Structure-Activity Study of Bioisosteric Trifluoromethyl and Pentafluorosulfanyl Indole Inhibitors of the AAA ATPase p97

Celeste Alverez, Michelle R. Arkin, Stacie L. Bulfer, Raffaele Colombo, Marina Kovaliov, Matthew G. Laporte, Chaemin Lim, Mary Liang, William J. Moore, R. Jeffrey Neitz, Yongzhao Yan, Zhizhou Yue, Donna M. Huryn, Peter Wipf

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46 Scopus citations

Abstract

Exploratory SAR studies of a new phenyl indole chemotype for p97 inhibition revealed C-5 indole substituent effects in the ADPGlo assay that did not fully correlate with either electronic or steric factors. A focused series of methoxy-, trifluoromethoxy-, methyl-, trifluoromethyl-, pentafluorosulfanyl-, and nitro-analogues was found to exhibit IC50s from low nanomolar to double-digit micromolar. Surprisingly, we found that the trifluoromethoxy-analogue was biochemically a better match of the trifluoromethyl-substituted lead structure than a pentafluorosulfanyl-analogue. Moreover, in spite of their almost equivalent strongly electron-depleting effect on the indole core, pentafluorosulfanyl- and nitro-derivatives were found to exhibit a 430-fold difference in p97 inhibitory activities. Conversely, the electronically divergent C-5 methyl- and nitro-analogues both showed low nanomolar activities.

Original languageEnglish
Pages (from-to)1225-1230
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume6
Issue number12
DOIs
StatePublished - 10 Dec 2015
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2015 American Chemical Society.

Keywords

  • AAA ATPase
  • fluorinated substituent effects
  • p97 inhibitors
  • pentafluorosulfanyl-indole
  • structure-activity relationships
  • trifluoromethyl-indole

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