Syntheses and highly enantioselective fluorescent recognition of α-aminocarboxylic acid anions using chiral oxacalix[2]arene[2]bisbinaphthes

The triazine-based bisbinaphthyl crown ethers oxacalix[2]arene[2]bisbinaphthes R-1, R-2, R-3 and S-1, S-2, S-3 were synthesized. The interactions of these compounds with various α-aminocarboxylic acid anions were studied. The crown ethers were found to carry out highly enantioselective fluorescent recognition of α-aminocarboxylic acid anions. It is observed that within a certain concentration range, one enantiomer of the chiral α-aminocarboxylic acid anions can increase the fluorescence intensity of the crown ethers by fivefold to sixfold, whereas the other enantiomer scarcely enhances the fluorescence. Such unusually high enantioselective responses make these crown ethers very attractive as fluorescent sensors in determining the enantiomeric composition of α-aminocarboxylic acid anions.     

Diaryl ether inhibitors of farnesyl-protein transferase

Imidazolemethyl diaryl ethers are potent inhibitors of farnesyl-protein transferase. The SNAr displacement reaction used to prepare these diaryl ethers was amenable to rapid parallel synthesis of FPTase inhibitors. The use of a broad range of commercially available phenols quickly identified compounds which proved active in cells.     

Mutagenicities of glycidyl ethers for Salmonella typhimurium: relationship between mutagenic potencies and chemical reactivity

The lethal and mutagenic effects of ethyl, benzyl, 1-naphthylmethyl, 2-naphthylmethyl, 1-naphthylethyl, 2-naphthylethyl and 9-anthrylmethyl glycidyl ethers on Salmonella typhimurium (TA100, TA1535, TA98 and TA1538) were investigated. LD30-value became smaller with an increase in compound hydrophobicity. The mutagenicities of these compounds in TA100 increased in the order: 1-naphthylethyl glycidyl ether less than 2-naphthylethyl glycidyl ether less than benzyl glycidyl ether less than 2-naphthylmethyl glycidyl ether less than 1-naphthylmethyl glycidyl ether less than 9-anthrylmethyl glycidyl ether. 1-Naphthylmethyl and 2-naphthylmethyl glycidyl ethers were mutagenic toward TA1535. In TA98, 1-naphthylmethyl and 9-anthrylmethyl glycidyl ethers showed mutagenic activity and 9-anthrylmethyl glycidyl ether was more mutagenic than 1-naphthylmethyl glycidyl ether. 9-Anthrylmethyl glycidyl ether was also active in TA1538. In the reaction of glycidyl ethers with deoxyguanosine and related compounds, glycidyl ethers attacked at only N-7 of guanine. The alkylation rates of glycidyl ethers toward guanine residues in DNA were determined and the exciplex-formation ability of 7-substituted guanines was studied. The reactivity of glycidyl ethers with guanine residues in DNA has not provided a sufficient explanation for the variation in mutagenic potencies of glycidyl ethers.     

Synthesis of low molecular weight compounds with complement inhibition activity

An attempt was made to synthesize a series of non-cytotoxic low molecular weight meta-substituted aromatic ethers (2-4, 5-7) and some of their bioisosteres (14-16) and to evaluate their activity on the activation of human complement (classical pathway) and their intrinsic hemolytic activity. The in vitro assay results of the inhibition of complement-mediated hemolysis by these analogues indicate that the aldehydic meta substituted aromatic ethers show inhibitory potency, while carboxylic acid meta substituted aromatic ethers show hemolytic activity. Some of the bioisosteres exhibit both inhibitory as well as hemolytic property.     

Lipase-catalyzed conversions of trimethylsilyl ethers: deprotection, acetylation, epoxidation and one-pot-multi-step reactions

Unsaturated trimethylsilyl ethers are converted by lipase-catalyzed hydrolysis of ethyl acetate directly to alkenol acetates; the hydrolysis of diethyl carbonate yields unstable carbonic acid monoethylester, which deprotects trimethylsilyl ethers under mild conditions and without remaining acid. By the analogous lipase-catalyzed perhydrolysis of these esters with hydrogen peroxide, epoxyalkanol acetates and epoxyalkanols are obtained in one-pot reactions with selectivities of 90–97%. Using longer chain peroxy fatty acids, generated in-situ by lipase-catalyzed reaction of fatty acid and hydrogen peroxide, trimethylsilyl ethers are selectively (83–95%) epoxidized without removal of the protecting trimethylsilyl group.     

Synthesis, DNA cleavage, and cytotoxicity of a series of bis(propargylic) sulfone crown ethers

Compounds that couple molecular recognition of specific alkali metal ions with DNA damage may display selective cleavage of DNA under conditions of elevated alkali metal ion levels reported to exist in certain cancer cells. We have prepared a homologous series of compounds in which a DNA reactive moiety, a bis(propargylic) sulfone, is incorporated into an alkali metal ion binding crown ether ring. Using the alkali metal ion pricrate extraction assay, the ability of these crown ethers to bind Li(+), Na(+), and K(+) ions was determined. For the series of crown ethers, the association constants for Li(+) ions are generally low (< 2 x 10(4)M(-1)). Only two of the bis(propargylic) sulfone crown ethers associate with Na(+) or K(+) ions (K(a) 4-8 x 10(4)M(-1)), with little discrimination between Na(+) or K(+) ions. The ability of these compounds to cleave supercoiled DNA at pH 7.4 in the presence of Li(+), Na(+), and K(+) ions was determined. The two crown ethers that bind Na(+) and K(+) display a modest increase in DNA cleavage efficiency in the presence of Na(+) or K(+) ions as compared to Li(+) ions. These two bis(propargylic) sulfone crown ethers are also more cytotoxic against a panel of human cancer cell lines when compared to a non-crown ether macrocyclic bis(propargylic) sulfone.     

Radiolabeled cholesteryl ethers: A need to analyze for biological stability before use

Radiolabeled cholesteryl ethers are widely used as non-metabolizable tracers for lipoproteins and lipid emulsions in a variety of in vitro and in vivo experiments. Since cholesteryl ethers do not leave cells after uptake and are not hydrolyzed by mammalian cellular enzymes, these compounds can act as markers for cumulative cell uptakes of labeled particles. We have employed [³H]cholesteryl oleoyl ether to study the uptake and distribution of triglyceride-rich emulsion particles on animal models. However, questionable unexpected results compelled us to analyze the stability of these ethers. We tested the stability of two commercially available radiolabeled cholesteryl ethers - [³H]cholesteryl oleoyl ether and [³H]cholesteryl hexadecyl ether from different suppliers, employing in vitro, in vivo and chemical model systems. Our results show that, among the two cholesteryl ethers tested, one ether was hydrolyzed to free cholesterol in vitro, in vivo and chemically under alkaline hydrolyzing agent. Free cholesterol, unlike cholesteryl ether, can then re-enter the circulation leading to confounding results. The other ether was not hydrolyzed to free cholesterol and remained as a stable ether. Hence, radiolabeled cholesteryl ethers should be analyzed for biological stability before utilizing them for in vitro or in vivo experiments.     

Efficient synthesis of 'redox-switched' naphthoquinone thiol-crown ethers and their biological activity evaluation

Series of naphthoquinone thiol-crown ethers had been prepared. The antibacterial, antifungal, and cytotoxic activities of these synthetic naphthoquinone thiol-crown ethers were investigated. All of the compounds tested displayed antibacterial, cytotoxic and antifungal activities. The bis-naphthoquinone thiol-crown ether 7a was the most potent inhibitor among tested analogues against Staphylococcus aureus methicillin resistance with MIC value of 2.68 microM.     

Novel diphenyl ethers: design, docking studies, synthesis and inhibition of enoyl ACP reductase of Plasmodium falciparum and Escherichia coli

We designed some novel diphenyl ethers and determined their binding energies for Enoyl-Acyl Carrier Protein Reductase (ENR) of Plasmodium falciparum using Autodock. Out of these, we synthesized the promising compounds and tested them for their inhibitory activity against ENRs of P. falciparum as well as Escherichia coli. Some of these compounds show nanomolar inhibition of PfENR and low micromolar inhibition of EcENR. They also exhibit low micromolar potency against in vitro cultures of P. falciparum and E. coli. The study of structure-activity relationship of these compounds paves the way for further improvements in the design of novel diphenyl ethers with improved activity against purified enzyme and the pathogens.     

Chromatography of methyl ethers of D-glucosamine

Identification of methyl ethers obtained by methylation and subsequent hydrolysis is a powerful technique for determination of linkage positions in structure studies of complex carbohydrates. Although methyl ethers of neutral sugars have been separated by various chromatographic methods, separation of methyl ethers of 2-amino-2-deoxy-d-glucose has been more difficult. Only recently, successful procedures for separation of methyl ethers of d-glucosamine based on thin-layer (1), gas (2), and column (3) chromatography have appeared in literature. We wish to report here a method for separation of d-glucosamine methyl ethers using a combination of partition and ion-exchange chromatography.     

Separation of mono- and diglycerides by gas--liquid chromatography

The parameters affecting the separation and quantification of trimethylsilyl ethers of mono- and diglycerides have been investigated by gas-liquid chromatography with QF-1 and SE-30 as stationary phases and a flame ionization detector. Results have been compared with those obtained earlier for triglycerides. The isothermal characteristics of a range of trimethylsilyl ethers of mono- and diglycerides on both stationary phases showed that log retention volume was directly proportional to carbon number and inversely proportional to absolute temperature. However, glyceride derivatives with lower carbon numbers deviated from these relationships. By using various rates of programmed temperature rise, we have determined the elution temperatures (Kelvin scale) of the mono- and diglyceride trimethylsilyl ethers relative to that of glycerol trilaurate. The "carbon equivalent of a trimethylsilyl group" is defined and shown to be useful in comparing the chromatographic properties of different glyceride classes. Weight and molar correction factors have been obtained and used to analyze diglycerides derived from egg and bovine brain lecithins.     

Mutagenicity of aromatic glycidyl ethers with Salmonella

6 aromatic glycidyl ethers containing naphthyl, biphenyl or benzylphenyl substituents were synthesized. These epoxides together with the commercially available compounds 2-biphenylyl glycidyl ether were examined for dose-mutagenicity relationships using the plate incorporation Ames test with Salmonella typhimurium strains TA100 and TA1535. Structure-mutagenicity relationships were further examined for these compounds and 3 phenyl glycidyl ethers by concurrent testing at a single dose with strain TA100. Meaningful correlations could not be established for the mutagenicity of these epoxides to their molecular volumes, partition values, nor to their reactivities with the model nucleophile, 4-(4-nitrobenzyl) pyridine. However, it was noted that increased conjugated aromatic unsaturation with its resulting planarity led to increased mutagenicity and that this effect decreased when it was further removed from the epoxide moiety.     

The biological activity of complex esters of saccharose and higher fatty acids

Sucrose/fatty acid ethers from Astasia longa culture have been studied. Biological activity of different ethers has been studied on calf kidney cells. The activity depends on the lipid component of the ethers. The highest stimulation of cell layer formation was observed with ethers of sucrose and polyunsaturated fatty acids.     

Enantioselective recognition of ammonium perchlorate salts by optically active monoaza-15-crown-5 ethers

Chiral monoaza-15-crown-5 ethers (1, 2) were prepared from (R)-(-)-2-amino-1-butanol in high yield. The chiral monoaza-15-crown-5 ethers were purified directly as NaClO(4) complexes. Molecular recognition by these chiral monoaza-crown ethers of (R)- and (S)-PhEtHClO(4) and (R)- and (S)-NapEtHClO(4) as characterized by UV-vis spectroscopy. The order of enantiomeric selectivity is (R)- > (S)- PhEtHClO(4) and (S)- > (R)-NapEtHClO(4) for 1. In the case of 2 it was (R)- > (S)-PhEtHClO(4) and (R)- > (S)- NapEtHClO(4). The cavity of macrocycle and steric hindrance of the benzene units appears to play an important role in recognition.     

External chiral ligand-induced enantioselective versions of the [2,3]-Wittig sigmatropic rearrangement

The external chiral ligand-induced enantioselective [2,3]-Wittig rearrangements of crotyl benzyl ethers and crotyl propargylic ethers are described. The most notable is that treatment of (E)-crotyl propargylic ethers with a t-butyllithium/(S;S)-bis(oxazoline) complex provides a relatively high enantioselectivity (up to 89% ee), together with a high threo-diastereoselectivity. Furthermore, examples of the "asymmetric catalytic version" of the rearrangement of crotyl benzyl ethers are presented.     

Relative teratogenicity of nitrofen analogs in mice: unchlorinated, monochlorinated, and dichlorinated-phenyl ethers

To determine the role of number and position of chlorine substituents on the developmental toxicity of diphenyl ether analogs of nitrofen, we have evaluated one unchlorinated, three monochlorinated, and five dichlorinated-phenyl 4'-nitrophenyl ethers with respect to effects on liver weight and on maintenance of pregnancy in females, and with respect to postnatal survival and the occurrence of small or absent Harderian glands in offspring. None of the diphenyl ethers evaluated in these experiments was as active as nitrofen with respect to any parameter evaluated. Both the position and the number of chlorine substituents affected toxicity, but no simple relationship between number or position of chlorine substituents and either maternal or fetal endpoints was established.     

Transprotection of silyl ethers of nucleosides in FeCl3 based ionic liquids

Ionic liquid mediated deprotection of tert-butyldimethyl silyl (TBDMS) ethers derived from various primary and secondary alcohols have been studied and the reaction conditions optimized. Deprotection of the silyl ethers in FeCl3 based ionic liquids in presence of acetic anhydride yielded the acetate esters of the corresponding alcohols in good yields. The transprotection methodology was extended to the silyl ethers of nucleosides to yield the corresponding acetylated products.     

Synthesis and characterization of water-soluble hydroxybutenyl cyclomaltooligosaccharides (cyclodextrins)

We have examined the synthesis of hydroxybutenyl cyclomaltooligosaccharides (cyclodextrins) and the ability of these cyclodextrin ethers to form guest-host complexes with guest molecules. The hydroxybutenyl cyclodextrin ethers were prepared by a base-catalyzed reaction of 3,4-epoxy-1-butene with the parent cyclodextrins in an aqueous medium. Reaction byproducts were removed by nanofiltration before the hydroxybutenyl cyclodextrins were isolated by co-evaporation of water-EtOH. Hydroxybutenyl cyclodextrins containing no unsubstituted parent cyclodextrin typically have a degree of substitution of 2-4 and a molar substitution of 4-7. These hydroxybutenyl cyclodextrins are randomly substituted, amorphous solids. The hydroxybutenyl cyclodextrin ethers were found to be highly water soluble. Complexes of HBen-beta-CD with glibenclamide and ibuprofen were prepared and isolated. In both cases, the guest content of the complexes was large, and a significant increase in the solubility of the free drug was observed. Dissolution of the complexes in pH 1.4 water was very rapid, and significant increases in the solubility of the free drugs were observed. Significantly, after reaching equilibrium concentration, a decrease in the drug concentration over time was not observed.     

Enzymatic Synthesis of 1,4-di-α-d-Glucosyl-l-sorbose and 1-α-Iso-maltosyl-l-sorbose

Several new methylenedioxyphenyl (MDP) ethers were synthesised from sesamol and methoxy substituted sesamols and screened as pyrethrum synergists. In general, the synergistic activity increased with the methoxyl substituents and decreased in the corresponding alkenyl analogs. The synergistic activity of alkyl ethers was found to vary with the alkyl chain, n-propyl ethers showing the maximum. In the case of alkenyl ethers, the activity followed the order γ,γ-dimethyl allyl>β-methallyl > allyl and showed no correlation between R_m and synergistic activity.     

Quantitative analysis and comparison of the physical properties of O-alkyl and S-alkyl monoethers of glycerol

A homologous series (C(10), C(12), C(14), C(16), C(18)) of synthetic O-alkyl and S-alkyl ethers of glycerol was analyzed by gas-liquid chromatography (GLC) and thin-layer chromatography (TLC), and examined by IR and n.m.r. spectroscopy; the physical properties of the O-alkyl and S-alkyl ethers were compared. Isopropylidene derivatives of the glycerol ethers and thioethers were quantitatively analyzed by GLC on polar and nonpolar liquid phases. On a medium polar liquid phase (ethylene glycol succinate), mixtures of the O-alkyl and S-alkyl ethers were completely resolved. Isopropylidene derivatives of glycerol ethers and of thioethers could be separated as classes (though not into individual homologues) by TLC. O-hexadecyl and S-hexadecyl ethers of glycerol are easily distinguished by IR and n.m.r. spectroscopy.