Abstract 3259: An efficient total synthesis of Tubulysin B

Abstract The tubulysins are members of a new class of natural products isolated from myxobacterial species.[1] As cytoskeleton interacting agents, the tubulysins are mitotic poisons that inhibit tubulin polymerization and lead to cell cycle arrest and apoptosis.[2-4] Tubulysins are extremely potent cytotoxic molecules, exceeding the cell growth inhibition of any clinicaly relevant traditional chemotherapeutic e.g. paclitaxel, vinblastine, and epothilones. Furthermore, they are potent against multidrug resistant cell lines.[5] Structurally, tubulysins are closely related linear tetrapeptides comprised of distinctive, unusual, or hydrophobic amino acid segments: D-N-methyl pipecolinic acid, L-isoleucine, the heterocyclic tubuvalin, and the γ-amino acid tubutyrosine/tubuphenylalanine. The most prominent feature in the molecular architecture of these natural occurring compounds is the acid and base sensitive N-acyloxymethyl substituent (or a N,O-acetal of formaldehyde). In this poster we present an efficient yet simplified synthesis of Tubulysin B. The optimized synthetic protocol relyes on chemical as well as enzymatic steps and is readily scalable to industrial meaningful quantities. All the synthesized intermediates and final compound are well charectreized by several analytical methods including HPLC, MS, 1H and 13C NMR, etc. Biological activty of synthetic tubulysin B is identical with natural tubulysin B. This synthetic protocol is amenable to all other natural tubulysins and analogs. [1] F. Sasse, H. Steinmetz, G. Höfle, H. Reichenbach, J. Antibiot. 2000, 53, 879-885. [2] H. Steinmetz, N. Glasser, E. Herdtweck, F. Sasse, H. Reichenbach, G. Höfle, Angew. Chem. Int. Ed. 2004, 43, 4888-4892. [3] M. Khalil, F. Sasse, H. Lünsdorf, Y. Elnakady, H. Reichenbach, ChemBioChem. 2006, 7, 678-683. [4] G. Kaur, M. Hollingshead, S. Holbeck, Schauer-Vikašinovic, R. Camalier, A. Dömling, S. Agarwal, Biochem. J. 2006, 396, 235-242. [5] For a review see: A. Dömling, W.Richter, Mol. Diversity 2005, 9, 141-147 and references therein. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3259. doi:10.1158/1538-7445.AM2011-3259