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Synthesis and Sulfur Electrophilicity of the Nuphar Thiaspirane Pharmacophore.

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 ?-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.

SUBMITTER: Tada N

PROVIDER: S-EPMC4919772 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Synthesis and Sulfur Electrophilicity of the Nuphar Thiaspirane Pharmacophore.

Tada Norihiro N Jansen Daniel J DJ Mower Matthew P MP Blewett Megan M MM Umotoy Jeffrey C JC Cravatt Benjamin F BF Wolan Dennis W DW Shenvi Ryan A RA

ACS central science 20160613 6

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 si ...[more]

PMID: 27413784

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