Total Synthesis of Tubulysin U and V

Abstract

Tubulysins (1) are compounds of extraordinary potency, rapidly degrading the tubulin cytoskeleton, with tubulysin D being the most active tubulin-modifier known so far.[1, 2] The tubulysins were first described by Höfle, Reichenbach, and co-workers in 2000. [3,4] Several representatives are active with GI 50 values (growth inhibition of 50 %) in the low picomolar range against the NCI-60 cancer cell-line panel, and some are highly antiangiogenic.[5] Semisynthetic tubulysins, derived from isolated material, show promising in vivo anticancer properties and are candidates for antibody conjugates. Thus, tubulysins are attractive leads as novel anticancer agents. [5] However, so far, tubulysins can only be produced by a fermentation process that yields less than 10 mg L À1 by several rather tedious chromatographic purification steps. Thus, and

Prätubulysin, eine potente und synthetisch leicht zugängliche Vorstufe von Tubulysin aus Angiococcus disciformis

“…Dies macht sie zu interessanten Kandidaten für die Behandlung vor allem auch gegen mehrere Wirkstoffe resistenter Tumore (MDR-Tumore) und initiierte intensive Forschungen zur Chemie und Biologie dieser Verbindungsklasse. Struktur-Aktivitäts-Untersuchungen an synthetischen Analoga von Tubulysin D, [3][4][5][6] dem aktivsten Metaboliten, ergaben ein klares Bild, welche Strukturmerkmale für die biologische Aktivität essenziell sind, und führten zu Vorschlägen, wie sich die pharmakologischen Eigenschaften dieser Metabolite optimieren lassen. So scheint eine Reihe von Strukturmodifikationen ohne signifikanten Einbruch der biologischen Wirkung toleriert zu werden.…”

“…Diese Daten ergänzen die anderer Gruppen [3][4][5][6] hinsichtlich der Struktur-Aktivitäts-Beziehung. Die hohe biologische Aktivität von Prätubulysin (2) zeigt, dass weder das N,OAcetal noch die Acetoxygruppe von Tuv essenziell für eine hohe Cytotoxizität sind, wobei jedoch ein moderater Aktivitätsverlust (auf etwa ein Zehntel) gegenüber analogen Verbindungen mit Acetoxygruppen beobachtet wird.…”

Total Synthesis of Tubulysins U and V

“…We also show that the tubulysins U and V previously obtained by Dömling et al [9] are actually stereoisomers of the natural molecules.…”

“…The coupling of Boc-Tuv-OH (17 a) with H-Tup-OMe (8 b) using HATU/HOAt delivered the dipeptide Boc-Tuv-Tup-OMe (18) (c = 1.0 g cm À3 , CHCl 3 ) for Dömlings dipeptide. These findings strongly suggest that the Boc-Tuv-Tup-OMe dipeptide previously described by Dömling et al [9] should actually be a different stereoisomer, with the incorrect stereochemistry. [15] Treatment of 18 with TFA delivered H-Tuv-Tup-OMe (19) in a stereopure form and excellent yield.…”

“…The same problem was observed by Dömling et al who could not suppress the epimerization. [9] A number of different conditions were tried, including a HATU/HOAt-promoted coupling, but the formation of the tetrapeptide methyl ester 20 was always accompanied by at least 40 % epimerization of the Ile stereocenter. Eventually, we found that the use of ethyl chloroformate and N-methylmorpholine (NMM) in ethyl acetate afforded the target 20 in very good yields, with very little epimerization (< 5 %).…”