title: Acid mediated formation of an N-acyliminium ion from tubulysins: a new methodology for the synthesis of natural tubulysins and their analogs.
abstract: Tubuylsins are extremely potent cytotoxic agents which inhibit tubulin polymerization and lead to cell cycle arrest and apoptosis. Tubulysins have been isolated from fermentation mixtures and have been chemically synthesized; however, these efforts have been hampered by poor yields and arduous purifications. In contrast, treatment of a mixture of natural tubulysins A, B, C, G, and I, obtained from a fermentation batch with trifluoroacetic acid results in the formation of a single N-acyliminium ion. Subsequent addition of butyric, isopentyl, or acetic acid results in the formation of tubulysin B, A, or I, respectively, as a single species. New tubulysin analogs can be formed upon treatment of the acyliminium ion with other nucleophiles such as alcohols, thiols, and nitriles, resulting in corresponding N-acyl-N,O-acetals, N-acyl-N,S-thioacetals, and N,N'-diacyl-aminals. Carbon-carbon bond formation is also possible with a modification of this protocol. The cytotoxicies of the natural tubulysins and tubulysin analogs synthesized by this method were evaluated on KB cells.
authors.affiliation: Endocyte, Inc., 3000 Kent Ave., W. Lafayette, IN 47906, USA. ivlahov@endocyte.com
authors.forename: Iontcho R
authors.initials: IR
authors.lastname: Vlahov
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Marilynn
authors.initials: M
authors.lastname: Vetzel
authors.forename: Spencer
authors.initials: S
authors.lastname: Hahn
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Kleindl
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Reddy
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Leamon
mesh_terms: D019342:Acetic Acid / Q000737:chemistry; D001688:Biological Products / Q000138:chemical synthesis* / Q000737:chemistry; D060326:Chemistry Techniques, Synthetic / Q000191:economics / Q000379:methods*; D007097:Imines / Q000737:chemistry; D007477:Ions / Q000737:chemistry; D009231:Myxococcales / Q000737:chemistry*; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry; D010875:Pipecolic Acids / Q000138:chemical synthesis* / Q000737:chemistry; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D001688:Biological Products; D007097:Imines; D007477:Ions; D009842:Oligopeptides; D010875:Pipecolic Acids; D050257:Tubulin Modulators; C510756:tubulysin A; C546650:tubulysin B; D019342:Acetic Acid