Pretubulysin: from hypothetical biosynthetic intermediate to potential lead in tumor therapy.
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herrmann,jennifer et al_final.pdf
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Authors
Herrmann, JenniferElnakady, Yasser A
Wiedmann, Romina M
Ullrich, Angelika
Rohde, Manfred
Kazmaier, Uli
Vollmar, Angelika M
Müller, Rolf
Issue Date
2012
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Show full item recordAbstract
Pretubulysin is a natural product that is found in strains of myxobacteria in only minute amounts. It represents the first enzyme-free intermediate in the biosynthesis of tubulysins and undergoes post-assembly acylation and oxidation reactions. Pretubulysin inhibits the growth of cultured mammalian cells, as do tubulysins, which are already in advanced preclinical development as anticancer and antiangiogenic agents. The mechanism of action of this highly potent compound class involves the depolymerization of microtubules, thereby inducing mitotic arrest. Supply issues with naturally occurring derivatives can now be circumvented by the total synthesis of pretubulysin, which, in contrast to tubulysin, is synthetically accessible in gram-scale quantities. We show that the simplified precursor is nearly equally potent to the parent compound. Pretubulysin induces apoptosis and inhibits cancer cell migration and tubulin assembly in vitro. Consequently, pretubulysin appears to be an ideal candidate for future development in preclinical trials and is a very promising early lead structure in cancer therapy.Citation
Pretubulysin: from hypothetical biosynthetic intermediate to potential lead in tumor therapy. 2012, 7 (5):e37416 PLoS ONEAffiliation
Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research and Department of Pharmaceutical Biotechnology, Saarland University, Saarbrücken, Germany.Journal
PloS onePubMed ID
22616003Type
ArticleLanguage
enISSN
1932-6203ae974a485f413a2113503eed53cd6c53
10.1371/journal.pone.0037416
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