Journal of the American Chemical Society
COMMUNICATION
like their lead natural products. They exhibited potential equal to
that of tubulysin A within the error limits of the experiments.
In summary, we have reported the first synthesis of natural-
product analogues by means of a combination of three different
types of isonitrile-based multicomponent reactions in a concise
and convergent manner. The new cytotoxic tubulysin analogues
(“tubugis”) show GI50 values in the high picomolar range. The
rare peptoid N,O-acetalꢀester functionality has been replaced by
a more stable N-branched peptide backbone with retention of the
cytotoxic activity. Most importantly, the unreliable multistep
generation of the sterically hindered tertiary amide function
could be substituted with the more reliable one-pot multicom-
ponent assembly. The simplicity of the synthesis highlights the
extraordinary value and scope of multiple MCRs in the con-
struction of complex target molecules.
The use of natural product leads and multiple MCRs together
can be considered a valuable strategy for the generation of
bioactive derivatives. To our knowledge, tubugis are among the
most potent artificial anticancer agents ever discovered and
represent the first example of a target-oriented synthesis ap-
proach using multiple MCRs. Other synthetic strategies based on
multiple MCRs are currently under development in our group.
We hope that the findings presented herein encourage further
investigations of the application or development of new
(combinations of) MCRs as a powerful means for the synthesis
of complex natural products and related compounds.
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’ ASSOCIATED CONTENT
S
Supporting Information. Detailed experimental proce-
b
dures; full characterization of new compounds; and selected
copies of 1H and 13C NMR spectra, HPLC chromatograms, and
HRMS (ESI-FT-ICR) spectra. This material is available free of
’ AUTHOR INFORMATION
Corresponding Author
(7) Preusentanz, R.; Pando, O.; Wessjohann, L. Nachr. Chem. 2010,
58, 526.
’ ACKNOWLEDGMENT
(8) (a) Wessjohann, L. A.; Rivera, D. G.; Vercillo, O. E. Chem. Rev.
2009, 109, 796. (b) Wessjohann, L. A.; Andrade, C. K. Z.; Vercillo, O. E.;
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(9) Patent application: Wessjohann, L. A.; Pando, O. Tubugis. EP 10
007 468.1, 2010.
The authors acknowledge support from the State of Saxony-
Anhalt (MK-LSA, Projekt “Lipopeptide”). We thank Prof. Dr.
Bernhard Westermann, Dr. Daniel G. Rivera, and M.Sc. Fredy
Leꢀon-Reyes for fruitful suggestions. We also thank Annett
Werner for HPLC support, Dr. Sander van Berkel for manuscript
advice, and Dr. Wolfgang Richter (R&D Biopharmaceuticals) for
a reference sample of tubulysin A.
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