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Total Synthesis and Biological Evaluation of Tubulysin Analogues

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journal contribution
posted on 22.07.2016, 00:00 by Raffaele Colombo, Zhiyong Wang, Junyan Han, Raghavan Balachandran, Hikmat N. Daghestani, Daniel P. Camarco, Andreas Vogt, Billy W. Day, David Mendel, Peter Wipf
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.