Isolation, Crystal and Solution Structure Determination, and Biosynthesis of Tubulysins—Powerful Inhibitors of Tubulin Polymerization from Myxobacteria

Pretubulysin, a Potent and Chemically Accessible Tubulysin Precursor from Angiococcus disciformis

“…The tubulysins (1) are a family of nine secondary metabolites (Scheme 1) produced by several strains of myxobacteria, including Angiococcus disciformis An d48 and Archangium gepyhra Ar315. [1] The compounds share a linear tetrapeptide core, consisting of N-methylpipecolic acid (Mep), isoleucine (Ile), a novel amino acid called tubuvaline (Tuv), and a chainextended analogue of either phenylalanine or tyrosine, referred to as tubuphenylalanine (Tup) or tubutyrosine (Tut), respectively.…”

“…The tubulysins (1) are a family of nine secondary metabolites (Scheme 1) produced by several strains of myxobacteria, including Angiococcus disciformis An d48 and Archangium gepyhra Ar315. [1] The compounds share a linear tetrapeptide core, consisting of N-methylpipecolic acid (Mep), isoleucine (Ile), a novel amino acid called tubuvaline (Tuv), and a chainextended analogue of either phenylalanine or tyrosine, referred to as tubuphenylalanine (Tup) or tubutyrosine (Tut), respectively. An acetoxy moiety is common to all structures, while the acyl group within the bis-acyl N,O-acetal substituent varies in size from acetate in tubulysins H and I, to 3-methyl butyrate in tubulysins A and D. The tubulysins are among a handful of natural products that interact with the eukaryotic cytoskeleton, inhibiting the polymerization of tubulin at very low concentrations (< 50 pg mL À1 ).…”

Current advances of tubulin inhibitors as dual acting small molecules for cancer therapy

“…The MOA of tubulysins resembled dolastatin-10 and hemiasterlin, which bind to the vinca domain site, arrest cancer cells in the G 2 /M phase, and trigger subsequent cell apoptosis. 106,107 Tubulysins are highly active in MDR cell lines that either overexpress P-gp pumps or have tubulin mutations, suggesting an alternative solution to treating MDR cancers. PM050489 (34a) and PM060184 (34b), polyketides isolated from marine natural products that are able to be totally synthesized, are highly potent tubulin binding agents.…”

Kleine, ungewöhnliche Peptide gegen Krebs

“…Die Myxobakterienarten Angiococcus disciformis und Archangium gephyra produzieren sie in geringen Mengen (< 4 mgL—1) . Die Tubulysine sind außergewöhnlich zytotoxisch 9. Wie die Epothilone, Vinblastin oder Taxol wirken sie auf das Tubulinzytoskelett — jedoch deutlich effektiver, nämlich um einen Faktor von 20 bis 1000.…”