title: Pretubulysin: from hypothetical biosynthetic intermediate to potential lead in tumor therapy.
abstract: 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.
authors.affiliation: Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research and Department of Pharmaceutical Biotechnology, Saarland University, Saarbrücken, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Herrmann
authors.forename: Yasser A
authors.initials: YA
authors.lastname: Elnakady
authors.forename: Romina M
authors.initials: RM
authors.lastname: Wiedmann
authors.forename: Angelika
authors.initials: A
authors.lastname: Ullrich
authors.forename: Manfred
authors.initials: M
authors.lastname: Rohde
authors.forename: Uli
authors.initials: U
authors.lastname: Kazmaier
authors.forename: Angelika M
authors.initials: AM
authors.lastname: Vollmar
authors.forename: Rolf
authors.initials: R
authors.lastname: Müller
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002464:Cell Migration Inhibition; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D008870:Microtubules / Q000187:drug effects*; D008938:Mitosis / Q000187:drug effects; D009231:Myxococcales / Q000737:chemistry; D009842:Oligopeptides / Q000494:pharmacology* / Q000627:therapeutic use; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014404:Tubulin / Q000187:drug effects
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D009842:Oligopeptides; D019253:Proto-Oncogene Proteins c-bcl-2; D014404:Tubulin; C510756:tubulysin A; C575012:pretubulysin