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Tada N, Jansen DJ, Mower MP, et al. Synthesis and Sulfur Electrophilicity of the Nuphar Thiaspirane Pharmacophore. ACS Cent Sci. 2016;2(6):401-8doi: 10.1021/acscentsci.6b00113.
Tada, N., Jansen, D. J., Mower, M. P., Blewett, M. M., Umotoy, J. C., Cravatt, B. F., Wolan, D. W., & Shenvi, R. A. (2016). Synthesis and Sulfur Electrophilicity of the Nuphar Thiaspirane Pharmacophore. ACS central science, 2(6), 401-8. https://doi.org/10.1021/acscentsci.6b00113
Tada, Norihiro, et al. "Synthesis and Sulfur Electrophilicity of the Nuphar Thiaspirane Pharmacophore." ACS central science vol. 2,6 (2016): 401-8. doi: https://doi.org/10.1021/acscentsci.6b00113
Tada N, Jansen DJ, Mower MP, Blewett MM, Umotoy JC, Cravatt BF, Wolan DW, Shenvi RA. Synthesis and Sulfur Electrophilicity of the Nuphar Thiaspirane Pharmacophore. ACS Cent Sci. 2016 Jun 22;2(6):401-8. doi: 10.1021/acscentsci.6b00113. Epub 2016 Jun 13. PMID: 27413784; PMCID: PMC4919772.
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ACS Cent Sci. 2016 Jun 22;2(6):401-8. doi: 10.1021/acscentsci.6b00113. Epub 2016 Jun 13.

Synthesis and Sulfur Electrophilicity of the Nuphar Thiaspirane Pharmacophore.

ACS central science

Norihiro Tada, Daniel J Jansen, Matthew P Mower, Megan M Blewett, Jeffrey C Umotoy, Benjamin F Cravatt, Dennis W Wolan, Ryan A Shenvi

Affiliations

  1. Department of Chemistry, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.

PMID: 27413784 PMCID: PMC4919772 DOI: 10.1021/acscentsci.6b00113

Abstract

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 pK a 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.

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