Trioxide Complex Research Articles

Sulfatobetaine Synthesis from Epoxides and Tertiary Amine‐Sulfur Trioxide Complexes

AbstractThe sulfatobetaine formation from epoxides and tertiary amine‐sulfur trioxide complexes was studied. It was revealed that heterocyclic tertiary amine‐sulfur trioxide complexes being the most electrophilic and reactive complexes produce sulfatobetaines in 15.5–62.6 % isolation yields, the aliphatic tertiary amine sulfur‐trioxide complexes failed to form the expected products. The presence of the amine taken in 5‐fold excess improves the isolation yields of the sulfatobetaines (52–100 %).

Sulfated modification of hyaluronan tetrasaccharide enhances its antitumor activity on human lung adenocarcinoma A549 cells in vitro and in vivo

Hyaluronan (HA) is a glycosaminoglycan polymer involved in cell phenotype change, inflammation modulation, and tumor metastasis progression. HA oligosaccharides have a higher solubility and drug-forming ability than polysaccharides. HA tetrasaccharide was reported as the smallest fragment required for inhibiting triple-negative breast cancer, but the anti-tumor activity of HA tetrasaccharide (HA4) and its sulfated derivatives in lung cancer is still unknown. In this study, HA4 was prepared via HA degradation by chondroitinase ABC (CSABC), while its sulfated derivatives were prepared by sulfur pyridine trioxide complex in N, N-dimethylformamide (DMF). Then, the anti-tumor activity was detected via MTT assay and xenograft tumor experiments, while the expression level change of apoptosis genes was analyzed by qRT-PCR. Electrospray mass spectrometry (ESI-MS) analysis showed several HA4 sulfated derivatives, GlcA2GlcNAc2 (SO3H)n contains 0–6 sulfation groups, which mainly contain 3–6, 2–3, and 0–1 sulfation groups were classified as HA4S1, HA4S2, and HA4S3, respectively. After the addition of 1.82 mg/mL HA4, HA4S1, HA4S2, and HA4S3, the cell viability of A549 cells was reduced to 81.2 %, 62.1 %, 50.3 %, and 65.9 %, respectively. Thus, HA4S2 was chosen for further measurement, the qRT-PCR results showed it significantly up-regulated the expression of genes in the apoptosis pathway. Moreover, HA4S2 exhibited stronger antitumor activity than HA4 in vivo and the tumor inhibition rate reached 36.90 %. In summary, this study indicated that the CSABC enzyme could effectively degrade HA into oligosaccharides, and sulfation modification was an effective method to enhance the antitumor activity of HA tetrasaccharides.

An Accurate and Precise Analytical Method for Estimation of Active Sulfur Trioxide and Sulfuric acid in Triethylamine Sulfur Trioxide Complex

Triethylamine sulfur trioxide complex (TEA-SO3) is an important sulfating agent used in the synthesis of various drug substances, dyes and other chemicals. Quality of TEA-SO3 is very crucial because it provides the active sulfur trioxide (SO3) in the sulfation reaction. We developed an accurate, precise and robust analytical method for determination of quality of TEA-SO3. The potentiometric titrimetry methods are capable to estimate SO3 as well as degradation product sulfuric acid (H2SO4) present in the TEA-SO3. Estimation of SO3 involves hydrolysis of the complex using H2SO4 under reflux condition and titrating excess H2SO4 against alkali solution. H2SO4 is quantified by direct titration against alkali solution. Both assay and impurity quantification methods were validated as per the ICH guideline. Accuracy of H2SO4 determination was 102.80% with precision of 0.75% and could be detected as low as 0.01%. Method to estimate SO3 was accurate with recovery of 99.92% and precision of 0.25%. The developed methods were employed for quality check of the reagent.

Effects of co-administration of arsenic trioxide and Schiff base oxovanadium complex on the induction of apoptosis in acute promyelocytic leukemia cells.

Acute promyelocytic leukaemia (APL) is commonly treated with arsenic trioxide (As2O3) that has many side effects. Given the increasing trend of studies on beneficial therapeutic properties of synthetic compounds containing vanadium, the present study sought to use Schiff base oxovanadium complex to reduce the needed concentration of arsenic trioxide. The HL-60 cell line, which is a model of APL, was selected and the effects of arsenic trioxide and Schiff base oxovanadium complex were individually and simultaneously evaluated on the cell viability by the MTT assay. Flow cytometry and Real-time RT-PCR were also performed to investigate the rate of apoptosis and the expression of P53 and P21 genes, respectively. The IC50 of arsenic trioxide and Schiff base oxovanadium complex on Hl-60 cells was 8.37 ± 0.36µM and 34.12 ± 1.52µg/ml, respectively. At the simultaneous administration of both compounds, the maximum decrease in the cell viability was seen in co-administration of 40µg/ml of Schiff base oxovanadium complex and 0.001µM of arsenic trioxide. Real-time RT-PCR indicated that the co-administration of Schiff base oxovanadium complex 40µg/ml and arsenic trioxide 0.001µM could increase the expression of P53 and P21 genes by 3.76 ± 0.19 and 6.57 ± 1.29 fold change, respectively to the control sample. The flow cytometry studies also indicated that this co-administration could induce apoptosis up to 67% ± 0.9% significantly higher than the control sample. The use of Schiff base oxovanadium complex could significantly reduce the required dose of arsenic trioxide to induce apoptosis in HL-60 cells.

Alcohol Oxidation in the Presence of Methyl Chlorosulfonate and Dimethyl Sulfoxide

AbstractThe reaction of methyl chlorosulfonate with dimethyl sulfoxide (DMSO) was studied at various temperatures. The interaction of dimethyl sulfoxide‐sulfur trioxide complex with various alcohols in the presence of triethylamine (Et3N) was investigated. The results showed that this complex oxidizes the primary and secondary alcohols to the corresponding carbonyl compounds in excellent yields.

Preparation, structural changes and adsorption performance of heavy metal ions on sulfonated cellulose with varying degrees of substitution

Abstract Sulfonated cellulose (SC) with varying degrees of substitution (DS) were prepared with the pyridine sulfur trioxide complex (Py-SO3) as a sulfonation reagent (as a source of sulfur trioxide) in dimethyl formamide (DMF) as a solvent, where the DS was primarily affected by the molar ratio between Py-SO3 and the anhydroglucose (AHG) unit. Sulfonation temperature and residence time have less effect on DS. The ratio of the crystalline domain of SC decreased gradually with incremental DS, and the crystalline cellulose I of SC at DS0.81 nearly disappeared, and the moiety of the paracrystalline SC with high hydrophilicity increased. The thermostability decreased with increasing DS as a consequence of crystalline domain decrement. The adsorption performance of SC to metal ions was enhanced with increasing DS. However, above DS 0.62, the adsorption capacity enhancement is negligible. For an economic adsorption of heavy meatal ions in effluents, the DS of SC must be optimized.

Computational study on mechanisms of C2H5O2+OH reaction and properties of C2H5O3H complex

A comprehensive theoretical study on the bimolecular reaction of C2H5O2 with OH radicals was performed at the CCSD(T)/6-311++G(2df,2p)//B3LYP/6-311+G(d,p) level of theory. The calculation results show that C2H5O2 + OH reaction proceeds on both the singlet and the triplet potential energy surfaces(PESs). On the singlet PES, the favorable pathway is the addition of OH radical to the terminal oxygen atom of C2H5O2 radical, leading to the formation of trioxide C2H5O3H with a barrierless process. Then, the trioxide directly decomposes to the products C2H5O and HO2 radicals. On the triplet PES, the predominant pathways are α and β hydrogen atom abstractions of C2H5O2 radical by OH radical-forming products 3CH3CHO2+H2O and 3CH2CH2O2+H2O, and the corresponding barriers are 12.02(3TS8) and 19.19 kJ/mol(3TS9), respectively. In addition, the comprehensive properties of trioxide C2H5O3H were investigated for the first time. The results indicate that the trioxide complex RC1 can exist stably in the atmosphere owing to a significantly large and negative enthalpy of formation(‒118.44 kJ/mol) as well as a high first excitation energy(5.94 eV).

Reversible Graphite Anode Cycling with PC-Based Electrolytes Enabled by Added Sulfur Trioxide Complexes

Pyridine sulfur trioxide (PyrSO3), trimethyl amine sulfur trioxide (Me3NSO3), and triethyl amine sulfur trioxide (Et3NSO3) complexes have been investigated as electrolyte additives for lithium ion batteries. Incorporation of 0.5 to 2.0% of the SO3 complexes into a PC/EMC (1:1 v/v) 1 M LiPF6 baseline electrolyte affords reversible cycling of graphite anodes confirming generation of a stable Solid Electrolyte Interphase (SEI). Good cycling performance is observed for graphite/LiNi0.5Mn1.5O4 cells cycled to high potential (4.8 V vs Li) containing PC based electrolyte with added SO3 complexes. Ex-situ surface analysis via X-ray Photoelectron Spectroscopy (XPS) of the anodes reveals SO3 complex reduction on the surface of the graphite anode generates a sulfur-based SEI containing sulfites, sulfide, and sulfate species. The presence of the sulfur containing species is likely critical for the stability of the SEI. Ex-situ XPS analyses of the LiNi0.5Mn1.5O4 cathodes suggest that reaction of Me3NSO3 or Et3NSO3 complexes at high potential result in the generation of a stable passivation layer which affords good capacity retention and coulombic efficiency.

Improving the Performance of Graphite/LiNi0.5Mn1.5O4 Cells with Added N,N-dimethylformamide Sulfur Trioxide Complex

N,N-dimethylformamide sulfur trioxide complex (DMF-SO3) has been investigated as an electrolyte additive for LiNi0.5Mn1.5O4/graphite cells cycled to 4.8 V. Addition of 0.1% DMF-SO3 to 1.2 M LiPF6 in EC/EMC (3/7, v/v) standard electrolyte (STD) results in a significant improvement in the capacity retention and coulombic efficiency of LiNi0.5Mn1.5O4/graphite cells after 50 cycles at 45°C. Ex-situ surface analysis of the electrodes after cycling has been conducted via scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), and infrared spectroscopy with attenuated total reflectance (IR-ATR). The surface analysis suggests that a uniform interfacial film is formed on the LiNi0.5Mn1.5O4 surface composed of the decomposition products of DMF-SO3. The novel cathode surface films passivates the surface at high potential leading to the improved electrochemical performance.

Synthesis of sulfated brassinosteroids

A number of water soluble sulfates of 24-epibrassinolide including the 2α,3α-disulfate and all possible monosulfates were synthesized. The target compounds were isolated in crystalline form as the corresponding sodium salts. Pyridine–sulfur trioxide complex was used as sulfating agent followed by transformation of the resulting pyridinium salts into the sodium sulfates by treatment with NaOH. The control of the regioselectivity was achieved by an appropriate use of acetyl and benzyl protecting groups.

Heparin-derived supersulfated disaccharide inhibits allergic airway responses in sheep

The tetrasaccharide sequence of heparin oligosaccharides is the minimum chain length possessing anti-allergic activity, as the disaccharide fraction is inactive. Since sulfation pattern can modify the biological actions of heparin, we hypothesized that “supersulfation” of the inactive heparin disaccharide could confer anti-allergic activity to this molecule. To test this, we produced a supersulfated heparin disaccharide (Hep-SSD) and evaluated its anti-allergic activity in sheep with documented antigen-induced early and late airway responses (EAR and LAR) and airway hyperresponsiveness (AHR). Porcine intestinal heparin was depolymerized with nitrous acid, the disaccharide fraction separated by size exclusion chromatography, and then treated with pyridine-sulfur trioxide complex to yield Hep-SSD. Its chemical structure [IdoU2′,3′,4′S (1→4) AMan1,3,6S] was confirmed by HPLC, Mass Spectrometry and NMR analysis. Inhaled doses of 5 mg, 10 mg and 20 mg Hep-SSD produced inhibition of EAR (8%, 35% and 35%), LAR (50%, 80%, and 77%) and AHR (67%, 100% and 75%), respectively. A single oral dose of 2 mg/kg Hep-SSD given 90 min before challenge significantly inhibited EAR, LAR and AHR, but 1 mg/kg was ineffective. Multi dose oral treatment with Hep-SSD had a cumulative effect, as a once daily dose of 2 mg/kg for 3 days (last dose, 16 h before antigen) inhibited EAR, LAR and AHR by 30%, 75% and 74%, respectively. Finally, the oral activity of Hep-SSD could be enhanced 4 fold by formulating it with Carbopol®934P, in an enteric coated capsule. These data demonstrate that “supersulfation” can confer biological activity to the inactive heparin disaccharide. Both inhaled and oral Hep-SSD demonstrate significant anti-allergic activity and, therefore, may have therapeutic potential.

Xylan derivatives and their application potential – Mini-review of own results

The chemical modification of xylan is a promising path to new biopolymer ethers and esters with specific properties depending on the functional groups, the degree of substitution, and the substitution pattern. The reaction of 4-O-methylglucuronoxylan (GX) from birch with sodium monochloroacetate and 2,3-epoxypropyltrimethylammonium chloride in aqueous sodium hydroxide/slurry medium is described. The influence of the conditions of activation on product structure and properties are discussed in some detail. Methylation of GX was investigated under completely heterogeneous conditions or starting with dissolved polymer using methyl halides as reagents in the presence of NaOH. An activation of the biopolymer has been carried out before the reaction to enhance the accessibility of the reagents. Furthermore, novel xylan esters were efficiently synthesized by conversion of the hemicellulose with furan- and pyroglutamic acid as well as ibuprofen and N,N′-carbonyldiimidazole as activating agent under homogeneous conditions in dimethyl sulfoxide. This conditions are also appropriate to synthesize novel xylan ester containing xylan-4-[N,N,N-trimethylammonium]butyrate chloride moieties. Homogeneous syntheses of xylan sulfates could be carried out in a N,N-dimethylformamide (DMF)/LiCl as solvent applying sulfur trioxide complexes with DMF or pyridine. Advanced analytical techniques including NMR spectroscopy, HPLC, scanning electron microscopy, rheology, measurements of turbidity and surface tension allow description of structure–property-relationships; selected results will be briefly discussed. Xylan esters may form spherical nanoparticles of a size down to 60nm and a narrow particle size distribution applying a simple dialysis process and may be used for drug delivery applications. For cationic xylan derivatives a wide range of applications as paper strength additives, flocculation aids, and antimicrobial agents are proposed.

Synthesis and acetylcholinesterase inhibitory activity of 2β,3α-disulfoxy-5α-cholestan-6-one

Disodium 2β,3α-dihydroxy-5α-cholestan-6-one disulfate ( 8) has been synthesized using cholesterol ( 1) as starting material. Sulfation was performed using trimethylamine–sulfur trioxide complex in dimethylformamide as the sulfating agent. The acetylcholinesterase inhibitory activity of compound 8 was evaluated and compared to that of disodium 2β,3α-dihydroxy-5α-cholestane disulfate ( 10) and diols 7 and 9. Compounds 8 and 10 were active with IC 50 values of 14.59 and 59.65 μM, respectively. Diols 7 and 9 showed no inhibitory activity (IC 50 > 500 μM).

Gellan sulfate selectively suppresses the activation of hemocoagulation factors XI and XII

In this study, gellan sulfate (GS), a novel anticoagulant, was prepared by mixing deacetylated gellan and the dimethylformamide/sulfur trioxide (DMF-SO3) complex; this complex was prepared by adding varying volumes of chlorosulfonic acid (ClSO 3H) to DMF. The anticoagulant properties of GS were measured by determining the coagulation time, prothrombin time (PT), and activated partial thromboplastin time (aPTT) of normal whole blood samples and by analyzing the activation of hemocoagulation factors V, VIII, IX, X, and XII. We found that 0.04 mg/mL of GS with 40% sulfonation exhibits anticoagulant properties. GS selectively suppressed the activation of hemocoagulation factors XI and XII in the initial steps of the contact activation pathway. On the basis of our results, it can be concluded that the mechanism underlying the anticoagulation effects of GS was different from that of heparin. In addition, GS did not react with other hemocoagulation factors such as factors IX and X, and its activity was independent of antithrombin.

Synthesis and cytotoxic analysis of some disodium 3β,6β-dihydroxysterol disulfates

Disodium 3β,6β-dihydroxy-5α-cholestane disulfate ( 1) was synthesized in 4 steps with a high overall yield from cholesterol. First, cholesterol ( 4a) was converted to cholest-4-en-3,6-dione ( 5a) via oxidation with pyridinium chlorochromate (PCC) and then 5a was reduced by NaBH 4 in the presence of NiCl 2 to produce cholest-3β,6β-diol ( 6a). The reaction of 6a with the triethylamine-sulfur trioxide complex generated diammonium 3β,6β-dihydroxy-5α-cholestane disulfate ( 7a) and the treatment of 7a by cation exchange resin 732 (sodium form)(Na +) yielded the target steroid 1. Disodium 24-ethyl-3β,6β-dihydroxycholest-22-ene disulfate ( 2) and disodium 24-ethyl-3β,6β-dihydroxycholestane disulfate ( 3) were synthesized using a similar method. The cytotoxicity of these compounds against Sk-Hep-1 (human liver carcinoma cell line), H-292 (human lung carcinoma cell line), PC-3 (human prostate carcinoma cell line) and Hey-1B (human ovarian carcinoma cell line) cells was investigated. Our results indicate that presence of a cholesterol-type side chain at position 17 is necessary for their biological activity.

Synthesis of regioselectively sulfated xylodextrins and crystal structure of sodium methyl β- d-xylopyranoside 4- O-sulfate hemihydrate

Methyl xylobioside and methyl xylotrioside were prepared from the peracetylated anomeric xylosyl trichloroacetimidates by reaction with methanol followed by Zemplén deacetylation. Methyl β- d-xylopyranoside, methyl β- d-xylobioside and methyl β- d-xylotrioside were subjected to treatment with dibutyltin oxide followed by reaction with the trimethylamine/sulfur trioxide complex in tetrahydrofuran. This way, preferential sulfation of the terminal 4-hydroxy group at the nonreducing xylopyranosyl unit was achieved. In addition, partial sulfation at position 2 of the distal xylose unit was observed. The substitution pattern was derived from NMR spectroscopic data and was confirmed by the X-ray structure determination of sodium methyl β- d-xylopyranoside 4- O-sulfate. The compound crystallized as a hemihydrate in a triclinic lattice of space group P1 and possesses a pseudomonoclinic 2D supramolecular structure. The sulfation of free pentose oligomers via their intermediate stannylene acetals may thus be exploited to generate biologically active oligosaccharides for biomedical applications.

Novel chemo-enzymatic oligomers of cinnamic acids as direct and indirect inhibitors of coagulation proteinases

Thrombin and factor Xa, two important procoagulant enzymes, have been prime targets for regulation of clotting through the direct and indirect mechanism of inhibition. Our efforts on exploiting the indirect mechanism led us to study a carboxylic acid-based scaffold, which displayed major acceleration in the inhibition of these enzymes [J. Med. Chem.2005, 48, 1269, 5360]. This work advances the study to chemo-enzymatically prepared oligomers of 4-hydroxycinnamic acids, DHPs, which display interesting anticoagulant properties. Oligomers, ranging in size from tetramers to pentadecamers, were prepared through peroxidase-catalyzed oxidative coupling of caffeic, ferulic, and sinapic acids, and sulfated using triethylamine–sulfur trioxide complex. Chromatographic, spectroscopic, and elemental studies suggest that the DHPs are heterogeneous, polydisperse preparations composed of inter-monomer linkages similar to those found in natural lignins. Measurement of activated thromboplastin and prothrombin time indicates that both the sulfated and unsulfated derivatives of the DHPs display anticoagulant activity, which is dramatically higher than that of the reference polyacrylic acids. More interestingly, this activity approaches that of low-molecular-weight heparin with the sulfated derivative showing ∼2- to 3-fold greater potency than the unsulfated parent. Studies on the inhibition of factor Xa and thrombin indicate that the oligomers exert their anticoagulant effect through both direct and indirect inhibition mechanisms. This dual inhibition property of 4-hydroxycinnamic acid-based DHP oligomers is the first example in inhibitors of coagulation. This work puts forward a novel, non-heparin structure, which may be exploited for the design of potent, dual action inhibitors of coagulation through combinatorial virtual screening on a library of DHP oligomers.

Quantum-Chemical Study on Positional Selectivity in the Trimethylsilylation and Sulfonation of Pyrrole and N-Alkylpyrroles

Positional selectivity (α:β ratio) of electrophilic substitution in pyrrole, N-methylpyrrole, and N-tert-butylpyrrole was analyzed by ab initio [RHF/6-31G(d), MP2/6-31G(d)//RHF/6-31G(d)] and DFT [B3LYP/6-31G(d)] calculations of some σ-complexes derived from the substrates. The results of calculations with the use as model electrophilic species of trimethylsilyl cation [MP2/6-31G(d)//RHF/6-31G(d) and B3LYP/6-31G(d)] and SO3 molecule [B3LYP/6-31G(d)] instead of proton are fairly consistent with the experimental data, according to which trimethylsilylation of pyrrole and its N-substituted derivatives with trimethylsilyl trifluoromethanesulfonate, as well as sulfonation with pyridine-sulfur trioxide complex, gives the corresponding β-substituted products.

Structural Requirements of Dolichyl Phosphate as an Apoptosis Inducer

Physiologically active dolichyl phosphate (dol-P) is known to induce apoptosis in human promonoblastic leukemia cells U937 and rat glioma C6 cells. The study on the relation between chemical structure and apoptosis-inducing ability of dol-P indicated that phosphate head group is one of the essential structures. This study investigated the significance of phosphate group by using two structurally related compounds, dolichyl sulfate (dol-S) and dolichyl diphenylphosphate (dol-DPP). Dol-S prepared from dolichol and N, N-dimethyl formamide sulfur trioxide complex, maintains a charge but lacks a phosphate group. Dol-DPP, prepared from dolichol and diphenyl chlorophosphate, retains a phosphate group but has no charge. Human promonoblastic leukemia cells U937 were subjected to the two dol-P analogues, and apoptosis-inducing ability was determined by studies on cell viability, cell morphology, DNA fragmentation, and activations of caspase-3 and 8. Dol-S induced apoptosis but dol-DPP did not. Moreover, dol-S was found to mediate apoptosis at only one-twentieth of the concentration of dol-P. These findings indicated that in dol-P-induced apoptosis, the charged group rather than the phosphate group was the required key structure for apoptosis induction.

New Synthetic Capabilities of Sulfonium Salts.

AbstractFor Abstract see ChemInform Abstract in Full Text.