Total Synthesis and Biological Evaluation of Tubulysin Analogues

J Org Chem. 2016 Nov 4;81(21):10302-10320. doi: 10.1021/acs.joc.6b01314. Epub 2016 Aug 5.

Abstract

We report a second-generation synthesis of the exceedingly potent antimitotic agent N14-desacetoxytubulysin H (1) as well as the preparation of nine analogues of this lead structure. Highlights of our synthetic efforts include an efficient late-stage functionalization that allows for the preparation of new side-chain- and backbone-modified analogues. We also discovered C-terminal modifications that preserve the exquisite biological activity of acid 1 and offer the opportunity for effective conjugation to cell type-targeting moieties. All analogues had antiproliferative activities in the high picomolar to low nanomolar range and caused apoptosis and mitotic arrest as measured in a high content nuclear morphology assay. The ten synthetic agents described herein spanned a range of almost 4 orders of magnitude in biological activity and illustrate the continued potential to discover extraordinarily potent antiproliferative compounds based on natural product leads.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Carbon-13 Magnetic Resonance Spectroscopy
  • Cell Proliferation / drug effects
  • Drug Screening Assays, Antitumor
  • HeLa Cells
  • Humans
  • Mitosis / drug effects
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology*
  • Proton Magnetic Resonance Spectroscopy

Substances

  • N14-desacetoxytubulysin H
  • Oligopeptides