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. 2015 Oct 23;6(12):1225-30.
doi: 10.1021/acsmedchemlett.5b00364. eCollection 2015 Dec 10.

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

Celeste Alverez  1 , Michelle R Arkin  2 , Stacie L Bulfer  2 , Raffaele Colombo  3 , Marina Kovaliov  3 , Matthew G LaPorte  3 , Chaemin Lim  3 , Mary Liang  3 , William J Moore  4 , R Jeffrey Neitz  2 , Yongzhao Yan  3 , Zhizhou Yue  3 , Donna M Huryn  1 , Peter Wipf  1
Affiliations

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

Celeste Alverez et al. ACS Med Chem Lett. .

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.

Keywords: AAA ATPase; fluorinated substituent effects; p97 inhibitors; pentafluorosulfanyl-indole; structure−activity relationships; trifluoromethyl-indole.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Crystal structure of hexameric, full-length p97 in complex with ADP (PDB ID 3CF3).
Figure 2
Figure 2
Structures of p97 inhibitors.
Scheme 1
Scheme 1. Preparation of CF3- and SF5-Substituted p97 Inhibitors 12 and 13
Figure 3
Figure 3
Structures and steric/electronic features of new phenyl indole p97 inhibitors. The color coding on the electron-density surface of the indole moiety reflects the electrostatic potential experienced by a positive probe charge (red = attractive, blue = repulsive).
Scheme 2
Scheme 2. Preparation of NO2- and CH3-Substituted p97 Inhibitors 23 and 24
Scheme 3
Scheme 3. Preparation of CH3O- and CF3O-Substituted p97 Inhibitors 25 and 26
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