jm5b01292_si_002.csv (1.25 kB)
Design and Synthesis of Irreversible Analogues of Bardoxolone Methyl for the Identification of Pharmacologically Relevant Targets and Interaction Sites
dataset
posted on 2016-02-23, 00:00 authored by Michael
H. L. Wong, Holly
K. Bryan, Ian M. Copple, Rosalind
E. Jenkins, Pak Him Chiu, Jaclyn Bibby, Neil G. Berry, Neil R. Kitteringham, Christopher E. Goldring, Paul M. O’Neill, B. Kevin ParkSemisynthetic triterpenoids such
as bardoxolone methyl (methyl-2-cyano
3,12-dioxooleano-1,9-dien-28-oate; CDDO-Me) (4) are potent
inducers of antioxidant and anti-inflammatory signaling pathways,
including those regulated by the transcription factor Nrf2. However,
the reversible nature of the interaction between triterpenoids and
thiols has hindered attempts to identify pharmacologically relevant
targets and characterize the sites of interaction. Here, we report
a shortened synthesis and SAR profiling of 4, enabling
the design of analogues that react irreversibly with model thiols,
as well as the model protein glutathione S-transferase
P1, in vitro. We show that one of these analogues, CDDO-epoxide (13), is comparable to 4 in terms of cytotoxicity
and potency toward Nrf2 in rat hepatoma cells and stably modifies
specific cysteine residues (namely, Cys-257, -273, -288, -434, -489,
and -613) within Keap1, the major repressor of Nrf2, both in vitro
and in living cells. Supported by molecular modeling, these data demonstrate
the value of 13 for identifying site(s) of interaction
with pharmacologically relevant targets and informing the continuing
development of triterpenoids as novel drug candidates.