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

Abstract

Simplify, simplify, simplify! Pretubulysin (structure without the green substituents), a simplified tubulysin was prepared in the laboratory and also found in a natural myxobacterial source. This biosynthetic precursor of the tubulysins is not as active as tubulysins A and D but is still effective in picomolar concentrations against cancer cell lines.

Pretubulysin: a new option for the treatment of metastatic cancer

“…17 Extending the initial study of Herrmann et al 18 showing that pretubulysin inhibits tubulin assembly in vitro , induces apoptosis and abrogates migration of cancer cells, the here presented in vitro and in vivo assays clearly demonstrate that pretubulysin impedes tumor growth and metastasis equally potent to the already established but chemically not available antimitotic compound tubulysin.…”

“…17 Tubulysin A was from Merck Calbiochem (Darmstadt, Germany). Both compounds were dissolved in dimethyl sulfoxide (DMSO) in high concentrated stocks.…”

“…Unfortunately, tubulysins are only obtained in limited amounts as fermentation, isolation procedures as well as intricate chemical synthesis are quite challenging. 14, 15, 16 Pretubulysin, a natural precursor of tubulysins, although also of minute quantity in myxobacteria, was successfully synthesized in a large-scale setup 17 and firstly tested for its bioactivity and target in some tumor cell lines. 18, 19, 20 …”

Pretubulysin derived probes as novel tools for monitoring the microtubule network via activity-based protein profiling and fluorescence microscopy

“…Early studies suggested that tubulysins interact with the eukaryotic cytoskeleton by inhibition of tubulin polymerization with EC 50 values in the picomolar range. [10][11][12] This potency even exceeds that of other tubulin modifiers such as taxol, vinblastine and epothilone by 20-to 100-fold 13 and consequently rank tubulysins as the most promising lead structures for pharmaceutical application. However, several prerequisites have to be considered in order to initiate a drug development program.…”

“…13,19 Here we utilize this well-established route to develop two pretubulysin photoaffinity probes 4 and 5 which are applied in cellular activity based protein profiling and imaging studies in order to unravel and visualize dedicated targets (Fig. 2).…”