Sulfur-containing Analogs Research Articles

Synthesis and structure of 2,4,6,8-tetramethyl-3,7-dithia-2,4,6,8-tetraazabicyclo[3.3.0]octane 3,3,7,7-tetraoxide

Condensation of N,N′-dimethylsulfamide with glyoxal gave 2,4,6,8-tetramethyl-3,7-dithia-2,4,6,8-tetraazabicyclo[3.3.0]octane 3,3,7,7-tetraoxide, a sulfur-containing analog of 2,4,6,8-tetramethyl-2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7-dione (Mebicar). The product structure was studied by X-ray analysis.

Kinetic and Thermochemical Study of the Antioxidant Activity of Sulfur‐Containing Analogues of Vitamin E

Sulfur-containing analogues of vitamin E (thiachromanols), either linked or not to a catechol moiety, were synthesized and their hydrogen-atom donating ability evaluated. The determination of the O--H bond dissociation enthalpy (BDE) of the alpha-tocopherol analogue 4 by the electron paramagnetic resonance (EPR) equilibration technique provided a value of 78.9 kcal mol(-1), that is, approximately 1.8 kcal mol(-1) higher than that of alpha-tocopherol. The kinetic rate constants for the reaction with peroxyl radicals (kinh), measured by inhibited autoxidation studies, showed that thiachromanols react 2.5 times slower than the corresponding tocopherols, in agreement with the higher BDE value. This behavior was explained, on the basis of crystallographic analyses and DFT calculations, in terms of a change in the molecular geometry caused by insertion of a sulfur atom into the framework of vitamin E. This behavior implies a greater deviation of the condensed ring from coplanarity with the aromatic ring, thus giving rise to a decrease in the conjugative stabilization of the phenoxyl radical and consequently to an increase in the O--H bond strength. Although less reactive than tocopherols, thiachromanols may, however, act as bimodal antioxidants as a result of the hydroperoxide decomposing ability of the sulfur atom.

Soluble Neuroprotective Antioxidant Uric Acid Analogs Ameliorate Ischemic Brain Injury in Mice

Uric acid is a major antioxidant in the blood of humans that can protect cultured neurons against oxidative and metabolic insults. However, uric acid has a very low solubility which compromises its potential clinical use for neurodegenerative disorders. Here we describe the synthesis, characterization and preclinical development of neuroprotective methyl- and sulfur-containing analogs of uric acid with increased solubility. In vitro and cell culture screening identified 1,7-dimethyluric acid (mUA2) and 6,8-dithiouric acid (sUA2) as two analogs with high antioxidant and neuroprotective activities. When administered intravenously in mice, uric acid analogs mUA2 and sUA2 lessened damage to the brain and improved functional outcome in an ischemia-reperfusion mouse model of stroke. Analogs sUA2 and mUA2 were also effective in reducing damage to the cerebral cortex when administered up to 4 h after stroke onset in a permanent middle cerebral artery occlusion mouse model. These findings suggest a therapeutic potential for soluble analogs of uric acid in the treatment of stroke and related neurodegenerative conditions.

Effects of oxygen–sulfur substitution on glycosaminoglycan-priming naphthoxylosides

Three series of sulfur-containing analogs to the selectively antiproliferative 2-(6-hydroxynaphthyl) β- d-xylopyranoside were synthesized and their biological properties investigated. A short, general route to hydroxynaphthyl disulfides from dihydroxynaphthalenes was developed to utilize the disulfide bond as a sulfur-selective protecting group to enable the orthogonal protection of hydroxyls and thiols. The results indicate that hydrophobic, uncharged oxygen–sulfur substituted naphthoxylosides are taken up by cells and initiate priming of GAG chains to a greater extent compared to the oxygen analogs. No correlation between priming ability and antiproliferative activity was observed.

Cyano substituent effects on enol and enethiol acidity and basicity: The protonation and deprotonation of 3-hydroxy-2-propenenitrile and its thio analogue

The gas-phase basicity and acidity of 3-hydroxy-2-propenenitrile (3-hydroxyacrylonitrile) and its sulfur-containing analogue, 3-mercapto-2-propenenitrile, have been determined by means of high-level G3B3 ab initio calculations and, in the case of the latter compound, compared with the experimental values obtained by means of FT-ICR mass spectrometry techniques, and with previous reported values for the N C–CH CH–X (X = CH 3, NH 2, SiH 3, PH 2) analogues. For both compounds the Z-isomer is the dominant species in the gas-phase. Protonation takes place in both cases at the cyano group. The loss of the proton from the substituent, was found to be systematically much more favorable than the deprotonation at the HC CH group. 3-Hydroxy-2-propenenitrile is predicted to be a stronger base by ca. 5 kJ mol −1 than its thio analogue, but a weaker acid by 26 kJ mol −1. Both compounds are stronger acids than the corresponding unsubstituted vinyl compounds, because cyano substitution stabilizes much more the deprotonated species than the corresponding neutral compound. There is a clear disagreement between our theoretical estimates for both the gas-phase basicity and the gas-phase acidity of 3-mercapto-2-propenenitrile and the corresponding experimental values, which is consistent with its isomerization to yield isothiazole.

Effect of α-tocopherol and its sulfur-containing analogs on radiation-induced chemical transformations of hexane and ethanol

A series of sulfur-containing structural analogs of α-tocopherol was synthesized, and their effect on the formation of molecular products of ethanol and hexane radiolysis under aerated and deaerated conditions was studied. The O-H bond dissociation enthalpies (BDEs) were calculated for the compounds containing hydroxyl groups. It was found that α-tocopherol and its analogs have the most significant effect on the radiolysis of ethanol and hexane under air-free conditions when the products are formed in the reactions of carbon-centered radicals. The probability of the reaction of the test compounds with alkyl radicals increases with a decrease in the BDE for the OH groups present in these compounds. The carbonyl group in compounds (IV-VIII) makes them efficient oxidants of α-hydroxyalkyl radicals, thus resulting in a change in the product composition for the ethanol radiolysis in presence of these compounds.

Profiling acylated homoserine lactones in Yersinia ruckeri and influence of exogenous acyl homoserine lactones and known quorum-sensing inhibitors on protease production

To profile the quorum-sensing (QS) signals in Yersinia ruckeri and to examine the possible regulatory link between QS signals and a typical QS-regulated virulence phenotype, a protease. Liquid chromatography-high resolution mass spectrometry (HPLC-HRMS) showed that Y. ruckeri produced at least eight different acylated homoserine lactones (AHLs) with N-(3-oxooctanoyl)-L-homoserine lactone (3-oxo-C8-HSL) being the dominant molecule. Also, some uncommon AHL, N-(3-oxoheptanoyl)-L-homoserine lactone (3-oxo-C7-HSL) and N-(3-oxononanoyl)-L-homoserine lactone (3-oxo-C9-HSL), were produced. 3-oxo-C8-HSL was detected in organs from fish infected with Y. ruckeri. Protease production was significantly lower at temperatures above 23 degrees C than below although growth was faster at the higher temperatures. Neither addition of sterile filtered high-density Y. ruckeri culture supernatant nor the addition of pure exogenous AHLs induced protease production. Furthermore, three QS inhibitors (QSIs), sulfur-containing AHL analogues, did not inhibit protease production in Y. ruckeri. Exogenous AHL or sulfur-containing AHL analogues did not influence the protease production indicating that protease production may not be QS regulated in Y. ruckeri. The array of different AHLs produced indicates that the QS system of Y. ruckeri is complex and could involve several regulatory systems. In this case, neither AHLs nor QSI would be likely to directly affect a QS-regulated phenotype.

Carbonyl- and sulfur-containing analogs of suberoylanilide hydroxamic acid: Potent inhibition of histone deacetylases

Suberoylanilide hydroxamic acid (SAHA), an inhibitor of histone deacetylase, is used in clinical trials for a variety of advanced cancers. Twelve new analogs of SAHA were synthesized and tested as in vitro inhibitors of isolated histone deacetylases (HDACS) and in vivo inhibitors of interferon regulated transcriptional responses (a marker for HDAC activity). The analogs containing an α-mercaptoketone or an α-thioacetoxyketone were more potent than SAHA in both assays.

The syntheses and properties of tricyclic pyrrolo[2,3-d]pyrimidine analogues of S6-methylthioguanine and O6-methylguanine

The syntheses of novel tricyclic pyrrolo[2,3-d]pyrimidine analogues of S6-methylthioguanine are described. The crystal structures and pKa values of these and related O6-methylguanine analogues are reported. All compounds display higher pKa values than O6-methylguanine with the sulfur-containing analogues being the more basic and exhibiting higher stability in aqueous solution. In a standard substrate assay with the human repair protein O6-methylguanine-DNA methyltransferase (MGMT) only the oxygen-containing analogue displayed activity.

Effects of α-tocopherol and related compounds on reactions involving various organic radicals

Effects of α-tocopherol, PMC, and a number of the respective sulfur-containing analogues on reactions involving various organic radicals were studied. The test compounds were found to interact with alkyl radicals more effectively than with peroxyl radicals. The presence of a sulfur atom in structures of the respective analogues did not produce significant effects on reactivity. Derivatives of 5-hydroxy-1,3-benzoxathiol-2-one and 6-hydroxy-1,4-benzoxathiin-2(3 H)-one displayed a high reactivity toward α-hydroxyalkyl radicals.

Tautomerism and Various Coordination Modes of Typical Chelating Ligands with Metals

AbstractFor Abstract see ChemInform Abstract in Full Text.

Production of Novel Rapamycin Analogs by Precursor-Directed Biosynthesis

The natural product rapamycin, produced during fermentation by Streptomyces hygroscopicus, is known for its potent antifungal, immunosuppressive, and anticancer activities. During rapamycin biosynthesis, the amino acid l-pipecolate is incorporated into the rapamycin molecule. We investigated the use of precursor-directed biosynthesis to create new rapamycin analogs by substitution of unusual l-pipecolate analogs in place of the normal amino acid. Our results suggest that the l-pipecolate analog (+/-)-nipecotic acid inhibits the biosynthesis of l-pipecolate, thereby limiting the availability of this molecule for rapamycin biosynthesis. We used (+/-)-nipecotic acid in our precursor-directed biosynthesis studies to reduce l-pipecolate availability and thereby enhance the incorporation of other pipecolate analogs into the rapamycin molecule. We describe here the use of this method for production of two new sulfur-containing rapamycin analogs, 20-thiarapamycin and 15-deoxo-19-sulfoxylrapamycin, and report measurement of their binding to FKBP12.

Synthesis and interfacial behavior of sulfur-containing analogs of lung surfactant dipalmitoyl phosphatidylcholine

Synthesis methods and initial surface property characterizations are reported for two sulfur-containing phosphonolipids related structurally to dipalmitoyl phosphatidylcholine (DPPC), the major lung surfactant glycerophospholipid. Sulfur linkages in these compounds affect molecular interactions relative to ester linkages, and are structurally resistant to cleavage by phospholipases. The SO 2-linked analog synthesized here had increased adsorption and improved film respreading compared to DPPC, while reaching very low surface tensions (⩽1 mN/m) in cycled interfacial films on both the Wilhelmy balance and the pulsating bubble surfactometer. This compound appears to have potential utility as a component in future phospholipase-resistant synthetic exogenous surfactants for treating clinical forms of inflammatory lung injury.

Tetrazoles: XLVII. A route to tetrazole-containing dendrimers

The reaction of 5-methylsulfonyl-1-phenyltetrazole with pentaerythritol in acetonitrile in the presence of sodium hydroxide gave tetrakis(1-phenyltetrazol-5-yloxymethyl)methane. Sulfur-containing analog of the latter was obtained by alkylation of 1-phenyl-4,5-dihydrotetrazole-5-thione with 1,3-dibromo-2,2-bis-(bromomethyl)propane. Nitration of the resulting polytetrazoles afforded the corresponding tetrakis(p-nitrophenyl) derivatives which can be used in the synthesis of tetrazole-containing dendrimers according to the divergent scheme.

Interaction of selenium compounds with zinc finger proteins involved in DNA repair.

As an essential element, selenium is present in enzymes from several families, including glutathione peroxidases, and is thought to exert anticarcinogenic properties. A remarkable feature of selenium consists of its ability to oxidize thiols under reducing conditions. Thus, one mode of action recently suggested is the oxidation of thiol groups of metallothionein, thereby providing zinc for essential reactions. However, tetrahedral zinc ion complexation to four thiolates, similar to that found in metallothionein, is present in one of the major classes of transcription factors and other so-called zinc finger proteins. Within this study we investigated the effect of selenium compounds on the activity of the formamidopyrimidine-DNA glycosylase (Fpg), a zinc finger protein involved in base excision repair, and on the DNA-binding capacity and integrity of xeroderma pigmentosum group A protein (XPA), a zinc finger protein essential for nucleotide excision repair. The reducible selenium compounds phenylseleninic acid, phenylselenyl chloride, selenocystine, ebselen, and 2-nitrophenylselenocyanate caused a concentration-dependent decrease of Fpg activity, while no inhibition was detected with fully reduced selenomethionine, methylselenocysteine or some sulfur-containing analogs. Furthermore, reducible selenium compounds interfered with XPA-DNA binding and released zinc from the zinc finger motif, XPAzf. Zinc release was even evident at high glutathione/oxidised glutathine ratios prevailing under cellular conditions. Finally, comparative studies with metallothionein and XPAzf revealed similar or even accelerated zinc release from XPAzf. Altogether, the results indicate that zinc finger motifs are highly reactive towards oxidizing selenium compounds. This could affect gene expression, DNA repair and, thus, genomic stability.

Zeolite‐catalyzed simple synthesis of different heterocyclic rings, part 2

AbstractA simple and environmentally friendly synthesis was developed for the preparation of 2‐arylimidazoline derivatives and 2‐arylbenzoxazole derivatives using a small pore size zeolite. The similar reaction was not applicable to the preparation of the sulfur‐containing analogs cysteamine or 2‐aminothiophenol, probably because of a disadvantageous reaction between the zeolite and the thio compound. © 2004 Wiley Periodicals, Inc. Heteroatom Chem 15:428–431, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20036

Staphylococcus aureus mevalonate kinase: isolation and characterization of an enzyme of the isoprenoid biosynthetic pathway.

It has been proposed that isoprenoid biosynthesis in several gram-positive cocci depends on the mevalonate pathway for conversion of acetyl coenzyme A to isopentenyl diphosphate. Mevalonate kinase catalyzes a key reaction in this pathway. In this study the enzyme from Staphylococcus aureus was expressed in Escherichia coli, isolated in a highly purified form, and characterized. The overall amino acid sequence of this enzyme was very heterologous compared with the sequences of eukaryotic mevalonate kinases. Analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and analytical gel filtration chromatography suggested that the native enzyme is a monomer with a molecular mass of approximately 33 kDa. The specific activity was 12 U/mg, and the pH optimum was 7.0 to 8.5. The apparent K(m) values for R,S-mevalonate and ATP were 41 and 339 micro M, respectively. There was substantial substrate inhibition at millimolar levels of mevalonate. The sensitivity to feedback inhibition by farnesyl diphosphate and its sulfur-containing analog, farnesyl thiodiphosphate, was characterized. These compounds were competitive inhibitors with respect to ATP; the K(i) values were 46 and 45 micro M for farnesyl diphosphate and its thio analog, respectively. Parallel measurements with heterologous eukaryotic mevalonate kinases indicated that S. aureus mevalonate kinase is much less sensitive to feedback inhibition (K(i) difference, 3 orders of magnitude) than the human enzyme. In contrast, both enzymes tightly bound trinitrophenyl-ATP, a fluorescent substrate analog, suggesting that there are similarities in structural features that are important for catalytic function.

Novel sulfur-containing rapamycin analogs prepared by precursor-directed biosynthesis.

[reaction: see text] Two novel sulfur-containing analogs of the immunosuppressive natural product rapamycin (1) were obtained by feeding cultures of Streptomyces hygroscopicus with l-nipecotic acid (4) and either (S)-1,3-thiazane-4-carboxylic acid (5) or (S)-1,4-thiazane-3-carboxylic acid (6). The structures of the two new compounds, 20-thiarapamycin (2) and 15-deoxo-19-sulfoxylrapamycin (3), were determined by spectroscopic methods.

Preparation of 4-thia-10b-azaindeno[2,1,7-lma]fluorenes

The salt 2 condenses with dimethylformamide in acetic anhydride giving the Vilsmeier salt 3. This is cyclised to the parent 4-thia-10b-azaindeno[2,1,7-lma]fluorene 4 by triethylamine in dimethylformamide. When the salt 2 is heated in acetic anhydride in the presence of triethylamine the green thiacyclazine derivative 5 is isolated. Introduction Cycl[3.3.3]azine 1 and its derivatives have been studied extensively1 in connection with their structural relationship to the phenalenyl cation, anion and radical (C+, C–, C• respectively in place of N in 1).2 Numerous novel heterocyclic systems are possible, but as yet unknown, in which a =CH– or –CH=CH– moiety in 1 is replaced by a heteroatom unit. We report here syntheses of sulfur-containing analogues of 1, in which a –CH=CH– moiety is replaced by sulfur, starting from the indeno[2,1-d]pyrido[2,1-b]thiazolium salt 2.

Characterization of inhibitors acting at the synthetase site of Escherichia coli asparagine synthetase B.

Asparagine synthetase catalyzes the ATP-dependent formation of L-asparagine from L-aspartate and L-glutamine, via a beta-aspartyl-AMP intermediate. Since interfering with this enzyme activity might be useful for treating leukemia and solid tumors, we have sought small-molecule inhibitors of Escherichia coli asparagine synthetase B (AS-B) as a model system for the human enzyme. Prior work showed that L-cysteine sulfinic acid competitively inhibits this enzyme by interfering with L-aspartate binding. Here, we demonstrate that cysteine sulfinic acid is also a partial substrate for E. coli asparagine synthetase, acting as a nucleophile to form the sulfur analogue of beta-aspartyl-AMP, which is subsequently hydrolyzed back to cysteine sulfinic acid and AMP in a futile cycle. While cysteine sulfinic acid did not itself constitute a clinically useful inhibitor of asparagine synthetase B, these results suggested that replacing this linkage by a more stable analogue might lead to a more potent inhibitor. A sulfoximine reported recently by Koizumi et al. as a competitive inhibitor of the ammonia-dependent E. coli asparagine synthetase A (AS-A) [Koizumi, M., Hiratake, J., Nakatsu, T., Kato, H., and Oda, J. (1999) J. Am. Chem. Soc. 121, 5799-5800] can be regarded as such a species. We found that this sulfoximine also inhibited AS-B, effectively irreversibly. Unlike either the cysteine sulfinic acid interaction with AS-B or the sulfoximine interaction with AS-A, only AS-B productively engaged in asparagine synthesis could be inactivated by the sulfoximine; free enzyme was unaffected even after extended incubation with the sulfoximine. Taken together, these results support the notion that sulfur-containing analogues of aspartate can serve as platforms for developing useful inhibitors of AS-B.