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an MED of 0.2 mpk in the xenograft model.
In summary, conversion of the carboxylic acid group in
HTI-286 to other polar functionality gave potent tubu-
lin inhibitors with activity in taxane resistant cell lines
expressing P-glycoprotein. Potency was dependent on
the nature of the functional group. The ability of the
group to form hydrogen bonds and a correct spatial
orientation were factors critical to activity. In vivo
activity in a xenograft model in athymic mice was
achieved with proline analog 3.
Acknowledgements
The authors gratefully acknowledge the Wyeth Chemi-
cal Development Group and Discovery Synthesis Group
for supplies of HTI-286 and intermediates. The authors
thank Dr. Carolyn Discafani for in vivo testing of 3 in
the xenograft model and Dr. R. Thomas Williamson for
assignment of the stereochemistry of 31 and 32.
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