Design and Synthesis of Irreversible Analogues of Bardoxolone Methyl for the Identification of Pharmacologically Relevant Targets and Interaction Sites



Wong, Michael HL, Bryan, Holly K, Copple, Ian M ORCID: 0000-0003-4101-1913, Jenkins, Rosalind E ORCID: 0000-0002-3730-1136, Chiu, Pak Him, Bibby, Jaclyn, Berry, Neil G ORCID: 0000-0003-1928-0738, Kitteringham, Neil R, Goldring, Christopher E, O'Neill, Paul M ORCID: 0000-0003-4338-0317
et al (show 1 more authors) (2016) Design and Synthesis of Irreversible Analogues of Bardoxolone Methyl for the Identification of Pharmacologically Relevant Targets and Interaction Sites. JOURNAL OF MEDICINAL CHEMISTRY, 59 (6). 2396 - 2409.

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Abstract

Semisynthetic 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.

Item Type: Article
Uncontrolled Keywords: hydrocarbons, thiols, peptides and proteins, monomers, ethers
Depositing User: Symplectic Admin
Date Deposited: 25 Nov 2016 14:56
Last Modified: 27 May 2020 10:06
DOI: 10.1021/acs.jmedchem.5b01292
Related URLs:
URI: http://livrepository.liverpool.ac.uk/id/eprint/3004668