A general strategy for elaboration of the dithiocarbonyl functionality, -(C:O)SS-: application to the synthesis of bis(chlorocarbonyl)disulfane and related derivatives of thiocarbonic acids

Bárány, George; Schroll, Alayne L.; Mott, Andrew W.; Halsrud, David A.

doi:10.1021/jo00172a056

Cited by 97 publications

(117 citation statements)

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“…2b). To tether the maleimide to CTX, we first synthesized the cleavable bismaleimide 1b by reacting bis(chlorocarbonyl)disulfane (13,14) with a 3-maleimido-N-[2-(phenylamino)ethyl]propanamide [see supporting information (SI) Materials and Methods]. CTXClv was then synthesized by adding excess 1b to the CTX mutant R19C (Materials and Methods), which upon derivatization with cysteine-modifying reagents has been shown to maintain its high affinity for the ion conduction pore of K ϩ channels (15).…”

Section: Resultsmentioning

confidence: 99%

Counting membrane-embedded KCNE β-subunits in functioning K ⁺ channel complexes

Morin

Kobertz

2008

Proc. Natl. Acad. Sci. U.S.A.

113

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Ion channels are multisubunit proteins responsible for the generation and propagation of action potentials in nerve, skeletal muscle, and heart as well as maintaining salt and water homeostasis in epithelium. The subunit composition and stoichiometry of these membrane protein complexes underlies their physiological function, as different cells pair ion-conducting ␣-subunits with specific regulatory ␤-subunits to produce complexes with diverse ion-conducting and gating properties. However, determining the number of ␣-and ␤-subunits in functioning ion channel complexes is challenging and often fraught with contradictory results. Here we describe the synthesis of a chemically releasable, irreversible K ؉ channel inhibitor and its iterative application to tally the number of ␤-subunits in a KCNQ1/KCNE1 K ؉ channel complex. Using this inhibitor in electrical recordings, we definitively show that there are two KCNE subunits in a functioning tetrameric K ؉ channel, breaking the apparent fourfold arrangement of the ion-conducting subunits. This digital determination rules out any measurable contribution from supra, sub, and multiple stoichiometries, providing a uniform structural picture to interpret KCNE ␤-subunit modulation of voltage-gated K ؉ channels and the inherited mutations that cause dysfunction. Moreover, the architectural asymmetry of the K ؉ channel complex affords a unique opportunity to therapeutically target ion channels that coassemble with KCNE ␤-subunits.membrane proteins that open and close in response to changes in membrane potential. To regulate cellular potassium flow in both excitable and nonexcitable tissues, Q1 channels coassemble with regulatory KCNE peptides, forming membraneembedded K ϩ channel complexes with various voltage-sensing and gating properties (1). The importance of forming a properly assembled Q1-KCNE complex is underscored by the mutations that give rise to long QT syndrome and congenital hearing loss (2, 3). Although the fourfold arrangement of the Q1 ␣-subunits along the ion conduction pathway is established and unquestioned, the number of KCNE ␤-subunits in the K ϩ channel complex has been a long-standing and heated debate (4-7). Goldstein and coworkers (6) have strongly argued that Q1 channels average two KCNE peptides per complex; however, they could not definitively rule out K ϩ channel complexes containing a solitary KCNE peptide. Another complicating factor is the notion that Q1 channels form complexes with KCNE ␤-subunits with multiple stoichiometries (5, 8). Thus, approaches that measure the average number of KCNE peptides in the Q1 channel complex at the cell surface are unable to readily discern between fixed and various stoichiometries.To determine the stoichiometry or stoichiometries of Q1-KCNE K ϩ channel complexes, we devised an iterative cell surface modification scheme where the labeling reagent specifically binds to the outer vestibule of the K ϩ conduction pore while covalently modifying a cysteine-bearing KCNE peptide in the channel complex (Fig. 1). Once th...

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Section: Resultsmentioning

confidence: 99%

Counting membrane-embedded KCNE β-subunits in functioning K ⁺ channel complexes

Morin

Kobertz

2008

Proc. Natl. Acad. Sci. U.S.A.

113

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“…11 ' RESULTS AND DISCUSSION Preparation of (N-Methyl-N-phenylcarbamoyl)sulfenyl Chloride (1). While the ZumachÀK€ uhle review 1 alluded to a range of primary and secondary, aliphatic and aromatic carbamoyl moieties (legend to Scheme 1), we elected to study principally compounds based on N-methylaniline, especially because an extensive set of derivatives 13,14 were available in our laboratory that could be used as reference compounds in elucidating the subsequent chemistries. To facilitate and standardize spectroscopic characterization and comparisons, the described reactions (Scheme 2) were generally carried out in CDCl 3 solution, although for completeness, selected experiments were repeated in other aprotic solvents, specifically CD 3 CN, dioxane-d 8 , and benzene-d 6 .…”

Section: ' Introductionmentioning

confidence: 99%

Synthetic Routes to, Transformations of, and Rather Surprising Stabilities of (N-Methyl-N-phenylcarbamoyl)sulfenyl Chloride, ((N-Methyl-N-phenylcarbamoyl)dithio)carbonyl Chloride, and Related Compounds

2011

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The title compound classes, (carbamoyl)sulfenyl chlorides and ((carbamoyl)dithio)carbonyl chlorides, have been implicated previously as unstable, albeit trappable, intermediates in organosulfur chemistry. The present work reports for each of these functional groups: (i) several routes to prepare it in the N-methylaniline family; (ii) its direct structural characterization by several spectroscopic techniques; (iii) its rather unexpected stability and its ultimate fate when it decomposes; (iv) a series of further chemical transformations that give highly stable derivatives, each in turn subject to thorough characterization. Relevant kinetic and mechanistic experiments were carried out, including some with p-methyl- and 2,6-dimethyl-substituted N-methylanilines. Given that the title compounds can be isolated and are relatively stable, they may find applications in the preparation of thiolyzable and/or photolabile protecting groups for the sulfhydryl function of cysteine and for the development of new protein synthesis and modification reagents.

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“…As part of a multifaceted program in synthetic and mechanistic organosulfur chemistry (Barany et al, 1983;Barany & Mott, 1984;Schroll & Barany, 1986;Schrader et al, 2011, and references cited therein), we frequently encounter challenging-to-characterize compounds with one or more reactive acid chloride and/or sulfenyl chloride moieties. These are converted to the corresponding stable carbamoyl and/or sulfenamide derivatives, which are often crystalline, through their reliable, rapid, and high-yield reactions with N-methylaniline.…”

Section: Chemical Contextmentioning

confidence: 99%

“…The title compound (I) was prepared on scales of up to 0.1 mol by addition of a 0.5 M solution of (chlorocarbonyl)sulfenyl chloride in CHCl 3 to an equal volume of a 2 M solution of N-methylaniline in CHCl 3 at 273 K, followed by stirring for 30 min at 298 K (Barany et al, 1983). Workup by washing with equal volumes of 1 N aqueous HCl (3Â) and brine (once), drying (MgSO 4 ), filtering, and concentrating in vacuo gave the product as an oil (nominally quantitative), and recrystallization from hot hexanes (30 mL g À1 ) gave a white solid (typically 65-80% recovery), m.p.…”

Section: Synthesis and Crystallizationmentioning

confidence: 99%

Crystal structures of (N-methyl-N-phenylamino)(N-methyl-N-phenylcarbamoyl)sulfide and the corresponding disulfane

2015

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, (II), are stable derivatives of (chlorocarbonyl)sulfenyl chloride and (chlorocarbonyl)disulfanyl chloride, respectively. The torsion angle about the S-S bond in (II) is À92.62 (6) , which is close to the theoretical value of 90 . In the crystal of (II), non-classical intermolecular C-HÁ Á ÁO hydrogen bonds form centrosymmetric cyclic dimers [graph set R 2 2 (10)], while inter-dimer C-HÁ Á ÁS interactions generate chains extending along the b axis.

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A general strategy for elaboration of the dithiocarbonyl functionality, -(C:O)SS-: application to the synthesis of bis(chlorocarbonyl)disulfane and related derivatives of thiocarbonic acids

Cited by 97 publications

References 2 publications

Counting membrane-embedded KCNE β-subunits in functioning K ⁺ channel complexes

Counting membrane-embedded KCNE β-subunits in functioning K ⁺ channel complexes

Synthetic Routes to, Transformations of, and Rather Surprising Stabilities of (N-Methyl-N-phenylcarbamoyl)sulfenyl Chloride, ((N-Methyl-N-phenylcarbamoyl)dithio)carbonyl Chloride, and Related Compounds

Crystal structures of (N-methyl-N-phenylamino)(N-methyl-N-phenylcarbamoyl)sulfide and the corresponding disulfane

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A general strategy for elaboration of the dithiocarbonyl functionality, -(C:O)SS-: application to the synthesis of bis(chlorocarbonyl)disulfane and related derivatives of thiocarbonic acids

Cited by 97 publications

References 2 publications

Counting membrane-embedded KCNE β-subunits in functioning K + channel complexes

Counting membrane-embedded KCNE β-subunits in functioning K + channel complexes

Synthetic Routes to, Transformations of, and Rather Surprising Stabilities of (N-Methyl-N-phenylcarbamoyl)sulfenyl Chloride, ((N-Methyl-N-phenylcarbamoyl)dithio)carbonyl Chloride, and Related Compounds

Crystal structures of (N-methyl-N-phenylamino)(N-methyl-N-phenylcarbamoyl)sulfide and the corresponding disulfane

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Counting membrane-embedded KCNE β-subunits in functioning K ⁺ channel complexes

Counting membrane-embedded KCNE β-subunits in functioning K ⁺ channel complexes