title: Structure-Activity Study of Bioisosteric Trifluoromethyl and Pentafluorosulfanyl Indole Inhibitors of the AAA ATPase p97.
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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Pittsburgh , Pittsburgh, Pennsylvania 15261, United States ; Chemical Diversity Center, University of Pittsburgh , Pittsburgh, Pennsylvania 15260, United States.
authors.forename: Celeste
authors.initials: C
authors.lastname: Alverez
authors.affiliation: Department of Pharmaceutical Chemistry, Small Molecule Discovery Center, University of California , San Francisco, California 94158, United States.
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Arkin
authors.affiliation: Department of Pharmaceutical Chemistry, Small Molecule Discovery Center, University of California , San Francisco, California 94158, United States.
authors.forename: Stacie L
authors.initials: SL
authors.lastname: Bulfer
authors.affiliation: Chemical Diversity Center, University of Pittsburgh , Pittsburgh, Pennsylvania 15260, United States.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Colombo
authors.affiliation: Chemical Diversity Center, University of Pittsburgh , Pittsburgh, Pennsylvania 15260, United States.
authors.forename: Marina
authors.initials: M
authors.lastname: Kovaliov
authors.affiliation: Chemical Diversity Center, University of Pittsburgh , Pittsburgh, Pennsylvania 15260, United States.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: LaPorte
authors.affiliation: Chemical Diversity Center, University of Pittsburgh , Pittsburgh, Pennsylvania 15260, United States.
authors.forename: Chaemin
authors.initials: C
authors.lastname: Lim
authors.affiliation: Chemical Diversity Center, University of Pittsburgh , Pittsburgh, Pennsylvania 15260, United States.
authors.forename: Mary
authors.initials: M
authors.lastname: Liang
authors.affiliation: Leidos Biomedical Research, Inc. , Frederick, Maryland 21702, United States.
authors.forename: William J
authors.initials: WJ
authors.lastname: Moore
authors.affiliation: Department of Pharmaceutical Chemistry, Small Molecule Discovery Center, University of California , San Francisco, California 94158, United States.
authors.forename: R Jeffrey
authors.initials: RJ
authors.lastname: Neitz
authors.affiliation: Chemical Diversity Center, University of Pittsburgh , Pittsburgh, Pennsylvania 15260, United States.
authors.forename: Yongzhao
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Chemical Diversity Center, University of Pittsburgh , Pittsburgh, Pennsylvania 15260, United States.
authors.forename: Zhizhou
authors.initials: Z
authors.lastname: Yue
authors.affiliation: Department of Pharmaceutical Sciences, University of Pittsburgh , Pittsburgh, Pennsylvania 15261, United States ; Chemical Diversity Center, University of Pittsburgh , Pittsburgh, Pennsylvania 15260, United States.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Huryn
authors.affiliation: Department of Pharmaceutical Sciences, University of Pittsburgh , Pittsburgh, Pennsylvania 15261, United States ; Chemical Diversity Center, University of Pittsburgh , Pittsburgh, Pennsylvania 15260, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Wipf
keywords: AAA ATPase; fluorinated substituent effects; p97 inhibitors; pentafluorosulfanyl-indole; structure−activity relationships; trifluoromethyl-indole