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      C–H Methylation of Heteroarenes Inspired by Radical SAM Methyl Transferase

      rapid-communication

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          Abstract

          A practical C–H functionalization method for the methylation of heteroarenes is presented. Inspiration from Nature’s methylating agent, S-adenosylmethionine (SAM), allowed for the design and development of zinc bis(phenylsulfonylmethanesulfinate), or PSMS. The action of PSMS on a heteroarene generates a (phenylsulfonyl)methylated intermediate that can be easily separated from unreacted starting material. This intermediate can then be desulfonylated to the methylated product or elaborated to a deuteriomethylated product, and can divergently access medicinally important motifs. This mild, operationally simple protocol that can be conducted in open air at room temperature is compatible with sensitive functional groups for the late-stage functionalization of pharmacologically relevant substrates.

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          Rapid planetesimal formation in turbulent circumstellar discs

          Anders Johansen, Jeffrey S. Oishi, Mordecai-Mark Mac Low … (2007)
          The initial stages of planet formation in circumstellar gas discs proceed via dust grains that collide and build up larger and larger bodies (Safronov 1969). How this process continues from metre-sized boulders to kilometre-scale planetesimals is a major unsolved problem (Dominik et al. 2007): boulders stick together poorly (Benz 2000), and spiral into the protostar in a few hundred orbits due to a head wind from the slower rotating gas (Weidenschilling 1977). Gravitational collapse of the solid component has been suggested to overcome this barrier (Safronov 1969, Goldreich & Ward 1973, Youdin & Shu 2002). Even low levels of turbulence, however, inhibit sedimentation of solids to a sufficiently dense midplane layer (Weidenschilling & Cuzzi 1993, Dominik et al. 2007), but turbulence must be present to explain observed gas accretion in protostellar discs (Hartmann 1998). Here we report the discovery of efficient gravitational collapse of boulders in locally overdense regions in the midplane. The boulders concentrate initially in transient high pressures in the turbulent gas (Johansen, Klahr, & Henning 2006), and these concentrations are augmented a further order of magnitude by a streaming instability (Youdin & Goodman 2005, Johansen, Henning, & Klahr 2006, Johansen & Youdin 2007) driven by the relative flow of gas and solids. We find that gravitationally bound clusters form with masses comparable to dwarf planets and containing a distribution of boulder sizes. Gravitational collapse happens much faster than radial drift, offering a possible path to planetesimal formation in accreting circumstellar discs.
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            Synthesis of sulfones from organozinc reagents, DABSO, and alkyl halides.

            Benjamin Rocke, Kevin B Bahnck, Michael Herr … (2014)
            Organozinc reagents react with the SO2 surrogate DABSO, and the resulting zinc sulfinate salts are alkylated in situ to afford sulfones. This transformation has a broad scope and is compatible with a wide range of structural motifs of medicinal chemistry relevance including nitrile, secondary carbamates, and nitrogen-containing heterocycles.
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              Cysteine methylation disrupts ubiquitin-chain sensing in NF-κB activation.

              Li-Li Zhang, Xiaojun Ding, Jixin Cui … (2012)
              NF-κB is crucial for innate immune defence against microbial infection. Inhibition of NF-κB signalling has been observed with various bacterial infections. The NF-κB pathway critically requires multiple ubiquitin-chain signals of different natures. The question of whether ubiquitin-chain signalling and its specificity in NF-κB activation are regulated during infection, and how this regulation takes place, has not been explored. Here we show that human TAB2 and TAB3, ubiquitin-chain sensory proteins involved in NF-κB signalling, are directly inactivated by enteropathogenic Escherichia coli NleE, a conserved bacterial type-III-secreted effector responsible for blocking host NF-κB signalling. NleE harboured an unprecedented S-adenosyl-l-methionine-dependent methyltransferase activity that specifically modified a zinc-coordinating cysteine in the Npl4 zinc finger (NZF) domains in TAB2 and TAB3. Cysteine-methylated TAB2-NZF and TAB3-NZF (truncated proteins only comprising the NZF domain) lost the zinc ion as well as the ubiquitin-chain binding activity. Ectopically expressed or type-III-secretion-system-delivered NleE methylated TAB2 and TAB3 in host cells and diminished their ubiquitin-chain binding activity. Replacement of the NZF domain of TAB3 with the NleE methylation-insensitive Npl4 NZF domain resulted in NleE-resistant NF-κB activation. Given the prevalence of zinc-finger motifs and activation of cysteine thiol by zinc binding, methylation of zinc-finger cysteine might regulate other eukaryotic pathways in addition to NF-κB signalling.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Am Chem Soc
                Journal ID (iso-abbrev): J. Am. Chem. Soc
                Journal ID (publisher-id): ja
                Journal ID (coden): jacsat
                Title: Journal of the American Chemical Society
                Publisher: American Chemical Society
                ISSN (Print): 0002-7863
                ISSN (Electronic): 1520-5126
                Publication date (Electronic): 10 March 2014
                Publication date (Print): 02 April 2014
                Volume: 136
                Issue: 13
                Pages: 4853-4856
                Affiliations
                [† ]Department of Chemistry, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States
                [‡ ]Department of Chemistry, Pfizer Pharmaceuticals , La Jolla Laboratories, 10770 Science Center Drive, La Jolla, California 92121, United States
                Author notes
                Article
                DOI: 10.1021/ja5007838
                PMC ID: 3988686
                PubMed ID: 24611732
                SO-VID: 62d0bd32-d3e5-4105-b250-57197a9307f5
                Copyright © Copyright © 2014 American Chemical Society
                License:

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                History
                Date received : 23 January 2014
                Funding
                National Institutes of Health, United States
                Categories
                Subject: Communication
                Custom metadata
                document-id-old-9 ja5007838
                document-id-new-14 ja-2014-007838
                ccc-price

                ScienceOpen disciplines: Chemistry
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                ScienceOpen disciplines: Chemistry

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