Journal of the American Chemical Society
Article
modifications made in the Tup moiety of the tubulysin
molecule (e.g., shorter carboxylate chain, fluorophenyl, and
N-methylindolyl) led to significant loss of activity, suggesting
considerable sensitivity of the molecule toward modification of
this domain (see the potencies of Tb24, Tb25, Tb40, and
Tb41 in Table 2). Some of these results were unexpected [e.g.,
the loss of potency of Tb40 (MES SA) and Tb41 (HEK
293T)] and require further experimentation and understanding
before meaningful and reliable SARs can be derived for these
cases. However, substituting Tup with the cubane or [1.1.1]-
bicyclopentane structural motif resulted in comparable potencies
to those of Tb1 and Tb2 (i.e., Tb14; see Tables 1 and 2),
indicating tolerance of the receptor to these substitutions.
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ASSOCIATED CONTENT
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* Supporting Information
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AUTHOR INFORMATION
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(24) Vlahov, I. R.; Wang, Y.; Vetzel, M.; Hahn, S.; Kleindl, P. J.;
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Corresponding Author
Author Contributions
∥J.Y., D.M., R.D.E., and D.V. contributed equally.
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
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This work was supported by the Cancer Prevention & Research
Institute of Texas (CPRIT), the Welch Foundation (Grant
C-1819), and Stemcentrx. We thank Drs. L.B. Alemany and
Q. Kleerekoper for NMR spectroscopic assistance and C.
Pennington for mass spectrometric assistance.
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