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PubMed2001

Reactions of 2,6-dimethyl-1,3-dioxane-4-ol (aldoxane) with deoxyguanosine and DNA.

In a recent study, we identified several new DNA adducts of the carcinogen acetaldehyde, including N(2)-(2,6-dimethyl-1,3-dioxan-4-yl)deoxyguanosine (N(2)-aldoxane-dG, 2). Our goal in this study was to investigate further the formation of 2 by allowing 2,6-dimethyl-1,3-dioxane-4-ol (aldoxane, 5) to react with dG and DNA. Aldoxane is readily formed by trimerization of acetaldehyde. The reaction of aldoxane with dG and DNA produced diastereomers of N(2)-aldoxane-dG (2) as observed in the reactions of acetaldehyde with dG and DNA, supporting the intermediacy of aldoxane in their formation. Unexpectedly, however, an array of other adducts was formed in these reactions, including 3-(2-deoxyribos-1-yl)-5,6,7,8-tetrahydro-8-hydroxy-6-methylpyrimido[1,2-a]purine-10(3H)one (3), 2-amino-7,8-dihydro-8-hydroxy-6-methyl-3H-pyrrolo[2,1-f]purine-4(6H)one (13), N(2)-(3-hydroxybutylidene)dG (9), N(2)-[(2-hydroxypropyl)-6-methyl-1,3-dioxane-4-yl]dG (14), and N(2)-ethylidene-dG (1). Adduct 1 was the major product and was found to be quite stable in DNA. The adducts result from a cascade of aldehydes, e.g., 2-butenal (crotonaldehyde, 12), 3-hydroxybutanal (7) and its dimer (2-hydroxypropyl)-6-methyl-1,3-dioxane-4-ol (paraldol, 6), and acetaldehyde, produced from aldoxane under the reaction conditions. The reactions of aldoxane with dG and DNA were compared with those of paraldol. The paraldol reactions gave products resulting from reactions of dG and DNA with paraldol, 3-hydroxybutanal, and crotonaldehyde (adducts 3, 13, and 9) but the products of the aldoxane and acetaldehyde reactions (adducts 1 and 2) were not observed, indicating that paraldol is more stable under the reaction conditions than is aldoxane. The results of this study provide new insights about the formation of DNA adducts from aldehydes via condensation products of the latter.

Acetaldehyde↗
PubMed2001

A laser flash photolysis study of curcumin in dioxane-water mixtures.

Curcumin [bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] was studied by means of UV-VIS absorption spectroscopy and nanosecond laser flash photolysis in 1,4-dioxane-water mixtures in a series of dioxane-water volume ratios. The transient characteristics were found to be dependent on the amount of water. In pure dioxane the triplet state of the molecule in its enolic form was detected (lambda(max) = 720 nm, tau = 3.2 micros), whereas upon water addition, the diketo form was found to prevail, because of the perturbation of intramolecular H-bonded structure. This led to hydrogen abstraction from dioxane by curcumin triplet state and the formation of the corresponding ketyl radical (lambda(max) = 490 nm, tau approximately 10 micros). Laser flash photolysis measurements, carried out in solvents of different polarity and proticity (benzene, cyclohexane and various alcohols), allowed the transient assignments to be confirmed, supporting our interpretation.

Curcumin↗
PubMed2006

Synthesis and antihepatotoxic activity of some new chalcones containing 1, 4 - dioxane ring system.

Silybum marianum is a medicinal plant used widely for treating liver diseases. The silymarin, a mixture of three flavolignan isomers namely silybin (1), silydianin (2), and silychristin (3) is an active constituent of the plant. However, silybin containing 1, 4-dioxane ring is the most potent antihepatotoxic agent. In contrast, other isomers do not possess 1, 4-dioxane ring, and thus do not exhibit a significant activity. We, therefore, thought that 1, 4-dioxane ring plays an important role in displaying antihepatotoxic activity, and have prepared some chalcones containing 1, 4-dioxane ring. The synthesized compounds were evaluated for antihepatotoxic activity against carbon tetrachloride induced hepatotoxicity in albino rats. The degree of protection was measured by using biochemical parameters like serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvate transaminase (SGPT), alkaline phosphatase (ALKP), total protein (TP) and total albumin (TA). The compounds namely 2-hydroxy-4-methoxy-3',4'-(2"- hydroxy methyl-1", 4"- dioxano) chalcone (9b) and 2-hydroxy- 4, 6-dimethoxy-3', 4'-(2"-hydroxy methyl-1", 4"- dioxano) chalcone (9c) exhibited a potent activity in comparison to standard drug silybon-70. The other compounds also showed moderate activity.

Animals↗
PubMed1979

The influence of dioxan on the bilayer and monolayer phase transition of phospholipids.

The influence of 1.4.-dioxan on the bilayer phase transition of various phospholipids was studied by differential scanning calorimetry and turbidity measurements. The addition of 1.4.-dioxan to lipid bilayers decreases the transition temperature T(m) increases the transition enthalpy of the transition. The cooperativity of the transition is unaffected. The phospholipid monolayer transition from the liquid-condensed to the liquid-expanded phase was measured by recording area versus temperature curves at constant surface pressure (isobars). The monolayer transition temperature at constant surface pressure is increased when 1.4.-dioxan is added to the subphase. The change in molecular area becomes larger. A comparison of monolayer isobars on water and water/dioxan as subphase at constant surface tension rather than surface pressure leads to a decrease of the transition temperature on water/dioxan as subphase. This decrease as well as the larger change in molecular area at the monolayer transition can be correlated to the decrease in Tm and the increase in the transition enthalpy of the corresponding bilayer system. 1.4.-Dioxan seems to accumulate at the lipid head group/water interface, thus lowering the tension of the bilayer membrane. This cyclic ether can be used for altering the characteristics of bilayer membranes without disturbing the lipid chain organization.

Journal Article↗
PubMed2004

Salt effects on the conformational behavior of 5-carboxy- and 5-hydroxy-1,3-dioxane.

The varied and essential involvement of metal ions and inorganic salts in biological and chemical processes motivated the present study where 5-carboxy- and 5-hydroxy-1,3-dioxanes are used as model frameworks for the evaluation of the conformational behavior of oxygen-containing receptors in the presence of Li(+), Na(+), K(+), Ag(+), Mg(2+), Ca(2+), Ba(2+), and Zn(2+). Thus, the position of equilibria, established by means of BF(3), between diastereomeric cis- and trans-5-substituted-2-phenyl-1,3-dioxanes, in solvent THF and in the presence of 0, 1, and 5 equiv of salt, has been determined. The observed Delta G(o) degrees values for the conformational equilibria of 5-carboxy-1,3-dioxane show that Ag(+), Li(+), and Ca(2+) complexation leads to increased stability of the axial isomer. In the case of the 5-hydroxy-1,3-dioxane, Mg(2+), Ag(+), and Zn(2+) are the metal ions that stabilize the axial conformer of the heterocycle upon association. Interpretation of the experimental observations was based on DFT molecular modeling studies at the Becke3LYP/6-31G* and Becke3LYP/6-31+G** levels of theory. Although gas-phase calculations give Delta E values that are too large when modeling equilibria involving ionic species in polar solution, the computational results confirm the structural and energetic consequences of metal cation coordination to the oxygen atom in carbonyls or ethers. The results derived from the present study contribute to our understanding of the chemical processes involved in molecular recognition and physiological events.

Journal Article↗
PubMed1999

Anti-1,3-diols by Addition of Dialkylzinc Reagents to 4-Acetoxy-1,3-dioxanes.

Dialkylzincs couple with 4-acetoxy-6-alkyl-1,3-dioxanes in the presence of trimethylsilyl triflate (TMSOTf) to form trans-4,6-dialkyl-1,3-dioxanes with excellent diastereoselectivities. These dioxanes could be deprotected to yield anti-1,3-diols. A variety of functional groups are tolerated in the dialkylzinc, although silyl and benzyl ethers led to diminished diastereoselectivities. Substituents at the C5-position of the dioxane ring have little effect on the selectivity, while small C2 (acetal) substituents led to slightly reduced diastereoselectivity. These couplings work best with cyclic acetals, which can be difficult to hydrolyze. The 4-(benzyloxy)butanal (BOB) acetal has been developed as a new cyclic acetal protecting group that is compatible with dialkylzinc coupling reactions. BOB protecting groups are easily removed by catalytic hydrogenation followed by mild acid hydrolysis.

Journal Article↗
PubMed1999

Enantioselective Syntheses of 2-Deoxyxylono-1,4-lactone and 2-Deoxyribono-1,4-lactone from 1,3-Dioxan-5-yl Diazoacetates.

1,3-Dioxan-5-yl diazoacetates are valuable substrates for highly diastereoselective and enantioselective carbon-hydrogen insertion reactions. trans-2-(tert-Butyl)-1,3-dioxan-5-yl diazoacetate is a direct precursor to 2-deoxyribono-1,4-lactone in up to 81% ee, whereas cis-2-(tert-butyl)-1,3-dioxan-5-yl diazoacetate yields only the protected 2-deoxyxylono-1,4-lactone in up to 96% ee. However, trans-2-aryl-1,3-dioxan-5-yl diazoacetate (aryl = phenyl or 2-naphthyl) forms the precursor to 2-deoxyxylono-1,4-lactone in up to 95% ee but with the mirror image configuration of that produced from the trans-2-(tert-butyl) analogue. The catalysts that are most suitable for these carbon-hydrogen insertion reactions are chiral dirhodium(II) carboxamidates. 1,3-Dialkoxy-2-propyl diazoacetates give mainly 2-deoxyxylono-1,4-lactone derivatives (>90:10) with generally high enantiocontrol, but replacement of hydrogen at the 2-position of these 2-propyl diazoacetates led to a mixture of products.

Journal Article↗
PubMed2006

Solvation dynamics by computer simulation: coumarin C153 in 1,4-dioxane.

Computer simulation results are presented for an atomistic pair potential model of 1,4-dioxane which takes into account molecular flexibility. The model has been conceived to be applied to the study of solvatochromism and solvation dynamics in the presence of the polar probe coumarin C153. Computer simulations on the pure liquid have produced thermodynamical, structural, and dynamical data in good agreement with available experimental measures. This constitutes a valuable test of the 1,4-dioxane all-atom model employed. The study of solute-solvent interactions for C153 in 1,4-dioxane has been motivated by the aim of casting light, through simulations, on the interesting experimental findings according to which such a solvent behaves as a "polar" solvent with respect to dynamic solvation properties. Molecular dynamics is particularly suitable to model the process and provides an interpretation of the so-called "dioxane anomaly". An investigation of the structure of the solvation shell and of the dynamics of solvation is presented and discussed. In particular, the satisfactory accordance between simulated and experimental solvation response implies that the simulations give a reliable description of both solute and solvent at a molecular level and reinforces the idea that the explicit inclusion of discrete solvent molecules is needed for a realistic treatment of solvation phenomena in which the local structure of the liquid plays a key role.

Journal Article↗
PubMed2001

Gas chromatographic determination of 1,4-dioxane at low parts-per-million levels in glycols.

1,4-Dioxane is a flammable liquid and tends to form explosive peroxides. Its formation in glycols (low parts-per-million levels), which are used as dehumidifying agents in refineries, may take place by condensation. 1,4-Dioxane thus formed gets distilled over with benzene in the refinery process. Therefore, it is necessary to identify and determine the levels of 1,4-dioxane in glycols as well as benzene. Gas chromatography (GC) is probably the best technique for this purpose. GC analysis may be carried out using a flame ionization detector. Results show that 1,4-dioxane can be comfortably determined down to 2 ppm in glycols and benzene.

Journal Article↗
PubMed1998

1,4-Dioxane is not mutagenic in five in vitro assays and mouse peripheral blood micronucleus assay, but is in mouse liver micronucleus assay.

1,4-Dioxane, an animal carcinogen, was not previously genotoxic in in vitro assays. We reevaluated the compound's genotoxic potential in five in vitro genotoxicity tests in the presence and absence of S9 mix using recommended new protocols. We used the bacterial reverse mutation assay with Salmonella TA and E. coli WP2 strains, including the plate and preincubation methods, the CHO chromosomal aberration assay, including examination of polyploid induction and extended sampling time, the CHO sister-chromatid exchange assay with short and long treatment time, the mouse lymphoma tk assay (microtiter method), including longer treatment time (24 hr), and the CHO micronucleus assay with short and long treatment times. The highest concentration we used was five mg/ml or plate. We also evaluated the genotoxic effect of 1,4-dioxane in vivo by conducting peripheral blood and liver micronucleus assays in the same mice after single oral administration of up to 3,000 mg/kg. All in vitro assays and the peripheral blood micronucleus assay were negative. The mouse liver micronucleus assay, on the other hand, was positive, indicating that 1,4-dioxane might be genotoxic. It is also conceivable that the positive result in mouse liver micronucleus assay was due to a nongenotoxic mechanism, i.e., errors in genetic repair following enhancement of hepatocyte proliferation.

Animals↗
PubMed1992

1,4-Dioxane: prediction of in vivo clastogenicity.

1,4-Dioxane was analyzed with the CASE program to determine the structural basis of its potential genotoxicity and carcinogenicity. These investigations led to the prediction that while 1,4-dioxane was not genotoxic in vitro, it was an inducer of micronuclei in the bone marrow of rats and a carcinogen for both rats and mice. If it is assumed that the induction of micronuclei is the result of DNA damage, then this potential and the previous report of the in vivo induction of DNA strand breaks in rat liver raise the possibility of a genotoxic action for 1,4-dioxane. However it is also conceivable that we have identified a structural feature which contributes to the induction of micronuclei by a non-genotoxic mechanism.

Animals↗
PubMed2003

Ketalization of phosphonium ions by 1,4-dioxane: selective detection of the chemical warfare agent simulant DMMP in mixtures using ion/molecule reactions.

Phosphonium ions CH(3)P(O)OCH(3)(+) (93 Th) and CH(3)OP(O)OCH(3)(+) (109 Th) react with 1,4-dioxane to form unique cyclic ketalization products, 1,3,2-dioxaphospholanium ions. By contrast, a variety of other types of ions having multiple bonds, including the acylium ions CH(3)CO(+) (43 Th), CH(3)OCO(+) (59 Th), (CH(3))(2)NCO(+) (72 Th), and PhCO(+) (105 Th), the iminium ion H(2)C[double bond]NHC(2)H(5)(+) (58 Th) and the carbosulfonium ion H(2)C[double bond]SC(2)H(5)(+) (75 Th) do not react with 1,4-dioxane under the same conditions. The characteristic ketalization reaction can also be observed when CH(3)P(OH)(OCH(3))(2)(+), viz. protonated dimethyl methylphosphonate (DMMP), collides with 1,4-dioxane, as a result of fragmentation to yield the reactive phosphonium ion CH(3)P(O)OCH(3)(+) (93 Th). This novel ion/molecule reaction is highly selective to phosphonium ions and can be applied to identify DMMP selectively in the presence of ketone, ester, and amide compounds using a neutral gain MS/MS scan. This method of DMMP analysis can be applied to aqueous solutions using electrospray ionization; it shows a detection limit in the low ppb range and a linear response over the range 10 to 500 ppb.

Chemical Warfare Agents↗
PubMed1996

Acyl-CoA:Cholesterol O-acyltransferase (ACAT) inhibitors. 2. 2-(1,3-Dioxan-2-yl)-4,5-diphenyl-1H-imidazoles as potent inhibitors of ACAT.

The second in this series of papers concerns our further investigations into the search for a potent bioavailable acyl-CoA:cholesterol O-acyltransferase (ACAT) inhibitor suitable for the treatment of atherosclerosis. The design, synthesis, and structure-activity relationship for a series of ACAT inhibitors based on the 2-(1,3-dioxan-2-yl)-4,5-diphenyl-1H-imidazole pharmacophore are described. Compounds such as 13a bearing simple alkyl or hydroxymethyl substituents at the 5-position of the 1,3-dioxane ring are potent bioavailable inhibitors of the rat hepatic microsomal enzyme in vitro (IC50 < 100 nM) but are only weak inhibitors of the human hepatic enzyme. We have found however that 1,3-dioxanes substituted at the 5-cis position with pyrazolylalkyl or aminoalkyl groups are potent inhibitors in vitro of human macrophage ACAT, the potency depending on the nature of the terminal heterocycle and the length of the alkyl chain. An ex vivo bioassay herein demonstrates that potent inhibitors such as 13t (IC50 = 10 nM) which contain lipophilic terminal heterocycles do not appear to be systematically available. Less potent but more water soluble compounds such as 13h (IC50 = 60 nM) and 13n (IC50 = 70 nM) are absorbed following oral dosing and achieve plasma levels significantly in excess of their IC50 for ACAT inhibition. These compounds are therefore possible candidates for further investigation as oral antiatherosclerotic agents.

Animals↗
PubMed2000

Trace-level determination of 1,4-dioxane in water by isotopic dilution GC and GC-MS.

The volatile and polar solvent 1,4-dioxane has recently been reported as a contaminant of ground and surface waters, establishing the need to determine this substance in drinking water. This investigation established that 1,4-dioxane can be determined in water by various techniques including direct aqueous injection (DAI) gas chromatography (GC) and purge and trap GC-mass spectrometry (MS). Purge and trap GC-MS is limited by 1,4-dioxane's poor purge efficiency, resulting in detection limits up to 100 times greater than the efficiently purged volatile organic compounds. To attain the sensitivity required for drinking water monitoring, a method based on continuous liquid-liquid extraction with dichloromethane was developed. Isotope dilution was more accurate and reproducible than quantification with external standards, and the improvement in precision led to a lower method detection limit, 0.2 microgram L-1, using a quadrupole ion trap instrument in the electron ionization mode. Isotope dilution accuracy approached 100% in ppb determinations. Isotopic dilution quantification was also possible using a non-selective GC detector owing to the high efficiency of capillary GC columns that resolve the deuterium-labeled solvent from the natural isotopes.

Chromatography, Gas↗
PubMed2003

Determination of 1,4-dioxane impurity levels in Triton X-100 raw material by gas chromatography with mass spectrometric detection.

Triton X-100 (octoxynol 9) is a commercially available surfactant used as a solvent detergent in numerous pharmaceutical applications including virus inactivation. A byproduct formed during its synthesis is 1,4-dioxane, the cyclic dimer of ethylene oxide and a possible carcinogen to humans. The United States Pharmacopoeia (USP) contains a labor-intensive 1,4-dioxane test for Triton X-100. The method couples vacuum distillation to extract the 1,4-dioxane from the Triton X-100 matrix followed by gas chromatography (GC) using a packed column with flame-ionization detection. In order to provide a more automated and specific test methodology, a headspace GC-mass spectrometry (MS) method has been developed for this application. Analyte quantitation is accomplished by the method of standard additions. The automated sample preparation, coupled with the specificity inherent in high-efficiency capillary column separations together with single-ion MS detection, results in an assay that is more efficient, accurate, and precise than the USP procedure. Performance characteristics of the headspace GC-MS method are contrasted with those characteristics of the USP methodology.

Dioxanes↗
PubMed2006

The extraction and analysis of 1,4-dioxane from water using solid-phase microextraction coupled with gas chromatography and gas chromatography-mass spectrometry.

In this study, two methods are developed for the extraction of 1,4-dioxane (dioxane) from water using 80-microm carboxen-polydimethylsiloxane solid-phase microextraction fibers followed by either gas chromatography (GC)-flame ionization detection (FID) or GC-mass spectrometry (MS). With GC-FID, the lower limit of detection (LOD) for 1,4-dioxane is 2.5 microg/L (ppb) with a linear range of 5 to 10,000 microg/L, obtained by immersing the fiber in the sample for 20 min with agitation. Using GC-MS, the lower limit of quantitation is 0.5 microg/L, and the LOD is 0.25 microg/L. The upper linear range limit is 100 microg/L. Samples are extracted in 20 min using either heated headspace with agitation or direct immersion with agitation.

Dioxanes↗
PubMed2005

Pseudonocardia dioxanivorans sp. nov., a novel actinomycete that grows on 1,4-dioxane.

An actinomycete strain (CB1190(T)) was previously isolated from industrial sludge contaminated with 1,4-dioxane. The cells of this culture are Gram-positive and exhibit branching aerial and vegetative mycelium. Analysis of the 16S rRNA gene sequence indicates that the strain belongs to the genus Pseudonocardia, closely related to Pseudonocardia hydrocarbonoxydans, P. sulfidoxydans and P. halophobica. Physiological and biochemical characteristics of CB1190(T) are different from those of other known Pseudonocardia species. The novel organism described here is distinguished by its ability to grow on 1,4-dioxane, which is a probable human carcinogen. This culture can also grow on tetrahydrofuran, gasoline aromatics and several other toxic environmental contaminants. Strain CB1190(T) is capable of fixing dinitrogen. The predominant fatty acids are 16 : 0 iso, 16 : 1 iso cis9 and 17 : 1 iso cis9. The major phospholipid fatty acids are 16 : 0 iso, 16 : 0 10-Me and 17 : 0 10-Me. The peptidoglycan belongs to type A1gamma, meso-diaminopimelic acid. The major menaquinone is MK-8 (H(4)). Mycolic acids are absent. The G+C content is 74 mol%. Based on morphological, physiological, chemotaxonomic and phylogenetic evidence, it is proposed that strain CB1190(T) (=ATCC 55486(T)=DSM 44775(T)) be classified as the type strain of a novel species, Pseudonocardia dioxanivorans sp. nov. Further studies with this organism will provide insights into metabolic pathways, responsible enzymes, kinetics and the fate of 1,4-dioxane in the environment.

Actinomycetales↗
PubMed1999

Bis(1,3-dioxan-2-yl)arenes: precursors to linked porphyrins.

The crystal structures of two linked-prophyrin precursors have been determined. In the crystalline state, 1,4-bis[2-(1,3-dioxan-2-yl)phenyl]butane, C24H30O4, (I), exists in a stair-like conformation with dioxane rings in chair conformations. The molecule is positioned on an inversion center. In the crystalline state, 1,2-bis(1,3-dioxan-2-yl)benzene, C14H18O4, (II), is arranged in zigzag chains. In each chain, molecules of (II) are tilted 106.2 (1) degree relative to each other. They are also oriented to form a weak C-H...O contact (H...O 2.43 A).

Benzene Derivatives↗