Synthesis and Sulfur Electrophilicity of the Nuphar Thiaspirane Pharmacophore
| Autor: | Daniel J. Jansen, Ryan A. Shenvi, Matthew P. Mower, Norihiro Tada, Jeffrey C. Umotoy, Megan M. Blewett, Benjamin F. Cravatt, Dennis W. Wolan |
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| Rok vydání: | 2016 |
| Předmět: |
chemistry.chemical_classification
biology 010405 organic chemistry Stereochemistry General Chemical Engineering Thiophenol Iminium chemistry.chemical_element General Chemistry 010402 general chemistry biology.organism_classification 01 natural sciences Sulfur 0104 chemical sciences lcsh:Chemistry chemistry.chemical_compound lcsh:QD1-999 chemistry Electrophile Thiol Nuphar Pharmacophore Tetrahydrothiophene Research Article |
| Zdroj: | ACS Central Science, Vol 2, Iss 6, Pp 401-408 (2016) ACS Central Science |
| ISSN: | 2374-7951 2374-7943 |
| DOI: | 10.1021/acscentsci.6b00113 |
| Popis: | We describe a general method to synthesize the iminium tetrahydrothiophene embedded in the dimeric Nuphar alkaloids. In contrast to prior studies, the sulfur atom of the thiaspirane pharmacophore is shown to be electrophilic. This α-thioether reacts with thiophenol or glutathione at ambient temperature to cleave the C–S bond and form a disulfide. Rates of conversion are proportional to the corresponding ammonium ion pKa and exhibit half-lives less than 5 h at a 5 mM concentration of thiol. A simple thiophane analogue of the Nuphar dimers causes apoptosis at single-digit micromolar concentration and labels reactive cysteines at similar levels as the unsaturated iminium “warhead”. Our experiments combined with prior observations suggest the sulfur of the Nuphar dimers can react as an electrophile in cellular environments and that sulfur-triggered retrodimerization can occur in the cell. We describe a new method for the synthesis of the Nuphar iminium thiophane pharmacophore and disclose its previously unidentified sulfur electrophilicity. |
| Databáze: | OpenAIRE |
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