Asymmetric total synthesis of dibenzocyclooctadiene lignans (-)-schizandrin and (-)-isoschizandrin. Structure revision of (+)-isoschizandrin

Warshawsky, Alan M.; Meyers, A. I.

doi:10.1021/ja00178a037

Cited by 116 publications

(36 citation statements)

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“…The asymmetric carbon at position 7 yields Z(cis)-(+)-schizandrin (7R, 8R) and E(trans)-(+)-isoschizandrin (7S, 8R). These cis-and trans-lignans possess similar biologic properties, and the pharmacological activity resides mainly at the C7-hydroxyl (Ikeya et al, 1988;Warshawsky and Meyers, 1990). Then the further metabolism of ISZ in microsomes and recombinant P450s was also investigated.…”

Section: Discussionmentioning

confidence: 99%

Deoxyschizandrin, a Naturally Occurring Lignan, Is a Specific Probe Substrate of Human Cytochrome P450 3A

Cao

Zhang

et al. 2013

Drug Metab Dispos

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To accurately predict the modifications done during metabolic processes by cytochrome P450 (P450) 3A enzyme, selecting substrates that best represent a broad range of substrate substitutions and that follow the Michaelis-Menten kinetic properties is highly necessary. In the present study, the oxidative pathways of deoxyschizandrin (DS), the most abundant lignan in Fructus Schisandrae fruit extract, were characterized with liver microsomes from human (HLM) and rat (RLM). Only one monohydroxylated metabolite 7(S)-hydroxylated metabolite (isoschizandrin, ISZ), was identified using liquid chromatography-mass spectrometry and nuclear magnetic resonance techniques. CYP3A4 and CYP3A5 were found to be the major isoforms involved in the monohydroxylation of DS. Also, the kinetic studies showed that DS hydroxylation obeyed MichaelisMenten kinetics both in HLM and in RLM. However, the subsequent metabolism of ISZ was nearly nonexistent when DS was present. More importantly, the interactions between DS and three well characterized CYP3A probe substrates, testosterone (TST), midazolam (MDZ), and nifedipine (NIF), were studied. TST and MDZ were shown to compete with DS for the mutual binding site, causing K m to be increased. The presence of DS also lowered the binding affinities for MDZ and TST. However, DS showed only slight inhibitory effects on nifedipine (NIF) oxidation even though NIF was able to inhibit DS hydroxylation in a noncompetitive fashion. These results show that DS is a good representative substrate of MDZ and TST primarily due to their shared, large binding regions on CYP3A. Therefore, DS is an attractive candidate as a novel CYP3A probe substrate for predicting the metabolic modifications in CYP3A activity.

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Section: Discussionmentioning

confidence: 99%

Deoxyschizandrin, a Naturally Occurring Lignan, Is a Specific Probe Substrate of Human Cytochrome P450 3A

Cao

Zhang

et al. 2013

Drug Metab Dispos

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“…Mit diesem Verfahren sind mehrere axial-chirale BiarylNaturstoffe und Derivate hergestellt worden, [128,[132][133][134][135] von denen einige in Schema 17 gezeigt sind: (À)-Schizandrin ((P)-104) [128] und (+)-Isodiospyrin ((P)-105) [132] (in beiden Fällen die nichtnatürlichen Enantiomere), O-Methylancistroclin ((P)-106) [133] und (À)-Steganon ((M)-107). [134] Diese Methodik schafft einen einfachen und zuverlässigen Zugang zu kreuzgekuppelten (nicht-C 2 -symmetrischen) Biarylen.…”

Section: Intramolekulare Kupplung Unter Verwendung Chiraler Ortho-subunclassified

Atropselektive Synthese axial‐chiraler Biaryle

et al. 2005

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Eine rotationsgehinderte und dadurch stereogene Biarylachse ist das strukturell und stereochemisch entscheidende Element einer ständig wachsenden Zahl von Naturstoffen, chiralen Auxiliaren und Katalysatoren. Daher ist es nicht überraschend, dass im letzten Jahrzehnt bedeutende Fortschritte in der asymmetrischen Synthese axial‐chiraler Biaryle erzielt worden sind. Neben dem klassischen Zugangsweg, der direkten Aryl‐Aryl‐Kupplung, sind innovative Konzepte entwickelt worden, in denen die asymmetrische Information in ein schon vorhandenes, aber nicht optisch aktives – symmetrisches oder konfigurativ labiles – Biaryl eingeführt oder eine Aryl‐C‐Einfachbindung stereoselektiv in eine Achse umgewandelt wird. In diesem Aufsatz werden die Strategien nach den zugrunde liegenden Konzepten klassifiziert, und ihre Anwendungsbreite und ihre Beschränkungen werden anhand ausgewählter Beispiele kritisch beurteilt. Ferner werden die Voraussetzungen für das Auftreten von Axialchiralität diskutiert.

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“…[18] o-Bromobenzaldehyde acetals 7a, [19] 7b [20] and 7e [21] were synthesized following literature methods. General Procedure for the Synthesis of 2-(1,3-Dioxan-2-yl)benzaldehyde Derivatives 8a,b,e,g: nBuLi (6.6 mL, 16.5 mmol, 2.5  solution in hexanes) was slowly added to a stirred solution of the appropriate protected 2-bromobenzaldehyde 7a,b,e,g (15 mmol) in dry THF (50 mL) at -78°C under argon.…”

Section: Starting Materialsmentioning

confidence: 99%

First Asymmetric Synthesis of (Un)saturated 1‐Alkylbenzo[c]azepin‐3‐ones: Extension to the Corresponding Benzazepines

et al. 2009

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A flexible route for the stereoselective synthesis of a variety of structurally diverse (1R)‐1‐alkyldihydro and tetrahydrobenzazepin(ones) has been developed. The key step is a highly diastereoselective 1,2‐addition process applied to a stereopure aromatic hydrazone combined with a ring‐closing metathesis reaction to secure the formation of the seven‐membered azaheterocycle ring system.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

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Asymmetric total synthesis of dibenzocyclooctadiene lignans (-)-schizandrin and (-)-isoschizandrin. Structure revision of (+)-isoschizandrin

Cited by 116 publications

References 0 publications

Deoxyschizandrin, a Naturally Occurring Lignan, Is a Specific Probe Substrate of Human Cytochrome P450 3A

Deoxyschizandrin, a Naturally Occurring Lignan, Is a Specific Probe Substrate of Human Cytochrome P450 3A

Atropselektive Synthese axial‐chiraler Biaryle

First Asymmetric Synthesis of (Un)saturated 1‐Alkylbenzo[c]azepin‐3‐ones: Extension to the Corresponding Benzazepines

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