The Total Synthesis of Tubulysin D

Abstract

The first total synthesis of tubulysin D is reported. The development and application of new tert-butanesulfinamide methods allowed for rapid syntheses of the tubuvaline and tubuphenylalanine fragments. Most significantly, a route was devised and implemented to introduce and carry forward the highly labile N,O-acetal functionality. Tubulysin D is the most active member of the tubulysin family, and the efficient synthetic route described herein will allow for the rapid syntheses of analogues to probe the biological activity of this important class of natural products.

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

“…[8] The synthesis of the central Ile-dTuv unit (dTuv: desacetoxytubuvaline) is shown in Scheme 2. Starting from the N-Boc-protected valine ester, a DIBAL reduction and in situ Wittig reaction of the resulting aldehyde gave rise to the unsaturated nitrile 3 in enantiomerically pure form.…”

Polymeric Tubulysin-Peptide Nanoparticles with Potent Antitumor Activity

“…Treatment with tubulysin A resulted in a nonsignificant TGD and reduction in tumor burden on day 25, the time when tumors of control animals reached the predetermined average size of 2,000 mm 3 . The vinblastine and paclitaxel reference treatments resulted in TGDs of 109% and 77%, respectively.…”

“…Cells were further incubated with a mouse antia-tubulin antibody (1:1000, T6199, Sigma-Aldrich), washed with PBS, stained with a goat antimouse FITC antibody (1:250, sc-2010, Santa Cruz), washed again, and counter stained with 4 ¶-6-Diamidino-2-phenylindole (DAPI). Images were acquired at a 100Â magnification on a Zeiss 410 laser scanning microscope (Carl Zeiss) using two-photon excitation at 720 nm for DAPI, single photon excitation at 488 nm for 3 ) on the day the vehicle control group mean tumor volume reached the predetermined endpoint of 1,000 mm 3 . Mean BW nadir, lowest group mean body weight, as % change from Day 1; -, no decrease in mean body weight was observed.…”

“…All of the treatments were given i.v. The end point of the experiment was a tumor volume of 1,000 mm 3 or 90 d for HT29, and 2,000 mm 3 or 50 d for H460. When the tumor reached the end point the mouse was euthanized and the end point tumor growth delay was calculated consequently.…”

Novel Tubulin Antagonist Pretubulysin Displays Antivascular Properties In Vitro and In Vivo

“…12,13 Structurally, PT is a linear tetrapeptide consisting of isoleucine and 3 unnatural amino acids. 11 In contrast to tubulysin, [14][15][16][17] PT is synthetically more easily accessible; in 2009, PT was first synthesized in the gram scale by Ullrich et al 18,19 Although the structure of PT is less complex, it shows nearly the same microtubule-depolymerizing potency as tubulysin and is also able to inhibit tumor cell growth. 20 PT acts, like other tubulin-binding agents, through binding to the β-subunit of tubulin.…”