identified using online liquid chromatography/multi-stage mass spectrometry on an ion trap mass spectrometer. This was accomplished by trapping the reactive intermediates formed upon incubation of compounds with rat and human liver microsomes as their corresponding glutathione conjugates and mass spectral characterization of these thiol adducts. Based on the structures of the GSH adducts identified, potential sites and mechanisms of bioactivation within the chemical structure were proposed. These metabolism studies were interfaced with iterative structural modifications of the chemical series in order to block these bioactivation sites within the molecule. This strategy led to a significant reduction in the propensity of the compounds to undergo metabolic activation as evidenced by reductions in the irreversible binding of radioactivity to liver microsomal material upon incubation of tritium-labeled compounds with this in vitro system. With the efficiency and throughput achievable with such an approach, it appears feasible to identify and address the metabolic activation potential of new drug leads during routine metabolite identification studies in an early drug discovery setting.

Animals↗
PubMed1988

Peptide antibiotics, beta-lactams, and related compounds.

In the field of natural peptides, beta-lactams, and related compounds, recent exciting developments are discussed. The increasing interest in this class of bioactive amino-acid derived structures has been attributed to the use of new directed screens (enzyme inhibition assays, beta-lactam detection, immunomodulator studies), new and improved applications (antibiotic, transplantation, and cancer chemotherapy), and advances in functional studies (DNA binding peptides, nucleotide complexones, cell wall and protein processing inhibitors). Peptides offer unique access to modifications and analog production by in vivo (directed biosynthesis) and in vitro procedures (enzymatic synthesis) due to their general linear precursors permitting point replacements. Of special interest are recent developments in the genetics of these compounds (cyclic peptides and beta-lactams), which will find applications in production methods in the near future.

Amino Acid Sequence↗
PubMed2001

Sulfation of flavonoids and other phenolic dietary compounds by the human cytosolic sulfotransferases.

The protective effects of diet, especially soya products, tea, and many fruits, against a variety of human cancers, as suggested by epidemiological studies, has focused attention on flavonoids, isoflavonoids, and other phenolic dietary compounds as chemoprotectants. Among the mechanisms suggested for their chemoprotective action, their ability to inhibit the bioactivation of carcinogens by the human cytosolic sulfotransferases (STs) and the direct effects of their sulfoconjugates are being increasingly studied. We report here a systematic study on the sulfation of representative flavonoids, isoflavonoids, anti-oxidants, and other phenolic dietary compounds by all ten known human cytosolic STs. All ten recombinant human cytosolic STs were prepared in a pure form and tested for their sulfating activities with a variety of these compounds. P-form (SULT1A1) phenol ST (PST) showed high sulfating activity with most of these compounds. M-form (SULT1A3) PST showed high activity with the flavonoids but not with the isoflavonoids. SULT1C ST #2 showed high activity with the isoflavonoids and also sulfated most of the other compounds. Possible relevance of these results to the chemoprotective effects of these dietary compounds is discussed.

Antioxidants↗
PubMed1989

Metabolic activation and covalent binding to nucleic acids of pentachloroethane as short-term test of genotoxicity.

The in vivo covalent binding of 14C-pentachloroethane to DNA, RNA and proteins of rats and mouse organs was detected 22 hr after i.p. injection. The covalent binding index, calculated on the liver labeling was comparable to those of compounds considered as weak-moderate initiators. Like other haloalkanes, 14C-pentachloroethane was bioactivated in in vitro cell-free system by both microsomal and cytosolic enzymatic fractions from mouse and rat organs to react covalently with DNA and other macromolecules. The binding extents obtained from in vitro incubation and the binding values detected after in vivo administration of labeled pentachloroethane were comparable each other and showed a high correlation with oncogenic potency index of this compound. This result confirms the efficiency of in vitro binding as short-term test of genotoxicity prediction.

Animals↗
PubMed2002

Reactivity of atropaldehyde, a felbamate metabolite in human liver tissue in vitro.

Antiepileptic therapy with a broad spectrum drug felbamate (FBM) has been limited due to reports of hepatotoxicity and aplastic anemia associated with its use. It was proposed that a bioactivation of FBM leading to formation of alpha,beta-unsaturated aldehyde, atropaldehyde (ATPAL) could be responsible for toxicities associated with the parent drug. Other members of this class of compounds, acrolein and 4-hydroxynonenal (HNE), are known for their reactivity and toxicity. It has been proposed that the bioactivation of FBM to ATPAL proceeds though a more stable cyclized product, 4-hydroxy-5-phenyltetrahydro-1,3-oxazin-2-one (CCMF) whose formation has been shown recently. Aldehyde dehydrogenase (ALDH) and glutathione transferase (GST) are detoxifying enzymes and targets for reactive aldehydes. This study examined effects of ATPAL and its precursor, CCMF on ALDH, GST and cell viability in liver, the target tissue for its metabolism and toxicity. A known toxin, HNE, which is also a substrate for ALDH and GST, was used for comparison. Interspecies difference in metabolism of FBM is well documented, therefore, human tissue was deemed most relevant and used for these studies. ATPAL inhibited ALDH and GST activities and led to a loss of hepatocyte viability. Several fold greater concentrations of CCMF were necessary to demonstrate a similar degree of ALDH inhibition or cytotoxicity as observed with ATPAL. This is consistent with CCMF requiring prior conversion to the more proximate toxin, ATPAL. GSH was shown to protect against ALDH inhibition by ATPAL. In this context, ALDH and GST are detoxifying pathways and their inhibition would lead to an accumulation of reactive species from FBM metabolism and/or metabolism of other endogenous or exogenous compounds and predisposing to or causing toxicity. Therefore, mechanisms of reactive aldehydes toxicity could include direct interaction with critical cellular macromolecules or indirect interference with cellular detoxification mechanisms.

Aldehyde Dehydrogenase↗
PubMed2004

Recent advances in the investigation of the bioactive conformation of peptides active at the micro-opioid receptor. conformational analysis of endomorphins.

Despite of the recent advances in the structural investigation of complex molecules, the comprehension of the 3D features responsible for the interaction between opioid peptides and micro-opioid receptors still remains an elusive task. This has to be attributed to the intrinsic nature of opioid peptides, which can assume a number of different conformations of similar energy, and to the flexibility of the receptorial cavity, which can modify its inner shape to host different ligands. Due to this inherent mobility of the ligand-receptor system, massive efforts devoted to the definition of a rigid bioactive conformation to be used as a template for the design of new pharmacologically active compounds might be overstressed. The future goal might be the design of peptide or nonpeptide ligands capable of maximizing specific hydrophobic interactions. This review covers the recent opinions emerged on the nature of the ligand-receptor interaction, and the development of suitable models for the determination of the bioactive conformation of peptide ligands active towards micro-opioid receptors.

Binding Sites↗
PubMed2005

1-Aryl-4-(4-succinimidobutyl)piperazines and their conformationally constrained analogues: synthesis, binding to serotonin (5-HT1A, 5-HT2A, 5-HT7), alpha1-adrenergic, and dopaminergic D2 receptors, and in vivo 5-HT1A functional characteristics.

Starting with the structure of potent 5-HT(1A) ligands, that is, MM77 [1-(2-methoxyphenyl)-4-(4-succinimidobutyl)piperazine, 4] and its constrained version 5 (MP349), previously obtained in our laboratory, a series of their direct analogues with differently substituted aromatic ring (R=H, m-Cl, m-CF(3), m-OCH(3), p-OCH(3)) were synthesized. The flexible and the corresponding 1e,4e-disubstituted cyclohexane derivatives were designed in order to investigate the influence of rigidification on 5-HT(1A) affinity, selectivity for 5-HT(2A), 5-HT(7), D(1), and D(2) binding sites and functional profile at pre- and postsynaptic 5-HT(1A) receptors. The new compounds 19-25 were found to be highly active 5-HT(1A) receptor ligands (K(i)=4-44 nM) whereas their affinity for other receptors was: either significantly decreased after rigidification (5-HT(7)), or controlled by substituents in the aromatic ring (alpha(1)), or influenced by both those structural modifications (5-HT(2A)), or very low (D(2), K(i)=5.3-31 microM). Since a distinct disfavor towards rigid compounds was observed for 5-HT(7) receptors only, it seems that the bioactive conformation of chain derivatives at those sites should differ from the extended one. Several in vivo models were used to asses functional activity of 19-25 at pre- (hypothermia in mice) and postsynaptic 5-HT(1A) receptors (lower lip retraction in rats and serotonin syndrome in reserpinized rats). Unlike the parent antagonists 4 and 5, all the new derivatives tested were classified as partial agonists with different potency, however, similar effects were observed within pairs (flexible and rigid) of the analogues. The obtained results indicated that substitution in the aromatic ring, but not spacer rigidification, controls the 5-HT(1A) functional activity of the investigated compounds. Moreover, an o-methoxy substituent in the structure of 5 seems to be necessary for its full antagonistic properties. Of all the new compounds studied, trans-4-(4-succinimidocyclohexyl)-1-(3-trifluoromethylphenyl)piperazine 24 was the most potent 5-HT(1A) receptor ligand in vitro (K(i)=4 nM) and in vivo, with at least 100-fold selectivity for the other receptors tested.

Animals↗
PubMed1998

Eicosanoids and isoeicosanoids: indices of cellular function and oxidant stress.

Arachidonic acid (AA) is an unsaturated fatty acid constituent of the phospholipid domain of cell membranes. It is subject to release via mobilization of phospholipases, particularly a cytoplasmic phospholipase A2. Thereafter, it may be metabolized by at least two cyclooxygenase (COX) isoforms to prostaglandins and related compounds, via lipoxygenases to leukotrienes and via p450-catalyzed metabolism to epoxyeicosatrienoic acids. Collectively, these bioactive lipids are termed eicosanoids. All of these lipids express potent bioactivity in vitro. Clinical studies have already demonstrated the importance of COX and lipoxygenase (LOX) products in human disease. The generation of models of COX, LOX and prostaglandin receptor gene inactivation is likely to broaden our insight into the importance of these compounds in vivo. Crystallization of the biosynthetic enzymes is likely to facilitate the development of highly specific inhibitors, as is the case already for COX-2. AA possesses intrinsic biological properties. It is also subject to free radical attack, generating isomeric eicosanoid species, the isoeicosanoids. These compounds may also express biological activity in vitro, although their importance in vivo is unclear. Development of specific assays for these compounds in urine suggests their utility as noninvasive indices of oxidant stress in vivo.

Dinoprost↗
PubMed1976

Metabolic epoxidation of trans-4-acetylaminostilbene: a protective mechanism against its activation to a mutagen.

Trans-4-acetylaminostilbene is activated by liver preparations to mutagens for Salmonella typhimurium. Since this compound is metabolized to the trans-alpha,beta-epoxide and since many epoxides are ultimate mutagens, this epoxide was tested for direct mutagenicity. It was, however, found to be non-mutagenic, and, in contrast to the parent compound, the epoxide was no longer activated by liver preparations to mutagens. The same was found for the beta-ketone and for the threo-alpha,beta-dihydrodiol, which are formed metabolically from trans-4-acetylaminostilbene and from its alpha,beta-epoxide. 4-Acetylaminobibenzyl showed a very weak mutagenic activity in the presence of the liver preparation. Thus, it is important to realize that where epoxides are formed from compounds which are known to be metabolized to mutagens, they are not necessarily responsible for the mutagenicity. Epoxidation may even prevent the possibility of bioactivation to mutagens.

Animals↗
PubMed1991

Coffee contains cholinomimetic compound distinct from caffeine. I: Purification and chromatographic analysis.

Both regular and decaffeinated coffees were found to have cholinomimetic actions when tested in urethane-anesthetized rats. These actions were distinct from those of caffeine and reversible by atropine. The bioactive fraction was purified from alcoholic extracts of instant decaffeinated coffee by liquid column chromatography and preparative TLC. The purified compound showed similar pharmacological actions as the starting material. Chromatographic behavior was further characterized by analytical TLC and HPLC. Chromatographic analyses of extracts of green coffee beans and roasted ground coffees showed that the cardioactive compound was only present in roasted coffees. Similar analyses of other commonly consumed beverages, including teas and cocoa, showed that this compound was not present in beverages besides coffee.

Acetylcholine↗
PubMed2006

Micronization of insulin by high pressure homogenization.

PURPOSE: The aim of this study was to establish the high pressure homogenization of proteins in non-aqueous suspension as an alternative method for classical micronization strategies and to investigate the effect of high pressure on protein stability and bioactivity. METHODS: The influence of drug loading, homogenization pressure and cycles on particle size reduction was investigated by experimental design using a Box Behnken matrix with insulin as a model compound. Particle size measurements were performed by laser light scattering. Protein stability was investigated by HPLC and HPLC-MS analysis and the bioactivity of insulin was tested in a chondrocyte proliferation assay. For investigations into the effect of temperature on protein stability, insulin was micronized in molten lipid at 75 degrees C in one cycle at 1,000 bar. RESULTS: Within one homogenization cycle at 1,500 bar, the particle size of insulin could be reduced from 15.8 to 7.3 microm, six cycles resulted in a particle size of 3.7 microm d(0.5) (50% of the particles are smaller than the indicated value). Evaluation of the response surface diagram revealed that the homogenization pressure had the highest impact on micronization efficiency, followed by the number of homogenization cycles. Protein stability was maintained during the micronization process as well as bioactivity. Micronization at elevated temperature (75 degrees C) had no effect on protein stability. CONCLUSION: High pressure homogenization of protein suspensions can be used as an alternative method for the micronization of proteins without affecting protein stability or bioactivity.

Algorithms↗
PubMed2004

Novel 2',6'-dimethyl-L-tyrosine-containing pyrazinone opioid mimetic mu-agonists with potent antinociceptive activity in mice.

Novel bioactive opioid mimetic agonists containing 2',6'-dimethyl-l-tyrosine (Dmt) and a pyrazinone ring interact with mu- and delta-opioid receptors. Compound 1 [3-(4' -Dmt-aminobutyl)-6-(3'-Dmt-aminopropyl)-5-methyl-2(1H)pyrazinone] exhibited high mu-opioid receptor affinity and selectivity (K(i)mu = 0.021 nM and K(i)delta/K(i)mu = 1,519, respectively), and agonist activity on guinea pig ileum (IC(50) = 1.7 nM) with weaker delta-bioactivity on mouse vas deferens (IC(50) = 25.8 nM). Other compounds (2-4) had mu-opioid receptor affinities and selectivities 2- to 5-fold and 4- to 7-fold less than 1, respectively. Intracerebroventricular administration of 1 in mice exhibited potent naloxone reversible antinociception (65 to 71 times greater than morphine) in both tail-flick (TF) and hot-plate (HP) tests. Distinct opioid antagonists had differential effects on antinociception: naltrindole (delta-antagonist) partially blocked antinociception in the TF, but it was ineffective in the HP test, whereas beta-funaltrexamine (irreversible antagonist, mu(1)/mu(2)-subtypes) but not naloxonazine (mu(1)-subtype) inhibited TF test antinociception, yet both blocked antinociception in the HP test. Our data indicated that 1 acted through mu- and delta-opioid receptors to produce spinal antinociception, although primarily through the mu(2)-receptor subtype; however, the mu(1)-receptor subtype dominates supraspinally. Subcutaneous and oral administration indicated that 1 crossed gastrointestinal and blood-brain barriers to produce central nervous system-mediated antinociception. Furthermore, daily s.c. dosing of mice with 1 for 1 week developed tolerance in a similar manner to that of morphine in TF and HP tests, implicating that 1 also acts through a similar mechanism analogous to morphine at mu-opioid receptors.

Analgesics↗
PubMed1985

Effect of inhibitors of alpha-naphthylisothiocyanate-induced hepatotoxicity on the in vitro metabolism of alpha-naphthylisothiocyanate.

The role of S-oxidation in the toxic bioactivation of alpha-naphthylisothiocyanate (ANIT) was investigated. The effects of several thione compounds, inhibitors and an inducer of the cytochrome P-450-dependent mixed function oxidase systems on the in vitro metabolism of ANIT and aminopyrine were determined. Ethionamide, sodium diethyldithiocarbamate (Na-DDTC) and S-methyl diethyldithiocarbamate (Me-DDTC), three agents known to undergo metabolism by an S-oxidative pathway and diminish ANIT's toxicity, inhibited the in vitro enzymatic metabolism of ANIT by rat liver microsomes. Methimazole failed to alter either the hyperbilirubinemic response of ANIT or the in vitro metabolism of ANIT. All four thione compounds (i.e., ethionamide, Me-DDTC, Na-DDTC and methimazole) inhibited the enzymatic metabolism of aminopyrine by rat liver microsomes. Me-DDTC was the most potent, whereas methimazole was the least potent inhibitor of aminopyrine metabolism. Phenobarbital, which potentiates, and SKF-525A, which inhibits the hepatotoxicity of ANIT in vivo, correspondingly stimulated or inhibited the NADPH-dependent metabolism of ANIT and aminopyrine by liver microsomes. N-Decylimidazole (NDI), another classical inhibitor of cytochrome P-450-dependent monooxygenase system, inhibited both the in vivo toxicity and in vitro metabolism of ANIT. NDI also diminished the enzymatic metabolism of aminopyrine by liver microsomes. Thus the results of this study indicate that metabolism of ANIT is intimately related to its toxicity and that ANIT probably undergoes its toxic bioactivation via a cytochrome P-450-dependent S-oxidative pathway.

1-Naphthylisothiocyanate↗
PubMed2006

Secondary metabolites from the South China Sea invertebrates: chemistry and biological activity.

The increasing demand for new lead compounds in the pharmaceutical and agrochemical industries has driven scientists to search for new sources of bioactive natural products. Marine invertebrates are a rich source of novel, bioactive secondary metabolites and they have attracted a great deal of attention from scientists in the fields of chemistry, pharmacology, ecology, and molecular biology. During the past 25 years, many complex and structurally unique secondary metabolites have been isolated from the invertebrates inhabiting the South China Sea. These metabolites are responsible for various bioactivities such as anti-tumor, anti-inflammation and antioxidant activities, and/or they act on the cardiovascular system. This review will focus on the marine natural product chemistry of invertebrates from the South China Sea, aiming to give the reader a brief view of the compounds isolated from these invertebrates, as well as their biological activities. The article covers the literature published during the period from the beginning of 1980 to the end of 2005, with 340 citations and 811 compounds from invertebrates from the South China Sea, including sponges, coelenterates, molluscs and echinoderms.

Animals↗
PubMed1993

Synthesis and bioactivity of new phosphorodithioates derived from N-substituted maleamic esters.

1. A new series of organophosphorus compounds derived from N-substituted maleamic esters by reaction with dimethyl and diethyl phosphorodithioic acid was synthesized. 2. Two isomers, with chemical structures analogous to malathion were obtained for each maleamic ester assayed. 3. They were characterized, and their toxicity against a resistant strain of Musca domestica (strain G), a susceptible one (strain RAC) and Triatoma infestans (vector of Chagas' disease) were measured. 4. The structural chemical modification introduced by replacing a carboxyester group for a N-substituted amido one, reverted the resistance obtained for malathion. 5. Replacement of methyl by ethyl dithiophosphoric acid did not introduce significative differences. 6. In the case of Triatoma infestans, the synthesized compounds were less active than malathion.

Animals↗
PubMed2000

A new bioactive steroidal saponin, furcreastatin, from the plant Furcraea foetida.

Microbial and plant secondary metabolites were screened for compounds that are selectively cytotoxic to mutant p53-expressing mouse fibroblasts. As a result, furcreastatin, a novel steroidal saponin, was isolated from an EtOH extract of the leaves of Furcraea foetida. Furcreastatin consisted of hecogenin as the aglycone and a hexasaccharide containing D-galactose, L-rhamnose and four D-glucose residues. The structure was determined to be (3 beta,5 alpha,25R)- 3-hydroxyspirostan-12-one 3-O-[alpha-L-Rhap-(1-->4)-beta-D-Glcp-(1-->3)-¿beta-D-Glcp-(1-->3) -beta-D- Glcp-(1-->2)¿-beta-D-Glcp-(1-->4)-beta-D-Galp] by extensive NMR spectroscopic studies. Furcreastatin decreased the viability of mutant p53-over-expressing cells with an ED50 of 4.0 micrograms/mL, and decreased that of the parental cell-line with an ED50 of 9.6 micrograms/mL.

3T3 Cells↗
PubMed2002

Bioactive steroidal alkaloid glycosides from Solanum aculeastrum.

Solanum aculeastrum Dunal was investigated for the presence of molluscicidal compounds. This led to the isolation of solaculine A, from the root bark in addition to known steroidal alkaloids; solamargine and beta-solamarine from the berries. The structures were elucidated by spectroscopic techniques. Molluscicidal activity of the aqueous extracts of the berries and root bark, and the isolated compounds were investigated.

Animals↗

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