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PubMed1978

Alleviation of fluorine toxicity in starting turkeys and chicks with aluminum.

Aluminum (Al) compounds were evaluated as fluorine (F) toxicity alleviators in starting broiler chicks and turkeys. Added F levels from NaF ranged from 0 to 1000 ppm, whereas Al levels varied from 0 to 800 ppm. Al was fed either as Al2O3 or Al2 (SO4)3.18H2O. When fed as the sulphate salt, 800 ppm of Al completely prevented the toxic effect of at least 1000 ppm of F. Al2O3 was not effective as an alleviator of fluorine toxicity. When the mode of action of Al2(SO4)3.18H2O against F toxicity was studied in colostomized turkeys it was apparent that F absorption occurred but was probably less efficient than previously reported in ruminants. Al significantly (P less than .05) reduced F absorption in turkeys. Urinary F levels were: 2.4 ppm in birds fed a control diet (26 ppm F), 17.8 ppm in birds fed a diet with 1000 ppm F, and 6.7 ppm in birds fed the high F diet with 800 ppm Al as the sulphate salt. In addition, data from this study indicated that starting broiler chicks were more tolerant (800 ppm F) than starting turkeys (600 ppm F) to fluorine toxicosis.

Aluminum↗
PubMed1997

Enantioselective fluorination of organic molecules. I. Synthetic studies of the agents for electrophilic, enantioselective fluorination of carbanions.

In order to develop novel methods for electrophilic and enantioselective fluorination of active methine compounds, preliminary experiments were carried out. The N-tosyl derivative 5 obtained from D-phenylglycine was fluorinated with FClO3 or diluted F2 gas to give the N-fluoro-N-tosyl derivative 6. N-tosyl- or N-mesyl-(S)-alpha-phenethylamine 7 or 8 was subjected to FClO3 fluorination to produce the corresponding N-fluoro derivative, 10 or 11, respectively. Enantioselective fluorination of some methine compounds was attempted employing the above N-fluoro agents. Best result was obtained when 2-benzyl-1-tetralone/KHMDS was treated with 10 to produce the fluorinated tetralone 17 in 53% yield with enantiomeric excess (ee) of 48%.

Anions↗
PubMed1972

The metabolism of fluoroacetate in lettuce.

1. Whole lettuce plants were incubated with (1) [1-(14)C]acetate, (2) fluoroacetate followed by [1-(14)C]acetate, (3) fluoro[1-(14)C]acetate, (4) fluoro[2-(14)C]acetate or (5) S-carboxy[(14)C]methylglutathione. 2. Fluoroacetate did not affect the expiration of (14)CO(2) from [1-(14)C]acetate and only a small amount of (14)CO(2) was produced from either fluoro[1-(14)C]-acetate or fluoro[2-(14)C]acetate in 43h. 3. Fluoroacetate at 50mg/kg wet wt. doubled the plant citrate concentration after 43h incubation, and depending on the age and size of the plant 50-100% of the compound was metabolized. 4. With both fluoro[1-(14)C]acetate and fluoro[2-(14)C]acetate all the radioactivity except that in the CO(2) was found in the water-soluble acid fraction. About 2% was in fluorocitrate and the remainder, apart from unchanged fluoroacetate, was in a number of compounds devoid of fluorine but containing nitrogen and sulphur. These were peptide-like and could be separated by chromatography on an amino acid analyser. 5. Identical compounds were obtained from the spontaneous reaction between iodo[2-(14)C]acetate and glutathione, the major product being S-carboxymethylglutathione. 6. S-Carboxymethylcysteine was also isolated and its mass spectrum compared with a commercial sample. 7. Reaction rates of all the monohaloacetates with glutathione were studied at pH7 at 25 degrees C. No reaction was observed with fluoroacetate. 8. The metabolism of fluoroacetate by lettuce is discussed in relation to that of aliphatic and aromatic halogen compounds, including fluoroacetate, by mammalian liver and to the metabolism of fluoroacetate by different plants reported by other workers.

Amino Acids↗
PubMed1970

Interactions of p-nitrobenzene diazonium fluoroborate and analogs with the active sites of acetylcholine-receptor and -esterase.

p-Nitrobenzene diazonium fluoroborate (NDF) is a potent inhibitor of the carbamylcholine-induced depolarization of the electroplax and of acetylcholinesterase. It probably forms covalent bonds with the acetylcholine-receptor and -esterase at the active site of the proteins. Its inhibitory strength is at least the same as that of trimethylammonium diazonium fluoroborate (TDF). The p-acetoxy analog, with its weaker electron-withdrawing group, is about ten times weaker as an inhibitor than the trimethylammonium or p-nitro analogs, both of which have strong electron-withdrawing groups. After treatment of the electroplax preparation with dithiothreitol, NDF remains an irreversible receptor-inhibitor, while TDF becomes a potent reversible receptor-activator. TDF is self-inhibitory: applied before reduction, it no longer depolarizes. Although the first observations on TDF suggested that the compound labels both proteins by virtue of the steric complementary of its trimethylammonium group to a negative subsite in the proteins, the present study indicates that it is the positively charged diazonium group that reacts with the active sites of the proteins to form a covalent bond with an appropriate amino-acid residue.

Acetylcholinesterase↗
PubMed2004

Systemic activity of simeconazole and its derivatives in plants.

The systemic activity of simeconazole (RS-2-(4-fluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-trimethylsilylpropan-2-ol) and a number of its derivatives in plants has been investigated to establish which portion of the structure of the molecule contributes to this outstanding activity. The results revealed that the hydroxyl group of the simeconazole moiety is essential for vapour-phase activity and translocation from roots of the compound. They showed that the presence of a fluorine atom in the structure was not indispensable for vapour-phase activity or translocation from roots, although the fluorine atom contributed to these systemic movements. In addition, it was found that the fungicidal activity of simeconazole against Rhizoctonia solani Kühn and Blumeria graminis DC fsp hordei Marchal is potentiated by the fluorine atom, since the activity of a compound which lacked fluorine in the 4-position of the phenyl ring was inferior to that of simeconazole. A compound in which the silicon atom of simeconazole was replaced by a carbon atom showed lower antifungal activity than simeconazole, while phytotoxicity was caused in rice plants by soil drench of the compound. Therefore, the silicon atom of simeconazole may contribute to its selectivity between fungi and plants.

Ascomycota↗
PubMed1994

Synthesis and antitumor activity of 20(S)-camptothecin derivatives. A-ring-substituted 7-ethylcamptothecins and their E-ring-modified water-soluble derivatives.

Twenty-six novel A-ring-modified 7-ethylcamptothecins (6) were synthesized by Friedländer's condensation of the chiral tricyclic ketone (5) with aminopropiophenones (4). The compounds substituted with fluorine at the 11 position showed strong cytotoxicity to KB and L1210 cells. The 11-fluoro derivatives also exhibited strong inhibitory activity on DNA topoisomerase I. Nine compounds 6 with four to ten times stronger cytotoxicity than that of camptothecin were selected and converted into water-soluble 17-O-acyl amide derivatives (8). Compounds 8e (10-Me, O-COCH2CH2SCH3) and 8f (11-F, O-COC2H5) showed activity towards Meth A in mice that was comparable to that of CPT-11, at lower doses than CPT-11.

Animals↗
PubMed2001

Synthesis of 2-fluoro- and 6-fluoro-(2S,3R)-(3,4-dihydroxyphenyl)serine as potential in vivo precursors of fluorinated norepinephrines.

The title compounds were prepared by the aldol condensation of 3,4-dibenzyloxy-2-fluorobenzaldehyde and 4,5-dibenzyloxy-2-fluorobenzaldehyde with the oxazolidinone 2, a chiral glycine equivalent. Removal of the chiral auxiliary and blocking groups produced the target amino acids 2-fluoro- and 6-fluoro-(2S,3R)-(3,4-dihydroxyphenyl)serine (1b and 1c) in >98% ee.

Adrenergic Agonists↗
PubMed1999

[Development of asymmetric synthesis of optically active compounds including fluoroorganic molecules].

The synthesis of chiral fluorinated molecules is important in the biological and medicinal chemistry fields in view of the influence of fluorine's unique properties on biological activity. In recent years, we have studied asymmetric synthesis focussing on such optically active compounds. This review describes 1) diastereoselective trifluoromethylation of chiral N-acyloxazolidinones, 2) catalytic enantioselective aldol reactions of fluorine-substituted ketene silyl acetals, and 3) catalytic enantioselective allylation of aldehydes mediated by chiral Lewis bases. The trifluoromethylation of lithium enolates of N-acyloxazolidinones with iodotrifluoromethane is mediated by triethylborane to give the corresponding trifluoromethylated products with up to 86% diastereomeric excess. The stereoselective reaction is considered to proceed through the attack of the trifluoromethyl radical on the less hindered face of the lithium imide. Difluoroketene and bromofluoroketene trimethylsilyl ethyl acetals react with various aldehydes in the presence of chiral Lewis acids to afford the corresponding desired aldols with up to 99% enantiomeric excess (ee). It is noteworthy that the aldol reactions of the fluorine-substituted acetals at -78 degrees C and at higher temperatures (-45 or -20 degrees C) provide the (+)- and (-)-aldols, respectively, with excellent-to-good enantioselectivity. Chiral phosphoramides newly prepared from (S)-proline were found to catalyze the allylation and crotylation of aromatic aldehydes with allylic trichlorosilanes in good enantioselective yields (up to 90% ee). (S,S)-Bis(alpha-methylbenzyl)formamide developed as an efficient catalyst for the allylation and crotylation of aliphatic aldehydes mediates the enantioselective addition with the assistance of hexamethylphosphoramide (HMPA) to afford the corresponding homoallylic alcohols in up to 98% ee.

Chemical Phenomena↗
PubMed2003

Simultaneous variation of multipole parameters and Gram-Charlier coefficients in a charge-density study of tetrafluoroterephthalonitrile based on X-ray and neutron data.

Difficulties encountered in modelling the scattering of fluorine in organic compounds have been investigated through refinements of accurate X-ray and neutron diffraction data measured on tetrafluoroterephthalonitrile, TFT, at 122.4 K. Multipole refinements led to a highly contracted octopole on fluorine. The subsequent analysis revealed that fluorine does not possess a valence octopole but exhibits anharmonic thermal motion that can be modelled by the octopole multipole parameters. The scattering contribution from the octopole shows the same cubic dependence in the scattering vector as the Gram-Charlier expansion of the nuclear displacements to third order. The analysis also showed that refinement of third-order Gram-Charlier coefficients on fluorine requires data to at least 0.93 A(-1) resolution in sinthetas/lambda. The X-ray data extending to 1.27 A(-1) were of sufficient resolution to include third-order Gram-Charlier coefficients for N, F and the cyano C atoms in the refinement, whereas the neutron data only enabled refinement of the third-order Gram-Charlier coefficients for nitrogen. The refinements of the neutron and X-ray diffraction data yielded identical atomic displacement parameters for all the atoms. Though inclusion of anharmonic motion for N and F atoms provides the best model, it does not affect the crystal electron density, and all intramolecular bond critical points have identical features. Application of the anharmonic model, however, leads to small differences in the intermolecular interactions, which is illustrated by the electrostatic potential adjacent to the N atom. The characteristics of the C-F bond were elucidated by the topological analysis of the crystal electron density, which also supported the proposed quinonoid structure of the benzene ring.

Journal Article↗
PubMed1997

Inhibition of proliferation of prostate cancer cells by a 19-nor-hexafluoride vitamin D3 analogue involves the induction of p21waf1, p27kip1 and E-cadherin.

We have synthesized and studied the ability of a series of seven novel 1 alpha,25(OH)2 vitamin D3 analogues to inhibit clonal growth of prostate cancer cells (LNCaP, PC-3 and DU-145). Addition of double and triple bonds to the C/D ring (C-16) and side chain (C-22 and C-23) as well as lengthening of the side chain were important for enhanced activity against LNCaP and PC-3. Reorientation of the side chain in the 20-epi configuration resulted in analogues that were extremely potent only against LNCaP (ED50 approximately 5 x 10(-11) M). Compounds with six fluorines on the end of the side chain were very active against both PC-3 and LNCaP (ED50 approximately 2 x 10(-8) M). DU-145 cells were relatively resistant to compounds with all of these modifications, but removal of C-19 (e.g. 1,25(OH)2-16-ene-23-yne-26,27-F6-19-nor-D3) resulted in an analogue that was inhibitory against all three prostate cell lines. Further analysis showed that pulse exposure (3 days, 10(-7) M) to this analogue was enough to inhibit clonal growth of PC-3 cells by 50%. The same exposure also induced cell cycle arrest of all three cell lines, accompanied by upregulated protein expression of the cyclin-dependent kinase inhibitor (CDKI) known as p21waf1 in all three cell lines, and the CDKI known as p27kip1 in LNCaP cells. Associated with upregulation of these CDKIs, partial differentiation occurred as measured by increased expression of both prostate-specific antigen by LNCaP cells and E-cadherin, a cell adhesion protein that may act as a putative tumour suppressor (LNCaP and PC-3 cells). In summary, this is the first report of a potent series of 19-nor-vitamin D3 analogues with the ability to inhibit proliferation of LNCaP, PC-3 and DU-145 prostate cancer cell lines. These compounds may mediate their potent anti-proliferative activities through a cell cycle arrest pathway.

Antineoplastic Agents↗
PubMed1998

19-nor-26,27-bishomo-vitamin D3 analogs: a unique class of potent inhibitors of proliferation of prostate, breast, and hematopoietic cancer cells.

Vitamin D3 [1,25-dihydroxyvitamin-D3 (1,25(OH)2D3)] modulates the proliferation and differentiation of many cell types. Analogs of 1,25(OH)2D3 that have greater potency may become adjuvant therapy for breast and prostate cancers, myelodysplastic syndrome, acute myelogenous leukemia in remission and other cell types, especially in the setting of low disease burden. A new class of analogs of 1,25(OH)2D3 has been synthesized that has a novel 19-nor motif, as well as incorporating many structural elements previously shown to increase potency. These analogs were examined for their effects on prostate cancer cell lines (PC-3, LNCaP, and DU 145), a human breast cell line (MCF-7), and an acute myeloid leukemia cell line (HL-60). Dose-response clonogenic studies showed that each of these analogs had more potent antiproliferative activities against the cancer cells than 1,25(OH)2D3, and 1,25-(OH)2-16,23Z-diene-26,27-bishomo-19-nor-D3 (Ro 27-2014) was the most potent analog [10-fold increased activity compared to 1,25(OH)2D3]. Further studies were performed using Ro 27-2014. Pulse-exposure studies showed that a 5-day pulse-exposure to Ro 27-2014 (10(-7) M) in liquid culture was adequate to achieve a 50% inhibition of MCF-7 clonal growth in soft agar in the absence of the analog, suggesting that the growth inhibition mediated by the analog was irreversible. Cell cycle analyses using MCF-7 cells showed that Ro 27-2014 (10(-7) M for 4 days) induced a significant increase in the number of cells in G0-G1 (72.8+/-8.9% versus 49.9+/-3.5% in control cells), with a concomitant decrease in the percent of cells in S phase (13.1+/-6.2% versus 35.8+/-3.5% in control cells). The chief toxicity of vitamin D3 compounds is hypercalcemia, and therefore, we examined calcemic activity of Ro 27-2014 in mice and found it not to induce hypercalcemia at doses of 0.05 microg i.p. three times per week. In contrast, the same dose of a 19-nor vitamin D3 compound with 6 fluorines on the side chain (1,25-(OH)2-16-ene-23-yne-26,27-F6-19-nor-D3), although also having potent anticancer activity, caused severe hypercalcemia (18 mg/dl). In summary, 19-nor vitamin D3 compounds with desaturation and lengthening of their side chains result in a series of compounds with a good therapeutic index, having potent anticancer activity and low toxicity.

Animals↗
PubMed2001

Fluorous mixture synthesis: a fluorous-tagging strategy for the synthesis and separation of mixtures of organic compounds.

The solution-phase synthesis of organic compounds as mixtures rather than in individual pure form offers efficiency advantages that are negated by the difficulty in separating and identifying the components of the final mixture. Here, a strategy for mixture synthesis that addresses these separation and identification problems is presented. A series of organic substrates was tagged with a series of fluorous tags of increasing fluorine content. The compounds were then mixed, and multistep reactions were conducted to make enantiomers or analogs of the natural product mappicine. The resulting tagged products were then demixed by fluorous chromatography (eluting in order of increasing fluorine content) to provide the individual pure components of the mixture, which were detagged to release the final products.

Alkaloids↗
PubMed2001

Enantioselective fluorination mediated by cinchona alkaloid derivatives/Selectfluor combinations: reaction scope and structural information for N-fluorocinchona alkaloids.

Cinchona-alkaloid/Selectfluor combinations efficiently fluorinate a variety of carbonyl compounds in a highly enantioselective manner to furnish chiral alpha-fluorocarbonyl compounds. The DHQB/Selectfluor combination is effective for the enantioselective fluorination of indanones and tetralones 1 in up to 91% ee. The first enantioselective syntheses of chiral derivatizing reagents 3 was accomplished with high ee and in high chemical yields by the DHQDA/Selectfluor combination. 3-Fluorooxindoles 7 were prepared with ee up to 83% using the (DHQ)2AQN/Selectfluor or the (DHQD)2PYR/Selectfluor combination. Since the combinations are conveniently prepared in situ from readily available reagents, the present system represents a practical method for enantioselective fluorination. X-ray crystallography and 1H NMR analyses of the cinchona alkaloids/Selectfluor combination have established that the species that mediate this novel reaction are N-fluoroammonium cinchona alkaloid tetrafluoroborates, which adopt open conformations.

Cinchona Alkaloids↗
PubMed1996

Polyfluorinated Tris(pyrazolyl)borates. Syntheses and Spectroscopic and Structural Characterization of Group 1 and Group 11 Metal Complexes of [HB(3,5-(CF(3))(2)Pz)(3)](-) and [HB(3-(CF(3))Pz)(3)](-).

The fluorinated tris(pyrazolyl)borate ligands [HB(3,5-(CF(3))(2)Pz)(3)](-) and [HB(3-(CF(3))Pz)(3)](-) (where Pz = pyrazolyl) have been synthesized as their sodium salts from the corresponding pyrazoles and NaBH(4) in high yield. These sodium complexes and the related [HB(3,5-(CF(3))(2)Pz)(3)]K(DMAC) were used as ligand transfer agents in the preparation of the copper and silver complexes [HB(3,5-(CF(3))(2)Pz)(3)]Cu(DMAC), [HB(3,5-(CF(3))(2)Pz)(3)]CuPPh(3), [HB(3,5-(CF(3))(2)Pz)(3)]AgPPh(3), and [HB(3-(CF(3))Pz)(3)]AgPPh(3). Metal complexes of the fluorinated [HB(3,5-(CF(3))(2)Pz)(3)](-) ligand have highly electrophilic metal sites relative to their hydrocarbon analogs. This is evident from the formation of stable adducts with neutral oxygen donors such as H(2)O, dimethylacetamide, or thf. Furthermore, the metal compounds derived from fluorinated ligands show fairly long-range coupling between fluorines of the trifluoromethyl groups and the hydrogen, silver, or phosphorus. The solid state structures show that the fluorines are in close proximity to these nuclei, thus suggesting a possible through-space coupling mechanism. Crystal structures of the sodium adducts exhibit significant metal-fluorine interactions. The treatment of [HB(3,5-(CF(3))(2)Pz)(3)]Na(H(2)O) with Et(4)NBr led to [Et(4)N][HB(3,5-(CF(3))(2)Pz)(3)], which contains a well-separated [Et(4)N](+) cation and the [HB(3,5-(CF(3))(2)Pz)(3)](-) anion in the solid state. Crystal data with Mo Kalpha (lambda = 0.710 73 Å) at 193 K: [HB(3,5-(CF(3))(2)Pz)(3)]Na(H(2)O), C(15)H(6)BF(18)N(6)NaO, a = 7.992(2) Å, b = 15.049(2) Å, c = 9.934(2) Å, beta = 101.16(2) degrees, monoclinic, P2(1)/m, Z = 2; [{HB(3-(CF(3))Pz)(3)}Na(thf)](2), C(32)H(30)B(2)F(18)N(12)Na(2)O(2), a = 9.063(3) Å, b = 10.183(2) Å, c = 12.129(2) Å, alpha = 94.61(1) degrees, beta = 101.16(2) degrees, gamma = 95.66(2) degrees, triclinic, &Pmacr;1, Z = 1; [HB(3,5-(CF(3))(2)Pz)(3)]Cu(DMAC), C(19)H(13)BCuF(18)N(7)O, a = 15.124(4) Å, b = 8.833(2) Å, c = 21.637(6) Å, beta = 105.291(14) degrees, monoclinic, P2(1)/n, Z = 4; [HB(3,5-(CF(3))(2)Pz)(3)]CuPPh(3), C(33)H(19)BCuF(18)N(6)P, a = 9.1671(8) Å, b = 14.908(2) Å, c = 26.764(3) Å, beta = 94.891(1) degrees, monoclinic, P2(1)/c, Z = 4; [HB(3,5-(CF(3))(2)Pz)(3)]AgPPh(3).0.5C(6)H(14), C(36)H(26)AgBF(18)N(6)P, a = 13.929(2) Å, b = 16.498(2) Å, c = 18.752(2) Å, beta = 111.439(6) degrees, monoclinic, P2(1)/c, Z = 4; [Et(4)N][HB(3,5-(CF(3))(2)Pz)(3)], C(23)H(24)BF(18)N(7), a = 10.155(2) Å, b = 18.580(4) Å, c = 16.875(5) Å, beta = 99.01(2) degrees, monoclinic, P2(1)/n, Z = 4.

Journal Article↗
PubMed2004

CYP 17 and CYP 19 inhibitors. Evaluation of fluorine effects on the inhibiting activity of regioselectively fluorinated 1-(Naphthalen-2-ylmethyl)imidazoles.

Regioselectively fluorinated 1-(naphth-2-ylmethyl)imidazoles 1a-h have been synthesized starting from the corresponding (naphth-2-yl)methanols (2). 2a-d have been obtained by LiAlH4-promoted reduction of fluorinated 1-methyl-2-naphthaldehydes. The latter were easily prepared in fairly good overall yields by ceric ammonium nitrate (CAN)-promoted oxidative addition of the suitable 3-(fluoroaryl)-1-trimethylsilyloxy-1-butenes to ethyl vinyl ether in methanol followed by cyclization of the resulting acetals in strongly acidic medium in the presence of DDQ. 2e-h were prepared by LiAlH4-promoted reduction of the corresponding fluorinated methyl 2-naphthoates. The latter were more profitably obtained by reacting the suitable benzyl bromide with the sodium salt of dimethyl 2-(2,2-dimethoxyethyl)malonate in DMF followed by demethoxycarbonylation and acid catalysed cyclization of the resulting acetals. Compared with the nonfluorinated parent compounds 1i-1, fluorinated 1-(naphth-2-yl)methylimidazoles 1a-h turned out to be potent inhibitors of CYP17 and CYP19 enzymes. The most active inhibitor of CYP17 is 1c, whereas CYP19 is strongly inhibited by 1b, 1e, and 1g. Interestingly, 1g is a potent dual inhibitor also being very active towards CYP19.

Aromatase↗
PubMed1999

Vasorelaxation by new hybrid compounds containing dihydropyridine and pinacidil-like moieties.

The synthesis and pharmacological properties of a novel type of vasorelaxant hybrid compounds are described. The investigated compounds originate from fluorinated 4-aryl-1,4-dihydropyridines, which are known calcium channel blockers, and/or from fluorinated analogues of pinacidil, which is an opener of ATP-sensitive potassium channels. In particular, we studied the most potent hybrid, 2,6-dimethyl-3,5-dicarbomethoxy-4-(2-difluoromethoxy-5-N-(N' '-cyano-N'-1,2,2-trimethyl-propylguanidyl)-phenyl)-1, 4-dihydropyridine (4a), together with its parent compounds, the dihydropyridine 1b and the pinacidil analogue 3. In isolated rat mesenteric arteries, micromolar concentrations of 4a relaxed contractions exerted by K(+)-depolarization or by norepinephrine. The latter effect was sensitive to the potassium channel blocker glibenclamide. Micromolar 4a also inhibited [(3)H](+)-isradipine and [(3)H]P1075 binding to rat cardiac membranes, and it blocked L-type calcium channels expressed in a mammalian cell line. The respective parent compounds 1b and 3 were always more potent and more selective regarding calcium channel or potassium channel interaction, respectively. In contrast, 4a combined both effects within the same concentration range, indicating that it may represent a lead structure for a novel class of pharmacological hybrid compounds.

Animals↗