Neuroprotective effects of (E)-3,4-diacetoxystyryl sulfone and sulfoxide derivatives in vitro models of Parkinson's disease

(E)-3,4-dihydroxystyryl aralkyl sulfones and sulfoxides have been reported as novel multifunctional neuroprotective agents in previous studies, which as phenolic compounds display antioxidative and antineuroinflammatory properties. To further enhance the neuroprotective effects and study structure-activity relationship of the derivatives, we synthesized their acetylated derivatives, (E)-3,4-diacetoxystyryl sulfones and sulfoxides, and examined their neuroprotective effects in vitro models of Parkinson’s disease. The results indicate that (E)-3,4-diacetoxystyryl sulfones and sulfoxides can significantly inhibit kinds of neuron cell injury induced by toxicities, including 6-OHDA, NO, and H₂O₂. More important, they show higher antineuroinflammatory properties and similar antioxidative properties to corresponding un-acetylated compounds. Thus, we suggest that (E)-3,4-diacetoxystyryl sulfones and sulfoxides may have potential for the treatment of neurodegenerative disorders, especially Parkinson’s disease.     

An efficient and selective method for preparing glycosyl sulfoxides by oxidizing glycosyl sulfides with OXONE or t-BuOOH on SiO2

Silica gel adsorbed with OXONE or t-BuOOH was used as a mild oxidant to selectively oxidize glycosyl sulfides to corresponding sulfoxides in good yields and without sulfones formation. This method was also found compatible with various other functional groups in the glycosides.     

Biotransformations of aryl alkyl sulfides by whole cells of white-rot Basidiomycetes

White-rot Basidiomycetes promoted the oxidation of aromatic pro-chiral sulfides into sulfoxides with good enantioselectivity, conversion and a small production of sulfones. The reactions were carried out using whole cells of Irpex lacteus, Pycnoporus sanguineus, Trichaptum byssogenum, Trametes rigida, Trametes versicolor and Trametes villosa. The enantioselectivity for all the aryl alkyl sulfoxides was in favor of (S)-enantiomers. Oxidation of (phenylpropyl)sulfide produced (S)-(phenylpropyl)sulfoxide with high enantiomeric excess (e.e. ≥99%) by all the Basidiomycetes employed. Basidiomycetes isolated from Brazilian biomes were used as biocatalysts in the oxidation reaction.     

New, potent anthelmintic and acaricidal agents: 4″-deoxy-4″-thio-substituted avermectin derivatives

Sulfonylation of the 4″-(or β)-hydroxyl of 5-OTBDMS-avermectin B_1a with trifluoromethanesulfonic anhydride yield triflates which were displaced stereospecifically with diverse sulfur nucleophiles. This sulfonylation/substitution protocol also was performed on the 4′-(or β)-hydroxyl of the corresponding avermectin monosaccharide. The sulfides, sulfoxides and sulfones thus obtained exhibited potent, broad spectrum anthelmintic and acaricidal activity.     

An investigation of the biotransformation of organic selenides by fungi

A series of alkyl phenyl selenides has been incubated with the fungi Aspergillus niger, Aspergillus foetidus, Mortierella isabellina, and Helminthosporium sp. These fungi oxidize the corresponding sulfides to sulfoxides efficiently, but in no case was any evidence obtained that the microbial oxidation of selenide to selenoxide was occurring. The fate of methyl phenyl selenide following incubation with M. isabellina was investigated using methyl-¹⁴C-labeled substrate, and by quantitative selenium analysis. These techniques indicate that the selenide is taken into the fungal cell efficiently and that some metabolic cleavage of the selenium-methyl carbon bond may occur.     

A Method for the Synthesis of Aldehydes

Aldehydes were synthesized via α-acetoxy sulfldes from alkyl aryl sulfoxides by the Pummerer reaction with acetic anhydride in the presence of base. By this method, isobutyraldehyde, pentanal, benzaldehyde, and 2-acetylamino-5-methy]benzaldehyde were obtained from isobutyl phenyl sulfoxide, pentyl p-tolyl sulfoxide, benzyl phenyl sulfoxide, and 2-acetylamino-5-methylbenzyl phenyl sulfoxide, respectively. The starting sulfoxides are easily synthesized from olefins, alkyl halides, or alkyl aryl sulfldes.     

Enantioselective oxidations catalyzed by diketocamphane monooxygenase from Pseudomonas putida with macromolecular NAD in a membrane reactor

Summary Several sulfides and bicyclo[3.2.0]hept-2-en-6-one were enantioselectively oxidized to the corresponding sulfoxides and oxa lactones by a crude preparation of the two diketocamphane monooxygenases from Pseudomonas putida. The reactions were carried out in a membrane reactor with the use of poly(ethylene glycol)-N⁶-(2-aminoethyl)-NAD and coenzyme regeneration by the formate/formate dehydrogenase system.     

Stereoselective oxidation of sulfides by cloned naphthalene dioxygenase

Washed-cell preparations of recombinant Escherichia coli JM109(pDTG141), engineered to express the naphthalene dioxygenase (NDO) gene from Pseudomonas sp. NCIB 9816-4, have been used to biooxidise a range of aryl alkyl-, dialkyl- and bicyclic sulfides. A series of 16 phenyl alkyl sulfides was oxidised to equivalent sulfoxides, typically with moderate to high (>90%) yield and high enantioselectivity (>85% ee), the (S)-enantiomer being the predominant product, with little if any further oxidation. The addition of some electron-donating or electron-withdrawing groups to the phenyl ring decreased yield and/or stereoselectivity of the NDO-catalysed biotransformation, whereas increasing the size of the alkyl chain (nC₃H₇, iC₃H₇ and nC₄H₉) resulted in a notable inversion in selectivity to yield (R)-series sulfoxides (>74% ee) as the predominant products. The addition of one or more methylene groups between the phenyl ring and sulfur atom resulted in notable reductions in both the yield and stereoselectivity of the (S)-predominant sulfoxidations. With the exception of cyclohexyl- and n-hexyl methyl sulfide which both gave (S)-sulfoxides with good stereoselectivity and yield, other dialkyl- and bicyclic sulfides were poor substrates for sulfoxidation by NDO. Both the close agreement with data obtained using purified NDO and the absence of stereoselective sulfoxidation in equivalent controls with the E. coli JM109 host support the contribution made by the cloned NDO carried on the pDTG141 plasmid.     

Synthesis of antitumor 6-alkylidenepenicillanate sulfones and related 3-alkylidene-2-azetidinones

6-alkylidenepenicillanate sulfoxides and sulfones were synthesized on the base of 6-oxopenicillanate esters. The targeted splitting of their thiazolidine ring led to the formation of 3-alkylidene substituted 4-heteryldithio and 4-methylsulfonyl azetidin-2-ones. Some of mono and bicyclic beta-lactams revealed potent cytotoxic properties towards monolayer tumor cells in <10-microM concentrations.     

ω-Methylthioalkylglucosinolates and some oxidized congeners in seeds of Erysimum rhaeticum

The glucosinolates in seeds of Erysimum rhaeticum Schleich. ex DC. have been identified by structure analysis of their sulfur-containing enzymic hydrolysis products, comprising 5-methylthiopentyl and 6-methylthiohexyl isothiocyanate, the corresponding 3-hydroxylated isothiocyanates, and the sulfoxides and sulfones of the latter. The phytochemical results are evaluated in terms of their possible taxonomic significance.     

Biotransformation of organic sulfides: Part. 10. Formation of chiral ortho- and meta-substituted benzyl methyl sulfoxides by biotransformation using Helminthosporium species NRRL 4671

Benzyl methyl sulfides substituted with methyl, chloro, cyano, bromo, methoxy, nitro and amino groups in the ortho or meta positions of the aromatic ring have been converted to (S) sulfoxides by biotransformation using the fungal biocatalyst Helminthosporium species NRRL 4671. The enantiomeric excesses for meta-substituted examples were high in those cases where the substituent was of a polar nature, and comparable to those observed for the corresponding para-substituted substrates. With one exception (o-amino), the ortho-substituted examples gave sulfoxides of lower enantiomeric purity. The role of a suitably located polar substituent on an aryl ring of the substrate in ensuring a high enantiomeric excess in sulfoxidation by Helminthosporium species has been confirmed by the biotransformations of 4-(methylthiomethyl)benzyl alcohol and 2-(4-nitrophenyl) ethyl methyl sulfide, which give sulfoxides of much higher optical purity than those obtained from the corresponding unsubstituted substrates.     

Electroenzymatic Synthesis of Chiral Sulfoxides

Chloroperoxidase (CPO) from Caldariomyces fumago (E.C. 1.11.1.10) is able to enantioselectively oxidize various sulfides to the corresponding (R)‐enantiomer of the sulfoxides. For these oxidations the enzyme requires an oxidant. Most commonly, tert‐butyl hydroperoxide (TBHP) and hydrogen peroxide are used. As it is known that these oxidants inactivate the enzyme, the enzymatic reaction was combined with the electrochemical in situ generation of hydrogen peroxide. As substrates for this combination of an enzymatic and an electrochemical reaction methyl p‐tolyl sulfide, 1‐methoxy‐4‐(methylthio)benzene and N‐MOC‐L ‐methionine methyl ester were used to carry out batch experiments.     

Opposite Enantioselectivities of Two Phenotypically and Genotypically Similar Strains of Pseudomonas frederiksbergensis in Bacterial Whole-Cell Sulfoxidation

Soil samples were screened to select microorganisms with the capability to oxidize organic sulfides into the corresponding sulfoxides with differential enantioselectivities. Several bacterial strains that preferentially produced the S-configured sulfoxide enantiomer were isolated. Surprisingly, one bacterial strain, genotypically and phenotypically characterized as Pseudomonas frederiksbergensis, selectively gave the R enantiomer. The finding that two apparently identical organisms displayed opposite enantioselectivities is novel for non-genetically modified organisms.     

Reductive thiocyanolysis of tetraoxorhenate (VII): Synthesis, crystal structure, catalytic oxidation and kinetic studies of (PPh4)2[Re(NCS)6] and (PPh4)2[ReO(NCS)5]

Thiocyanate ions reduce perrhenate in aqueous acidic solution, and on addition of a suitable countercation (PPh₄Cl) afford (PPh₄)₂[Re(NCS)₆] (1) and (PPh₄)₂[ReO(NCS)₅] (2), which have been confirmed by X-ray crystallography. The kinetics of the above reaction has been studied. Both the complexes exhibit efficient and highly selective catalytic epoxidation ability in the presence of NaHCO₃ as a co-catalyst and competent catalytic properties in the selective oxidation of alcohols to the corresponding aldehydes or ketones in the presence of pyrazole as an additive and sulfides to sulfoxides and sulfones. H₂O₂ was used as the terminal oxidant in all the above-mentioned oxidation reactions.     

Characterization of cytochrome P450 monooxygenase CYP154H1 from the thermophilic soil bacterium Thermobifida fusca

Cytochrome P450 monooxygenases are valuable biocatalysts due to their ability to hydroxylate unactivated carbon atoms using molecular oxygen. We have cloned the gene for a new cytochrome P450 monooxygenase, named CYP154H1, from the moderately thermophilic soil bacterium Thermobifida fusca. The enzyme was overexpressed in Escherichia coli at up to 14% of total soluble protein and purified to homogeneity in three steps. CYP154H1 activity was reconstituted using putidaredoxin reductase and putidaredoxin from Pseudomonas putida DSM 50198 as surrogate electron transfer partners. In biocatalytic reactions with different aliphatic and aromatic substrates of varying size, the enzyme converted small aromatic and arylaliphatic compounds like ethylbenzene, styrene, and indole. Furthermore, CYP154H1 also accepted different arylaliphatic sulfides as substrates chemoselectively forming the corresponding sulfoxides and sulfones. The enzyme is moderately thermostable with an apparent melting temperature of 67°C and exhibited still 90% of initial activity after incubation at 50°C.     

Steric Considerations on Improving the Diastereomeric Ratio of (+)‐ and (−)‐Neomenthyl Phenyl Sulfoxides Using Bulky‐Headed Oxidant Hexadecyltrimethylammonium Periodate and Assignment of Their Configuration

The bulky‐headed oxidant hexadecyltrimethylammonium periodate affords the diastereomeric pairs, (Ss)‐(+)/(Rs)‐(+) and (Ss)‐(?)/(Rs)‐(?)‐neomenthyl phenyl sulfoxides in stereochemically pure states with improved diastereomeric excess (48% diastereomeric excess [de]) as compared to its nonbulky counterpart, sodium metaperiodate (28% de) from respective (+)/(?)‐neomenthyl phenyl sulfides. Steric effects involving the head group volume of hexadecyltrimethylammonium periodate is found to play a role in improving the diastereomeric ratio of the products. The two diastereomers can be readily separated by column chromatography. Absolute configuration at the sulfur center in (+)‐neomenthyl phenyl sulfoxide was determined by single‐crystal X‐ray crystallography and found to be Ss. Relative configurations of other sulfoxides were assigned based on the configuration of (+)‐neomenthyl phenyl sulfoxide. Chirality 27:370–374, 2015. © 2015 Wiley Periodicals, Inc.     

An evidence of the peroxidase-dependent oxygen transfer from hydrogen peroxide to sulfides

Horseradish- and chloro-peroxidase catalyzed oxidation of sulfides have been investigated. Thioanisoles were oxygenated to the corresponding sulfoxides by such peroxidases at the expense of H2O2. Dealkylation was observed only in the chloroperoxidase-dependent oxidations of p-methoxy- and p-iso-propoxy-thioanisoles. The experiments with 18O-labeled H2O2 indicated that an oxygen atom of H2O2 is incorporated into the sulfoxides. These research lead to the conclusion that compound I or II is capable of acting as an oxygen donor as well as an electron acceptor.     

Aerobic and anaerobic degradation of a range of alkyl sulfides by a denitrifying marine bacterium.

A pure culture of a bacterium was obtained from a marine microbial mat by using an anoxic medium containing dimethyl sulfide (DMS) and nitrate. The isolate grew aerobically or anaerobically as a denitrifier on alkyl sulfides, including DMS, dimethyl disulfide, diethyl sulfide (DES), ethyl methyl sulfide, dipropyl sulfide, dibutyl sulfide, and dibutyl disulfide. Cells grown on an alkyl sulfide or disulfide also oxidized the corresponding thiols, namely, methanethiol, ethanethiol, propanethiol, or butanethiol. Alkyl sulfides were metabolized by induced or derepressed cells with oxygen, nitrate, or nitrite as electron acceptor. Cells grown on DMS immediately metabolized DMS, but there was a lag before DES was consumed; with DES-grown cells, DES was immediately used but DMS was used only after a lag. Chloramphenicol prevented the eventual use of DES by DMS-grown cells and DMS use by DES-grown cells, respectively, indicating separate enzymes for the metabolism of methyl and ethyl groups. Growth was rapid on formate, acetate, propionate, and butyrate but slow on methanol. The organism also grew chemolithotrophically on thiosulfate with a decrease in pH; growth required carbonate in the medium. Growth on sulfide was also carbonate dependent but slow. The isolate was identified as a Thiobacillus sp. and designated strain ASN-1. It may have utility for removing alkyl sulfides, and also nitrate, nitrite, and sulfide, from wastewaters.     

Sequence analysis and heterologous expression of a new cytochrome P450 monooxygenase from Rhodococcus sp. for asymmetric sulfoxidation

In this study, a 3.7-kb DNA fragment was cloned from Rhodococcus sp. ECU0066, and the sequence was analyzed. It was revealed that the largest one (2,361 bp) of this gene fragment encodes a protein consisting of 787 amino acids, with 73% identity to P450RhF (accession number AF45924) from Rhodococcus sp. NCIMB 9784. The gene of this new P450 monooxygenase (named as P450SMO) was successfully expressed in Escherichia coli BL21 (DE3), and the enzyme was also purified and characterized. In the presence of reduced nicotinamide adenine dinucleotide phosphate, the enzyme showed significant sulfoxidation activity towards several sulfides, with (S)-sulfoxides as the predominant product. The p-chlorothioanisole, p-fluorothioanisole, p-tolyl methyl sulfide, and p-methoxythioanisole showed relatively higher activities than the other sulfides, but the stereoselectivity for p-methoxythioanisole was much lower. The optimal activity of the purified enzyme toward p-chlorothioanisole occurred at pH 7.0 and 30°C. The current study is the first to report a recombinant cytochrome P450 enzyme of Rhodococcus sp. which is responsible for the asymmetric oxidation of sulfides. The new enzymatic activity of P450SMO on the above compounds makes it an attractive biocatalyst for asymmetric synthesis of enantiopure sulfoxides.     

Kojyl thioether derivatives having both tyrosinase inhibitory and anti-inflammatory properties

This study was conducted to examine the tyrosinase inhibitory and anti-inflammatory activities of kojic acid derivatives. A series of kojic acid derivatives containing thioether, sulfoxide, and sulfone linkages were synthesized. In the tyrosinase assay, kojyl thioether derivatives containing appropriate lipophilic alkyl chains (pentane, hexane, and cyclohexane) showed potent inhibitory activity. However, sulfoxides and sulfones exhibited decreased activity. Similar experimental results were obtained with inhibitory activities of NO production being induced by LPS. The presence of thioether linkage and appropriated lipophilic acid moiety was critical for the tyrosinase inhibitory and anti-inflammatory activities.