Total Synthesis of Tubulysin U and V

Dömling, Alexander; Beck, Barbara; Eichelberger, Uwe; Sakamuri, Sukumar; Menon, Sanjay; Chen, Quin-Zene; Lu, Yingchun; Wessjohann, Ludger A.

doi:10.1002/anie.200790053

Cited by 22 publications

(15 citation statements)

References 4 publications

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“…The oxazole analog of tubulysin U is slightly more potent than the natural product. 30 Drawing inspiration from pretubulysin D, replacement of the thiazole ring with a meta-substituted phenyl group to give phenylpretubulysin (33) and phenoxypretubulysin (34) resulted in potent analogs although 2-4 orders of magnitude less potent than pretubulysin D. 23 An analog (35) with a 1,2,3-triazole replacing the thiazole has been reported to have antiproliferative activity similar to tubulysin V. 22 Triazolyl analog 35 also replaces the C11-alcohol of tubulysin V with a methyl group due to decomposition of an intermediate with an alcohol at this position. 22 Natural tubulysins with Tup at the C-terminus (such as tubulysins D-F and H) instead of Tut (tubulysins A-C, G, and I) are more potent, which may be due to their enhanced lipophilicity and cell membrane permeability.…”

Section: Structure-activity Relationshipsmentioning

confidence: 99%

Chemistry and biology of tubulysins: antimitotic tetrapeptides with activity against drug resistant cancers

2015

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Since their first report in 2000, tubulysins have sparked great interest for development as anti-cancer agents due to their exceptionally potent antiproliferative activity. Progress in the discovery and development of tubulysins, especially tubulysin conjugates, has quickly advanced despite limitations in their availability from Nature. In this Highlight, the key research on the isolation and structure determination, biosynthesis, bioactivity, structure-activity relationships (SAR), synthesis, and conjugates of tubulysins is presented.

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Section: Structure-activity Relationshipsmentioning

confidence: 99%

Chemistry and biology of tubulysins: antimitotic tetrapeptides with activity against drug resistant cancers

2015

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“…It should be noted that previously reported total syntheses in 2006 of what were thought to be tubulysins Ua nd Vb yW essjohann et al, [95] turned out to be those of epimers of the natural products,a s subsequently corrected by the authors in 2007. [96] 4.5. N 14 -Desacetoxytubulysin H Based on the retrosynthetic disconnections shown in Scheme 9A and employing aC ÀHactivation tactic,our total synthesis of N 14 -desacetoxytubulysin H( 224) [98] is summarized in Scheme 9B.T hus,f ragments 225 and 226 were combined in the presence of PhI(OCOCF 3 ) 2 and TMSN 3 to provide ketone 227,w hose asymmetric reduction furnished selectively hydroxy compound 228.S tandard manipulations of this intermediate led to carboxylic acid 229,w hose sequential coupling with fragments 230 and 231 proceeded smoothly to generate tripeptide 232,asshown in Scheme 9B.…”

Section: Tubulysin Dmentioning

confidence: 99%

“…The N‐methylated analogue of tubulysin D (i.e., 223 , Scheme C) was also synthesized by the Ellman group and shown to retain the potency of the parent compound (Scheme C), whereas a truncated version (missing the aryl‐containing amino acid, not shown) proved significantly less potent. It should be noted that previously reported total syntheses in 2006 of what were thought to be tubulysins U and V by Wessjohann et al., turned out to be those of epimers of the natural products, as subsequently corrected by the authors in 2007 …”

Section: Total Synthesis Of Natural Products and Their Analogues As Pmentioning

confidence: 99%

The Role of Organic Synthesis in the Emergence and Development of Antibody–Drug Conjugates as Targeted Cancer Therapies

Nicolaou

Rigol

2019

Angew Chem Int Ed

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With a number of antibody–drug conjugates (ADCs) approved for clinical use as targeted cancer therapies and numerous candidates in clinical trials, the field of ADCs is emerging as one of the frontiers in biomedical research, particularly in the area of cancer treatment. Chemists, biologists and clinicians, among other scientists, are partnering their expertise to improve their design, synthesis, efficacy and precision as they strive to advance this paradigm of personalized and targeted medicine to treat cancer patients more effectively and to expand its scope to other indications. Just as Alexander Fleming's penicillin, and the myriad other bioactive natural products that followed its discovery and success in the clinic, ignited a revolution in medicine after the Second World War, so did calicheamicin γ1I, and other highly potent naturally occurring antitumor agents, play a pivotal role in enabling the advent of this new paradigm of “biological‐small molecule hybrid” medical intervention. Today there are four clinically approved drugs from the ADC paradigm, Mylotarg, Adcetris, Kadcyla and Besponsa, in order of approval, the first and the last of which carry the same calicheamicin γ1I‐derived payload. Covering oncological applications, and after a brief history of the emergence of the field of antibody–drug conjugates triggered more than a century ago by Paul Ehrlich's “magic bullet” concept, this Review is primarily focusing on the chemical synthesis aspects of the ADCs multidisciplinary research enterprise.

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“…Es sei darauf hingewiesen, dass sich die bereits 2006 veröffentlichten Totalsynthesen der Tubulysine U und V von Wessjohann et al . im Nachhinein als Synthesen von Epimeren der Naturstoffe herausgestellt haben, was in der Folge 2007 von den Autoren korrigiert wurde …”

Section: Totalsynthese Von Naturstoffen Und Ihrer Analoga Als Potentiunclassified

Die Bedeutung der organischen Synthese bei der Entstehung und Entwicklung von Antikörper‐Wirkstoff‐Konjugaten als gezielte Krebstherapien

Nicolaou

Rigol

2019

Angewandte Chemie

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Mit einigen Antikörper‐Wirkstoff‐Konjugaten (ADCs), die für den klinischen Einsatz als zielgerichtete Krebstherapien zugelassenen sind, und zahlreichen Kandidaten in klinischen Studien, entwickelt sich das Gebiet der ADCs zu einem hochaktuellen biomedizinischen Forschungsfeld, insbesondere im Bereich der Krebsbehandlung. Chemiker, Biologen und Mediziner kombinieren ihre Expertisen, um Design, Synthese, Wirksamkeit und Präzision zu verbessern, während sie danach streben, dieses Grundprinzip der personalisierten und zielgerichteten Medizin voranzutreiben, um Krebspatienten effektiver zu behandeln und ihren Anwendungsbereich auf andere Indikationen auszudehnen. So wie Alexander Flemings Penicillin und die unzähligen anderen bioaktiven Naturstoffe, die auf dessen Entdeckung und seinen Erfolg in der Klinik folgten, nach dem Zweiten Weltkrieg eine Revolution in der Medizin auslösten, so haben Calicheamicin γ1I und andere hochwirksame, natürlich vorkommende Antitumorverbindungen ebenso eine zentrale Rolle gespielt, wenn es darum geht, die Einführung dieses neuen Konzepts der medizinischen Intervention “biologisch‐niedermolekularer Hybride” zu ermöglichen. Heute gibt es vier klinisch zugelassene Medikamente des ADC‐Konzepts: Mylotarg, Adcetris, Kadcyla und Besponsa, von denen das erst‐ sowie das letztgenannte den gleichen von Calicheamicin γ1I abgeleiteten Wirkstoff tragen. Dieser Aufsatz deckt onkologische Anwendungen ab und konzentriert sich nach einer kurzen Geschichte der Entstehung des Bereichs der ADCs, welcher vor mehr als einem Jahrhundert durch Paul Ehrlichs Konzept der Zauberkugel begründet wurde, in erster Linie auf die Aspekte der chemischen Synthese des multidisziplinären Forschungsunternehmens der ADCs.

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Total Synthesis of Tubulysin U and V

Cited by 22 publications

References 4 publications

Chemistry and biology of tubulysins: antimitotic tetrapeptides with activity against drug resistant cancers

Chemistry and biology of tubulysins: antimitotic tetrapeptides with activity against drug resistant cancers

The Role of Organic Synthesis in the Emergence and Development of Antibody–Drug Conjugates as Targeted Cancer Therapies

Die Bedeutung der organischen Synthese bei der Entstehung und Entwicklung von Antikörper‐Wirkstoff‐Konjugaten als gezielte Krebstherapien

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