Conformations of amatoxins in the crystalline state

Shoham, G.; Lipscomb, W. N.; Wieland, Th.

doi:10.1021/ja00195a036

Cited by 19 publications

(24 citation statements)

References 2 publications

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“…The effect of the differently hydroxylated amino acids on the amatoxin toxicity was investigated in various studies. [8][9][10][11] In the past 30 years several approaches were made to synthesize amatoxin derivatives. [8,[12][13][14][15] Zanotti et al (1987) described the first synthesis of an amaninamide derivative starting from the linear octapeptide followed by thioether formation using the Savige-Fontana reaction and subsequent macrocyclization.…”

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confidence: 99%

A Convergent Total Synthesis of the Death Cap Toxin α‐Amanitin

2020

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The toxic bicyclic octapeptide α‐amanitin is mostly found in different species of the mushroom genus Amanita, with the death cap (Amanita phalloides) as one of the most prominent members. Due to its high selective inhibition of RNA polymerase II, which is directly linked to its high toxicity, particularly to hepatocytes, α‐amanitin received an increased attention as a toxin‐component of antibody‐drug conjugates (ADC) in cancer research. Furthermore, the isolation of α‐amanitin from mushrooms as the sole source severely restricts compound supply as well as further investigations, as structure–activity relationship (SAR) studies. Based on a straightforward access to the non‐proteinogenic amino acid dihydroxyisoleucine, we herein present a robust total synthesis of α‐amanitin providing options for production at larger scale as well as future structural diversifications.

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confidence: 99%

A Convergent Total Synthesis of the Death Cap Toxin α‐Amanitin

2020

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“…Relatively few crystal structures of cyclic octapeptides in the solid state have reported in Cambridge Crystallographic Database: five different amanitines structures11–15 and six structures other than amanitines 6, 7, 9, 16, 17. Five nonamanitines cyclic octapeptides have sequential C 2 symmetry—c( L ‐Cys–Gly–Pro–Phe) 2 (1),9 c( L ‐Ala–Gly– L ‐Pro– L ‐Phe) 2 4H 2 O (2),16 c( D ‐Ala–Gly– L ‐Pro– L ‐Phe) 2 5H 2 O (3),7 c( D ‐Ala–Gly– L ‐Pro– L ‐Phe) 2 6H 2 O (4),7 and c( D ‐Ala–Gly– L ‐Pro– D ‐Phe) 2 CH 3 OH 2H 2 O (5)6—and one cyclic octapeptide presents a C 4 symmetry—c( L ‐Phe– D ‐Me–Ala) 4 (6) 17…”

Section: Resultsmentioning

confidence: 99%

“…A limited number of crystallographic data of cyclooctapeptides are reported in the literature, and in all cases they concern chemically and structurally symmetrical compounds 4–17. In addition to these, only few asymmetric cyclic octapeptides have been characterized in solution 18–21.…”

Section: Introductionmentioning

confidence: 99%

Solid state structural analysis of the cyclooctapeptide cyclo- (Pro1-Pro-Phe-Phe-Ac6c-Ile-D-Ala-Val8)

et al. 2000

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“…Dies wurde in zahlreichen Studien untersucht. [8][9][10][11] In den letzten 30 Jahren wurden umfangreiche Versuche unternommen Amatoxin-Derivate zu synthetisieren. [8,[12][13][14][15] Zanotti et al (1987) beschrieben die erste Amaninamid-Derivatsynthese ausgehend von einem linearen Octapeptid, gefolgt von der Thioetherbildung unter Verwendung der Savige-Fontana-Reaktion und darauffolgender Macrocyclisierung.…”

Section: In Memoriam Gerhard Jasunclassified

Eine konvergente Totalsynthese des Pilztoxins α‐Amanitin

2020

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Das toxische bicyclische Octapeptid α‐Amanitin kommt hauptsächlich in Spezies der Pilzgattung Amanita vor, wobei der Grüne Knollenblätterpilz (Amanita phalloides) der bekannteste Vertreter ist. Seine Toxizität beruht auf der Inhibition von RNA Polymerase II, insbesondere in Hepatocyten. Dies macht α‐Amanitin zu einem interessanten Wirkstoff für Antikörper‐Wirkstoff‐Konjugate in der Krebsforschung. Allerdings stellt die Isolierung von ausreichenden Mengen an α‐Amanitin aus Pilzen ein schwieriges Unterfangen dar, was sich limitierend auf die medizinalchemische Anwendung auswirkt. Ausgehend von der Synthese der nicht‐proteinogenen Aminosäure Dihydroxyisoleucin entwickelten wir eine robuste Totalsynthese für α‐Amanitin, die sich sowohl für eine Synthese im industriellen Maßstab als auch für zukünftige strukturelle Diversifizierungen eignet.

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Conformations of amatoxins in the crystalline state

Cited by 19 publications

References 2 publications

A Convergent Total Synthesis of the Death Cap Toxin α‐Amanitin

A Convergent Total Synthesis of the Death Cap Toxin α‐Amanitin

Solid state structural analysis of the cyclooctapeptide cyclo- (Pro1-Pro-Phe-Phe-Ac6c-Ile-D-Ala-Val8)

Eine konvergente Totalsynthese des Pilztoxins α‐Amanitin

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