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At least 631 records · Page 35Linked to original sources
PubMed2003

Induction of CYP1A1 in tumor cells by the antitumor agent 2-[4-amino-3-methylphenyl]-5-fluoro-benzothiazole: a potential surrogate marker for patient sensitivity.

A candidate antitumor agent, 2-(4-amino-3-methylphenyl)-5-fluoro-benzothiazole (5F-203), like its non-fluorinated parent compound (DF-203), has a unique cytotoxicity pattern in the National Cancer Institute in vitro anticancer drug screen. These compounds show selective toxicity for a subset of cell types including estrogen receptor positive breast cancer and certain renal and ovarian cancer cell lines. Metabolic activation of these benzothiazoles seems to be mediated through the CYP1 family of cytochrome P450s. In an effort to characterize the involvement of CYP1A1 and CYP1B1 in the unique toxicity response of 5F-203, constitutive and 5F-203-induced gene expression patterns were measured in 60 cell lines of the National Cancer Institute drug screen using TaqMan real-time PCR. The patterns of CYP1A1 and CYP1B1 gene expression in the 60 cell lines were correlated with the toxicity pattern of 5F-203 and DF-203. There was significant correlation between drug sensitivity and induced CYP1A1 (R = 0.752, P < 0.001), but not constitutive CYP1A1 mRNA expression. CYP1A1 protein expression was found to mirror the corresponding gene expression, indicating that gene expression changes were concordant with function. Treatment of sensitive cell lines with 10 micro M resveratrol, an inhibitor of CYP1A1 induction, in combination with either 1 or 10 micro M 5F-203 showed an ablation of the observed CYP1A1, but not CYP1B1 mRNA induction in parallel with a decreased sensitivity to 5F-203. Fine needle aspirates were obtained from a variety of human tumor xenografts, and treated ex vivo with 1 micro M 5F-203 for 24 h. In these samples, induction of CYP1A1 by 5F-203 correlated with in vitro sensitivity (R = 0.711, P < 0.05), and corresponded to in vivo sensitivity in human tumor xenografts. These data are concordant with the idea that toxicity of 5F-203 requires activation by CYP1A1, and therefore induction of CYP1A1 mRNA in response to 5F-203 treatments ex vivo may provide a possible surrogate marker for determination of drug-sensitive tumors in patients.

Antineoplastic Agents↗
PubMed2005

[A study on the ultraviolet spectra of halogenated benzoylferrocenes].

The ultraviolet spectra of all of the o, m, p-halogenated benzoylferrocenes have been studied the following rules obtained: 1. The lambdamax of the ultraviolet spectrum R band and K band for the isomers is lambdamax(m-X) > lambdamax(p-X) > lambdamax(o-X). 2. With the same substituted positions of the different halogen on the benzene ring, the lambdamax of the ultraviolet spectrum K band is lambdamax(C1) > lambdamax(Br) > lambdamax(I) > lambdamax(F), then, the lambdamax of ultraviolet spectrum R band is lambdamax(I) > lambdamax(Br) > lambdamax(Cl) > lambdamax(F).

Benzene↗
PubMed1985

[Phase I study of 5'-deoxy-5-fluorouridine (5'-DFUR)].

A phase I study of a new fluorinated pyrimidine compound, 5'-deoxy-5-fluorouridine (5'-DFUR), was performed in 37 patients with various malignant cancers. Starting dose was 600 mg/m2/day (900 mg/body/day) and escalated up to 3900 mg/body/day. The dose given was divided into 3 administrations a day for 5 consecutive days. Subjective symptoms were observed in cases given a dose of over 2,100 mg/body/day. Gastro-intestinal disturbances such as nausea, vomiting and anorexia were the major side effects. In the hematological and urinary examinations, no severe abnormal signs were observed. The maximum tolerated dose was considered to be 2.100 mg/body/day, and the dose-limiting factor was gastro-intestinal disturbance. 5-FU levels were determined in the serum and tumor tissues. 5'-DFUR was well absorbed. The 5-FU level in tumor tissue was very high at 2 to 3 hours post-dose and then rapidly decreased, being 0.05 microgram/g 12 hours after administration. The optimal dosage for a phase II study was suggested to be less than 2,100 mg/body/day.

Administration, Oral↗
PubMed1986

[N-substituted p-fluorobenzencarboxyamides. Evaluation of the in vitro antimicrobial activity].

As part of our investigations on fluorine containing compounds of potential pharmacological interest, a series of N-substituted p-fluorobenzencarboxyamides, analogs of previously studied p-fluorobenzensolfonamides, was prepared. The in vitro antibacterial and antimycotic properties were also assayed. The replacement of the sulfonamide group with an isosteric carboxyamide one, was found to confer to trifluoromethylsubstituted compounds good activity against some strains of yeasts (Candida) and hyphomycetes (Tricophyton, Aspergillus, Microsporum, Epidermophyton). These compounds however are not very active against the gram-positive and gram-negative bacteria on which the corresponding sulfonanilides showed significant activity.

Anti-Bacterial Agents↗
PubMed1979

Metabolism of 1,3-bis(tetrahydro-2-furanyl)-5-fluorouracil in mice.

1,3-Bis(tetrahydro-2-furanyl)-5-fluorouracil (FD-1) is a new masked compound of fluorinated pyrimidine and a derivative of 1-(tetrahydro-2-furanyl)-5-fluorouracil (FT-207). The pharmacokinetics of FD-1 and FT-207 were compared in the livers and kidneys of control mice and in mice (DD males) pretreated with phenobarbital. The half-time in the liver of FD-1 orally administered was about 40 minutes, whereas that of FT-207 in the liver was about 3 hours. Hepatic concentrations of 5-fluorouracil (FUra) originating from FD-1 were three to five times as much as those originating from FT-207. FD-1 formed 3-(tetrahydro-2-furanyl)-5-fluorouracil (3-T-F-FU) and FT-207 by a ratio of about 3 to 10, respectively. Although FD-1 had a short period of half reduction, FT-207 and 3-T-F-FU had a half-time lasting for 3--4 hours. In contrast, the renal concentration of FD-1 was one-third that of FT-207. Oral administration of FD-1 to the mice pretreated with phenobarbital elevated the FT-207 and 3-T-F-FU levels in the livers to twice the levels in the control mice and further elevated the FUra levels in the livers to twice the levels in the controls. These results indicate that FD-1 is catabolized in the liver by microsomal enzymes (including cytochrome P450) faster than is FT-207, which consequently enlarges the hepatic pool of the intermediates on the way to FUra formation.

Animals↗
PubMed1983

[Perforation of the nasal septum of occupational origin].

Perforations of nasal septum as typical effects of exposure to certain hazards are a particular health problem among the diseases of upper respiratory tract mucous membranes (entry 10 on the list of occupational diseases). To obtain more data on etiopathogenetic factors and correlations between the clinical picture and exposure duration, the documentation of the patients in whom perforation was diagnosed during 1972-1979 was analysed epidemiologically. The examinations covered 185 workers of various industrial branches-salina, chemical plants, leather plants, tanneries, electroplating plants-who developed nasal septum perforation due to local effects of working environment irritants. In the test group the nasal septum was defected mostly in those exposed to chromium compounds (46.5%) and in salina workers (44.3%). In the remaining 9.2% of subjects the septum perforation resulted from exposure to arsenic, nickel, silicone compounds, cadmium, fluorine, soda and ammonia. The clinical course of the disease was presented as classified by industrial branch, occupational exposure, age and length of employment. In addition, procedures of diagnostics, certification and prevention were considered.

Abscess↗
PubMed1982

In-vitro metabolism of fluorinated diakylnitrosamines.

To elucidate differences in metabolism caused by fluorination of NDEA and NDBA, these compounds and their fluorinated analogs (NDEA-F3, NDEA-F6, NDBA-F3, NDBA-F6 and NDBA-F1 4) were incubated with rat liver microsomal fractions. Aldehydes, nitrite and unchanged nitrosamines were determined. Additionally, the mutagenicity was investigated with a Salmonella/mammalian microsome assay. NDEA-F6 and NDBA-F1 4 were not appreciably metabolized and were not mutagenic. NDEA, NDEA-F3, NDBA, NDBA-F3 and NDBA-F6 were dealkylated and, to a lesser extent, denitrosated. Dealkylation at the fluorinated alkyl group was inhibited, especially in the case of NDEA-F3. Whereas NDEA, NDBA, NDBA-F3 and NDBA-F6 were clearly mutagenic, mutagenicity of NDEA-F3 was only marginal.

Animals↗
PubMed1998

Studying the reaction between clozapine and glutathione with element-selective detection.

The target of these investigations was a study of covalent binding the antipsychotic drug clozapine and the tripeptide glutathione. Other workers, primarily using radioisotopes, have found many adducts of clozapine and glutathione. We wanted to see how well the chlorine atom in clozapine could serve as an alternate to the use of a radiolabel using the Chemical Reaction Interface/Mass Spectrometer technique with HPLC introduction (HPLC/CRIMS). Here, we examine the capabilities of two such schemes that were previously used with GC introduction: Cl detection with SO2 as the reactant gas; and Cl and S detection using NF3 as the reactant gas. Detecting chlorine as HCl with SO2 was accomplished giving linearity over an 80-fold range of sample size. Incubations of the drug and glutathione with a peroxidase/peroxide system system yielded several metabolites characterized as novel conjugates of clozapine by electrospray mass spectrometry. This tentative identification of two conjugates was confirmed by examining the incubation mixture with NF3 as the CRIMS reactant gas. The simultaneous appearance of both Cl and S is consistent with covalent binding of clozapine to glutathione. A nearly doubled ratio of S to Cl in one peak confirmed the presence of a di-glutathione conjugate. These experiments support our proposition that element selective detection of HPLC effluents with CRIMS can supply additional information, not previously available using radioisotopic methods.

Chromatography, High Pressure Liquid↗
PubMed2000

Synthesis, SARs, and pharmacological characterization of 2-amino-3 or 6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as potent, selective, and orally active group II metabotropic glutamate receptor agonists.

(+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (4, LY354740), a highly selective and orally active group II metabotropic glutamate receptor (mGluR) agonist, has increased interest in the study of group II mGluRs. Our interest focused on a conformationally constrained form of compound 4, because it appeared that the rigid form resulted in not only selectivity for group II mGluR but was orally active. Therefore, we introduced a fluorine atom to compound 4, based on the molecular size (close resemblance to hydrogen atom) and electronegativity (effects on the electron distribution in the molecule) of this atom and carbon-fluorine bond energy. Compound (+)-7 (MGS0008), the best compound among 3-fluoro derivatives 7-10, retained the agonist activity of compound 4 for mGluR2 and mGluR3 ((+)-7: EC(50) = 29.4 +/- 3.3 nM and 45.4 +/- 8.4 nM for mGluR2 and mGluR3, respectively; 4: EC(50) = 18.3 +/- 1.6 nM and 62.8 +/- 12 nM for mGluR2 and mGluR3, respectively) and increased the oral activity of compound 4 ((+)-7: ED(50) = 5.1 mg/kg and 0.26 mg/kg for phencyclidine (PCP)-induced hyperactivity and PCP-induced head-weaving behavior, respectively; 4: ED(50) = >100 mg/kg and 3.0 mg/kg for PCP-induced hyperactivity and PCP-induced head-weaving behavior, respectively). In addition, a compound [(3)H]-(+)-7 binding study using mGluR2 or 3 expressed in CHO cells was successful ((+)-7: K(i) = 47.7 +/- 17 nM and 65.9 +/- 7.1 nM for mGluR2 and mGluR3, respectively; 4: K(i) = 23.4 +/- 7.1 nM and 53.5 +/- 13 nM for mGluR2 and mGluR3, respectively). On the basis of a successful result of compound 7, we focused on the introduction of a fluorine atom on the C6 position of compound 4. (1R,2S,5R, 6R)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid ((-)-11) exhibited a high degree of agonist activity for group II mGluRs equal to that of compound 4 or 7 ((-)-11: K(i) = 16.6 +/- 5.6 and 80.9 +/- 31 nM for mGluR2 and mGluR3, respectively). Our interest shifted to modification on CH(2) at C4 position of compound 11, since replacement of the CH(2) group with either an oxygen atom or sulfur atom yielded compound 5 or 6, resulting in increased agonist activity. We selected a carbonyl group instead of CH(2) at the C4 position of compound 11. The carbonyl group might slightly change the relative conformation of three functional groups, the amino group and two carboxylic acids, which have important roles in mediating the interaction between group II mGluRs and their ligand, compared with the CH(2) group of 4, oxygen atom of 5, and sulfur atom of 6. (1R,2S,5S,6S)-2-Amino-6-fluoro-4-oxobicyclo[3.1. 0]hexane-2,6-dicarboxylic acid monohydrate ((+)-14, MGS0028) exhibited a remarkably high degree of agonist activity for mGluR2 (K(i) = 0.570 +/- 0.10 nM) and mGluR3 (K(i) = 2.07 +/- 0.40 nM) expressed in CHO cells but not mGluR4, 6, 7, 1a, or 5 expressed in CHO cells (K(i) = >100 000 nM). Furthermore, compound (+)-14 strongly inhibited phencyclidine (PCP)-induced head-weaving behavior (ED(50) = 0.090 microg/kg) and hyperactivity (ED(50) = 0.30 mg/kg) in rats. Thus, (+)-7 and (+)-14 are potent, selective, and orally active group II mGluR agonists and might be useful not only for exploring the functions of mGluRs but in the treatment of schizophrenia.

Administration, Oral↗
PubMed2002

Photoinduced transannular reaction of 1,3-dimethylcyclooctapyrimidine-2,4-diones.

This article reports further elaboration of the authors' investigations on the acid-catalyzed photorearrangements undergone by derivatives of 1,3-dimethylcyclooctapyrimidine-2,4-dione. In this case the results are represented for compounds containing a simple methyl or fluorine substituent at different positions in the eight-membered ring. Upon photolysis in frozen benzene containing trifluoroacetic acid, the monomethylated compounds give varying yields of pentalenopyrimidinedione products that are not generated from the fluorinated compounds, which are either inert or undergo hydration accompanied by dehyrofluorination. Plausible mechanisms are advanced to account for the formation of the observed photoproduct species. The work represents an interesting extension and uncovered new aspects of the photorearrangement process.

Magnetic Resonance Spectroscopy↗
PubMed2006

CF(3)-bearing aromatic and heterocyclic building blocks.

Fluorine remains an insiders' tip in the life sciences as it enables the fine-tuning of biological properties. However, the synthesis of fluorine-substituted target compounds is not always trivial. Virtually any fluorine atom attached to an organic backbone has ultimately to be imported from inorganic sources. Crucial for the entire synthetic planning in medicinal and agricultural research is the decision on at what stage and how the halogen will be introduced. Standard technical processes, in particular the displacement of chlorine using anhydrous hydrogen fluoride or potassium fluoride, can hardly be implemented rationally on the laboratory scale. Universal methods that are applicable by both industrial and academic researchers thus have great appeal. If a trifluoromethyl-substituted arene or heterocycle is the target compound, two splendid options exist. The CF(3) group can be delivered packagewise by coupling an appropriate substrate with in situ generated (trifluoromethyl)copper. Alternatively, one may start from a CF(3)-substituted arene or heterocycle as a core and complete it with the missing parts of the ultimate structure.

Chlorofluorocarbons, Methane↗
PubMed2000

The First Organoxenon(IV) Compound: Pentafluorophenyldifluoroxenonium(IV) Tetrafluoroborate.

Xenon(IV) - carbon bonding has been realized for the first time in the product formed from the reaction of XeF(4) with C(6)F(5)BF(2) in CH(2)Cl(2) at -55 degrees C [Eq. (1)]. [C(6)F(5)XeF(2)][BF(4)] is a strong oxidative fluorinating agent. This xenon(IV) compound fluorinates (C(6)F(5))(3)P to (C(6)F(5))(3)PF(2), C(6)F(5)I to C(6)F(5)IF(2), and I(2) to IF(5). In all cases, [C(6)F(5)Xe][BF(4)] was obtained as a by-product.

Journal Article↗