Darstellung schwefel‐haltiger Indol‐Derivate

Wieland, Theodor; Weiberg, Otto; Fischer, E.; Hörlein, Gerhard

doi:10.1002/jlac.19545870209

Cited by 38 publications

(11 citation statements)

References 12 publications

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“…However, even with a 4 8 h treatment with absolute trifluoroacetic acid at room temperature compound 9 did not yield any thioether whose formation can be easily recognized by its characteristic U.V. spectrum (Wieland et al, 1954). This result supports the suggestion that protonation of the hexahydropyrrole-N is the first step in the cleavage reaction leading to thioethers in the presence of thiols.…”

supporting

confidence: 70%

Syntheses of Monocyclic and Bicyclic Peptides of Tryptathionine and Glycine

Zanotti

Birr

Wieland

1978

International Journal of Peptide and Protein Research

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L‐3a‐Hydroxy‐1.2.3.3a.8.8a‐hexahydropyrrolo[2,3‐b‐]‐indole‐2‐carboxylic acid (Hpi)*, obtained from L‐tryptophan by oxidation with peroxyacetic acid (Savige, 1975), after introduction of the Boc‐residue at N‐1, is coupled with various glycine peptides of S‐trityl‐L‐cysteine to give the Hpi‐peptides 6(a‐f). By treatment with absolute trifluoroacetic acid these peptides are converted by an intramolecular thiolysis to the monocyclic thioethers 7(a‐f). Two of them, 7e and 7f, can be subjected to a second cyclization by the mixed anhydride method thus yielding the bicyclic tryptathionine heptapeptide 8e and octapeptide 8f. In their structures the bicyclic molecules resemble the mushroom phallotoxins and amatoxins, respectively. They show CD spectra closely related to the naturally occurring bicyclic peptides thus indicating conformational similarities. The CD spectra of the other cyclic peptides synthesized are also presented and discussed.

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supporting

confidence: 70%

Syntheses of Monocyclic and Bicyclic Peptides of Tryptathionine and Glycine

Zanotti

Birr

Wieland

1978

International Journal of Peptide and Protein Research

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“…(34) 6-Bromotryptamine ( 4 ) was prepared from 6-bromoindole according to the sequence reported by Davidson. (35) Protonation of 4 with trichloroacetic acid, followed by reaction with freshly distilled S 2 Cl 2 ,(36, 37) yielded a mixture of mono-, di-, and trisulfides 1a – c that was characterized by LC-MS. Using a protocol reported by Showalter for the preparation of bisindole diselenides as tyrosine kinase inhibitors,(38) we increased the yield of the desired disulfide product 1a by treating the mixture with sodium borohydride to reduce the di- and trisulfides.…”

Section: Resultsmentioning

confidence: 99%

Synthetic Analogues of the Snail Toxin 6-Bromo-2-mercaptotryptamine Dimer (BrMT) Reveal That Lipid Bilayer Perturbation Does Not Underlie Its Modulation of Voltage-Gated Potassium Channels

et al. 2018

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Drugs do not act solely by canonical ligand-receptor binding interactions. Amphiphilic drugs partition into membranes thereby perturbing bulk lipid bilayer properties and possibly altering the function of membrane proteins. Distinguishing membrane perturbation from more direct protein-ligand interactions is an ongoing challenge in chemical biology. Herein, we present one strategy for doing so, using dimeric 6-bromo-2-mercaptotryptamine (BrMT) and synthetic analogs. BrMT is a chemically unstable marine snail toxin that has unique effects on voltage-gated K+ channel proteins, making it an attractive medicinal chemistry lead. BrMT is amphiphilic and perturbs lipid bilayers, raising the question of whether its action against K+ channels is merely a manifestation of membrane perturbation. To determine whether medicinal chemistry approaches to improve BrMT might be viable, we synthesized BrMT and 11 analogs and determined their activities in parallel assays measuring K+ channel activity and lipid bilayer properties. Structure-activity relationships were determined for modulation of the Kv1.4 channel, bilayer partitioning, and bilayer perturbation. Neither membrane partitioning, nor bilayer perturbation, correlate with K+ channel modulation. We conclude that BrMT’s membrane interactions are not critical for its inhibition of Kv1.4 activation. Further, we found that alkyl or ether linkages can replace the chemically labile disulfide bond in the BrMT pharmacophore, and we identified additional regions of the scaffold that are amenable to chemical modification. Our work demonstrates a strategy for determining if drugs act by specific interactions or bilayer-dependent mechanisms, and chemically stable modulators of Kv1 channels are reported.

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“…The phallotoxins are bicyclic heptapeptides. L-methylthio-indolylacetic acid, 4, from indolylacetic acid and methylsulfenyl chloride (35,36). The latter may be considered a product of an oxidative condensation of L- Tryptathionine is the chromophoric system of the phallotoxins responsible for the u.v.maxima around 290 nm (Fig.…”

Section: Chemistry Of the Phallotoxinsmentioning

confidence: 99%

“…3). In these peptides 0-hydroxy-D-aspartic acid a-Amino-7-lactones from the different phallotoxins and amatoxins have been studied in extenso in the author's laboratory (40)(41)(42)(43)(44). L-methylthio-indolylacetic acid, 4, from indolylacetic acid and methylsulfenyl chloride (35,36).…”

Section: Chemistry Of the Phallotoxinsmentioning

confidence: 99%

The toxic peptides from Amanita mushrooms

Wieland

1983

International Journal of Peptide and Protein Research

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142

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The results of 50 years of effort in the chemistry of Amanita toxins are reviewed. The phallotoxins, fast acting components, but not responsible for fatal intoxications after ingestion, are bicyclic heptapeptides. They combine with F-actin, stabilizing this protein against several destabilizing influences. The virotoxins likewise fast acting are monocyclic heptapeptides. The amatoxins which are the real toxins lead to death within several days by inhibiting the enzymatic synthesis of m-RNA. They are bicyclic octapeptides. The' structures of all of these compounds are described, as well as conformations, chemical reactions and modifications, syntheses and correlations between structures and biological activities.

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Darstellung schwefel‐haltiger Indol‐Derivate

Cited by 38 publications

References 12 publications

Syntheses of Monocyclic and Bicyclic Peptides of Tryptathionine and Glycine

Syntheses of Monocyclic and Bicyclic Peptides of Tryptathionine and Glycine

Synthetic Analogues of the Snail Toxin 6-Bromo-2-mercaptotryptamine Dimer (BrMT) Reveal That Lipid Bilayer Perturbation Does Not Underlie Its Modulation of Voltage-Gated Potassium Channels

The toxic peptides from Amanita mushrooms

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