Aryl Sulfone Research Articles

Non-nucleoside HIV-1 reverse transcriptase inhibitors di-halo-indolyl aryl sulfones achieve tight binding to drug-resistant mutants by targeting the enzyme–substrate complex

Indolyl aryl sulfone (IAS) non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) have been previously shown to effectively inhibit wild-type (wt) and drug-resistant human immunodeficiency virus type 1 (HIV-1) replication. IASs proved to act through different mechanisms of action, depending on the nature and position of their chemical substituents. Here we describe selected novel IAS derivatives (di-halo-IASs). Our results show that these compounds are selective for the enzyme-substrate complex. The molecular basis for this selectivity was a different dissociation rate of the drug to a particular enzymatic form along the reaction pathway. By comparing the activities of the different compounds against wild-type RT and the resistant enzymes carrying the single mutations Lys103Asn, Leu100Ile, and Tyr181Ile (K103N, L100I, and Y181I), we found that one compound (RS1914) dissociated from the mutated enzymes almost 10-fold slower than from the wild type RT. These results demonstrate that IASs are very flexible molecules, interacting dynamically with the viral RT, and that this property can be successfully exploited to design inhibitors endowed with an enhanced binding to common NNRTI-resistant mutants.

Functionalized carbon nanotube-poly(arylene sulfone) composite membranes for direct methanol fuel cells with enhanced performance

A new type of composite membrane, consisting of functionalized carbon nanotubes (CNTs) and sulfonated poly(arylene sulfone) (sPAS), is prepared for direct methanol fuel cell (DMFC) applications. The CNTs modified with sulfonic acid or PtRu nanopaticles are dispersed within the sPAS matrix by a solution casting method to afford SO 3CNT-sPAS or PtRu/CNT-sPAS composite membranes, respectively. Characterization of the composite membranes reveals that the functionalized CNTs are homogeneously distributed within the sPAS matrix and the composite membranes contain smaller ion clusters than the neat sPAS. The composite membranes exhibit enhanced mechanical properties in terms of tensile strength, strain and toughness, which leads to improvements in ion conductivity and methanol permeability compared with the neat sPAS membrane. In DMFC performance tests, the use of a PtRu/CNT-sPAS membrane yields high power density compared with the neat sPAS membrane, which demonstrates that the improved properties of the composite membranes induce an increase in power density. The strategy for CNT-sPAS composite membranes presented in this work can potentially be extended to other CNT-polymer composite systems.

Fluorinated poly(aryl thioether)s and poly(aryl sulfone)s derived from 2,3,4,5,6-pentafluorobenzoic acid

Poly(aryl thioether)s (F-PTEs) containing 2,3,5,6-tetrafluoro-1,4-phenylene moiety and polar moiety, such as 1,3,4-ozadiazole, ether ketone, and amide groups, were synthesized by nucleophilic aromatic substitution reaction of aryl fluorides and 4,4′-thiobisbenzenthiol. F-PTEs were amorphous with good thermal properties including high glass transition temperature (Tg) and thermal stability, solubility, and hydrophobicity. F-PTEs were transformed into poly(aryl sulfone)s (F-PSs) by the oxidation reaction with hydrogen peroxide in acetic acid. Because of the sulfone group, the Tgs of the F-PSs were 30–40°C higher than those of the corresponding F-PTEs. F-PSs maintained solubility in polar aprotic solvents and exhibited hydrophobicity in spite of the content of polar sulfone groups due to the highly substituted fluorine atoms. These F-PTEs and F-PSs were a new class of high-performance polymers. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008

Novel thiol-based TACE inhibitors. Part 2: Rational design, synthesis, and SAR of thiol-containing aryl sulfones

A series of potent thiol-containing aryl sulfone TACE inhibitors were designed and synthesized. The SAR and MMP selectivity of the series were investigated. In particular, compound 8b showed excellent in vitro potency against the isolated enzyme and good selectivity over MMP-2, -7, -8, -9, and -13. The X-ray structure of 8b in complex with TACE was also obtained.

Effect of structure of aromatic imide–amines on curing behavior and thermal stability of diglycidyl ether of bisphenol‐A

AbstractThe curing behavior of diglycidyl ether of bisphenol‐A (DGEBA) with aromatic imide–amines having aryl ether, sulfone, and methylene linkages was studied using differential scanning calorimetry (DSC). Six imide–amines of varying structure were synthesized by reacting 1 mol of naphthalene 1,4,5,8‐tetracarboxylic dianhydride (N) or 4,4′‐oxodiphthalic anhydride (O) with excess (>2 mol) of 4,4′‐diaminodiphenylether [E] or 4,4′‐diaminodiphenyl methane [M] or 4,4′‐diaminodiphenyl sulfone [S]. The imide–amines prepared by reacting O or N with S, M, and E have been designated as OS/NS; OM/NM, and OE/NE, respectively. Structural characterization of imide–amines was done using FTIR, 1H NMR, 13C NMR, and elemental analysis. The curing behavior of DGEBA in the presence of stoichiometric amount of imide–amines was investigated by recording DSC scans. A broad exothermic transition was observed and the peak exotherm temperature was found to be dependent on the structure of imide–amines. The peak exotherm temperature (Tp) was lowest in case of imide–amines OE and highest in case of imide–amines NS/OS. Thermal stability of isothermally cured DGEBA in the presence of imide–amines was evaluated by dynamic thermogravimetry. The char yield was highest for resin cured with imide–amines NE. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci, 2008

Morphology of ultrathin polymer films based on poly(ethylene oxide) blends

The structure of ultrathin (15–200 nm) films of two types prepared from polymer blends based on PEO (the crystallizable component), namely, PEO-poly(arylene sulfone oxide) (the amorphous component) and PEO-PB (the amorphous component), has been studied by atomic force microscopy. The content of PEO in both blends is 76 wt %. Ultrathin blend films have been applied on a Si substrate via substrate dipping into dilute solutions of polymer blends in chloroform at room temperature. The rate of the substrate lift has been varied from 0.1 to 1 mm/min. The amorphous-amorphous separation takes place during formation of ultrathin films of the above blends in the course of the substrate lift at the stage of gelation. The crystallization of PEO and dewetting in the resulting two-phase blend gels depend on the rate of the substrate lift and the rigidity of macromolecules of the amorphous component. Moreover, the predominant interaction of the substrate with one of the components plays a significant role in structure formation of ultrathin films of both polymer blends.

Synthesis and Property of Poly(arylene sulfone)s Containing 9,9-Diarylfluorene Moiety in the Main Chain

Poly(arylene sulfone)s (PASs) were synthesized in quantitative yields by the oxidations of the corresponding fluorene-containing poly(arylene thioether)s, derived from 9,9-diarylfluorene-based dithiols and dihaloarenes, with 30% hydrogen peroxide in formic acid. PASs had good solubility in common organic solvents such as chloroform, N-methylpyrrolidone (NMP), and N,N-dimethylformamide (DMF). Highly transparent films were obtained by casting the chloroform solutions of PASs. PASs exhibited high glass transition and high decomposition temperatures (Tg 248–355 °C, Td5 > 400 °C under nitrogen).

Concise Syntheses of Cystothiazoles A, C, D, and Melithiazol B

A convergent synthesis of cystothiazoles C 1 and D 3 was achieved based on Julia coupling between the functionalized aldehyde 5b, corresponding to left half of the final molecule, and aryl sulfone 6 or 7, bearing a bithiazole moiety, corresponding to right half. Methylation of 1 and 3 gave cystothiazole A 2 and melithiazol B 4, respectively. The overall yield (5 steps from (2R,3S)-3-methylpent-4-yne-1,2-diol 10; 57%) of 5b via the present route was improved in comparison to that of the previously reported functionalized aldehyde 5a (7 steps from 10; 13%). By applying the modified Julia coupling method, selectivity (6E/6Z=20 : 1-26 : 1) toward the (6E)-form of the coupled products (15 or 19) against the corresponding (6Z)-form was improved in comparison to the Wittig method (6E/6Z=4 : 1-6.9 : 1).

In search of effective anti-HHV-6 agents

Since HHV-6, like HCMV, is a β-herpesvirus, anti-HCMV drugs such as (val)ganciclovir, foscarnet and cidofovir may, by extrapolation, be advocated for the treatment of HHV-6 infections. At present, no prime candidate for the treatment of HHV-6 infections has been identified or even proposed, which means that the search for antiviral drugs effective against HHV-6-associated diseases should be encouraged. In essence, this search is going into two directions: nucleoside and non-nucleoside analogues. To the first category belong S2242, an N7-substituted purine acyclic derivative; A-5021, a cyclopropyl nucleoside analogue; cyclopropavir, a methylene cyclopropane analogue; lipophilic ester prodrugs of the acyclic nucleoside phosphonate cidofovir; and various other “old” and “new” acyclic nucleoside phosphonate analogues including those derived from the 2, 4-diaminopyrimidine (DAPy) skeleton. To the non-nucleoside category belong a number of quinoline-3-carboxamide, aryl sulfone, benzimidazole riboside and phenylenediamine sulfonamide derivatives which could be further optimized from a structure-activity relationship (SAR) viewpoint so as to specifically target HHV-6 replication. Also, specific protein kinase inhibitors may be pursued as anti-HHV-6 agents, a representative example being the compound CMV423 which, being inhibitory to (cellular) protein tyrosine kinases, exhibits potent and selective activity against HHV-6.

High Potency of Indolyl Aryl Sulfone Nonnucleoside Inhibitors towards Drug-Resistant Human Immunodeficiency Virus Type 1 Reverse Transcriptase Mutants Is Due to Selective Targeting of Different Mechanistic Forms of the Enzyme

Indolyl aryl sulfone (IAS) nonnucleoside inhibitors have been shown to potently inhibit the growth of wild-type and drug-resistant human immunodeficiency virus type 1 (HIV-1), but their exact mechanism of action has not been elucidated yet. Here, we describe the mechanism of inhibition of HIV-1 reverse transcriptase (RT) by selected IAS derivatives. Our results showed that, depending on the substitutions introduced in the IAS common pharmacophore, these compounds can be made selective for different enzyme-substrate complexes. Moreover, we showed that the molecular basis for this selectivity was a different association rate of the drug to a particular enzymatic form along the reaction pathway. By comparing the activities of the different compounds against wild-type RT and the nonnucleoside reverse transcriptase inhibitor-resistant mutant Lys103Asn, it was possible to hypothesize, on the basis of their mechanism of action, a rationale for the design of drugs which could overcome the steric barrier imposed by the Lys103Asn mutation.

Synthesis of dendritic oligo(aryl sulfone)s as supports for synthesis

A short, divergent route to G 1 oligo(aryl sulfone)s and a G 2 oligo(aryl sulfone) dendrimer using nucleophilic aromatic substitution reactions is described. A range of tetrasubstituted pentasulfones are proposed for applications as homogeneous supports for synthesis. Key to achieving selectivity in the syntheses is the activation of leaving groups by sulfide to sulfone oxidation. Preparation of the G 2 oligo(aryl sulfone) is low-yielding due to competition from SET processes that are interesting from a mechanistic point of view. The utility of the supports is exemplified with a four step synthesis of a dipeptide and by ‘react and release’ synthesis of amides.

New organochlorine contaminants and metabolites in plasma and eggs of glaucous gulls (Larus hyperboreus) from the Norwegian Arctic

The present study investigated new or lesser-studied and legacy organochlorine (OC) contaminants and metabolites in plasma and eggs of glaucous gulls (Larus hyperboreus) collected from major breeding colonies on Bear Island in the Norwegian Arctic. Hexachlorobutadiene was below the method limit of detection (< 0.07 ng/g lipid wt) in all samples. The sum (sum) of 20 chlorobornane congener concentrations ranged between 294 and 986 ng/g lipid weight and 104 and 1,121 ng/g lipid weight in plasma and eggs, respectively, whereas those of sum 20polychlorinated naphthalene ranged between 1.34 and 126 ng/g lipid weight in plasma and 1.82 and 162 ng/g lipid weight in eggs. Bis(4-chlorophenyl) sulfone concentrations ranged between 5.24 and 143 ng/ g lipid weight plasma, which is the first report of this contaminant in arctic biota north of Sweden. Based on 2,3,7,8-tetrachlorodibenzo-p-dioxin toxic equivalents (TEQs), partial dioxin-like toxicity varied between 3.04 and 20.8 ng TEQ/g lipid weight in plasma and 0.94 and 46.5 ng TEQ/g lipid weight in eggs, and largely was due to concentrations of non-ortho polychlorinated biphenyls (PCBs), with a very minor contribution from mono-ortho PCBs and polychlorinated naphthalenes. The major aryl sulfone metabolite in plasma was an unidentified hexachlorinated MeSO2-PCB congener (range: 13.5-551 ng/g lipid wt), whereas the pentachlorinated congeners 3'- and 4'-MeSO2-CB101 (range: 4.49-38.1 ng/g lipid wt) dominated in eggs. The predominant halogenated phenolic compound (HPC) in plasma was consistently the PCB metabolite 4-OH-CB187 (range: 0.29-17.5 ng/g wet wt), whereas in eggs, detectable HPCs were at very low and transient concentrations. As part of a complex profile of contaminant exposure, these chemical classes and metabolites may be contributing factors to enhance physiological stress in breeding glaucous gulls.

Synthesis of Novel Non-Isoprenoid Phenolic Acids and 3-Alkylpyridines

For Abstract see ChemInform Abstract in Full Text.

Facile Method for Solid‐Phase Synthesis of Vinyl Sulfones Using Polystyrene‐Supported Selenomethyl Aryl Sulfone

Treatment of novel polystyrene‐supported selenomethyl aryl sulfone with LDA followed by alkylation and oxidation elimination efficiently afforded vinyl sulfones in good yields and purities.

Synthesis of novel non-isoprenoid phenolic acids and 3-alkylpyridines

Abstract A new strategy has been developed for the synthesis of naturally occurring 6-alkenyl phenolic acids and 3-alkylpyridine alkaloids of biological importance. This strategy makes use of the proper substituted aryl or pyridyl sulfone as the potent intermediate. A carbanion was generated from the sulfone by treating it with NaH in dimethylformamide (DMF) at –5 °C and was used for alkylation reaction with alkyl/alkenyl bromide in DMF at 0 °C to give product, which, on reduction with sodium-amalgam, yielded the desired natural product. Using this methodology, we have synthesized 11 natural 6-alkyl/alkenyl salicylic acids, which were known to possess strong antimicrobial activities against many pathogens and had also shown molluscicidal activity against the snail Biomphalaria glabrata. This methodology was also extended to synthesize two natural 3-alkylpyridine alkaloids that were known to possess strong cytotoxic activity against P-388 murine leukemia cells with IC50 values of 1–2.3 μg/ml. Taking leads from these natural products, we have also synthesized a number of related compounds in order to find a potential drug candidate for the future. This paper presents the highlights of the work done on the synthesis of these two classes of compounds.

Anti‐HIV‐1 Activity of Pyrryl Aryl Sulfone (PAS) Derivatives: Synthesis and SAR Studies of Novel Esters and Amides at the Position 2 of the Pyrrole Nucleus.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Vicarious nucleophilic substitution of hydrogen versus vinylic substitution of halogen in the reactions of carbanions of halomethyl aryl sulfones with dialkyl halofumarates and halomaleates

Reaction of halomethyl aryl sulfone carbanions with dialkyl halofumarates and halomaleates results in nucleophilic substitution of hydrogen and/or of the halogen. The reaction with halofumarates proceeds via addition of the carbanions to the vinylic carbon atom connected with hydrogen, followed by base promoted β-elimination of hydrogen halide in which the halogen originates from the carbanion moiety or from the alkene. In the case of halomaleates the reaction proceeds via an elimination–addition sequence.

Vicarious nucleophilic substitution of hydrogen versus vinylic substitution of halogen in the reactions of carbanions of halomethyl aryl sulfones with dialkyl halofumarates and halomaleates

Reaction of halomethyl aryl sulfone carbanions with dialkyl halofumarates and halomaleates results in nucleophilic substitution of hydrogen and/or of the halogen. The reaction with halofumarates proceeds via addition of the carbanions to the vinylic carbon atom connected with hydrogen, followed by base promoted β-elimination of hydrogen halide in which the halogen originates from the carbanion moiety or from the alkene. In the case of halomaleates the reaction proceeds via an elimination–addition sequence. Graphic

Direct Nucleophilic Addition versus a Single‐Electron Transfer Pathway of σH Adduct Formation in Vicarious Nucleophilic Substitution of Hydrogen

AbstractTwo mechanistic pathways of formation of σH adducts, which are key intermediates in the vicarious nucleophilic substitution of hydrogen, namely direct nucleophilic addition of carbanions to nitroarenes and a two‐step mechanism involving an electron‐transfer process, are discussed on the basis of the existing data and results of the VNS reactions in which a radical probe — chloromethyl aryl sulfone bearing a 2,2‐dimethylcyclopropyl substituent — was used as the carbanion precursor. (© Wiley‐VCH Verlag GmbH &amp; Co. KGaA, 69451 Weinheim, Germany, 2004)

Isopropyl 2,4,6-triisopropylphenyl sulfone: an aryl sulfone with unusual atom deviations from the aromatic least-squares plane

Iso­propyl 2,4,6-triiso­propyl­phenyl sulfone, C18H30O2S, (I), has been synthesized for the first time. In spite of the bulky iso­propyl substituents on both ortho positions, crystalline (I) does not exhibit rotational disorder of the iso­propyl group bonded to the sulfonyl. In contrast, the corresponding bromo- and chloro­iso­propyl groups of crystalline aryl sulfones possessing much smaller di-ortho-methyl substituents display striking rotational disorder. While the aryl rings of the latter compounds are essentially planar, considerable atom deviation from the aromatic least-squares plane of (I) was observed. None of the intra- or intermolecular distances between the methyl C atoms of the sulfonyl­iso­propyl group and those of the two ortho-iso­propyl groups of (I) is shorter than the sum of their van der Waals radii, making it unlikely that they would interfere with the rotation of the α-iso­propyl group prior to crystallization.