Tricyclic Compounds Containing Nonenolizable Cyano Enones. A Novel Class of Highly Potent Anti-Inflammatory and Cytoprotective Agents

Abstract

Forty-four novel tricycles containing non-enolizable cyano enones (TCEs) were designed and synthesized on the basis of a semisynthetic pentacyclic triterpenoid, bardoxolone methyl, which is currently being developed in Phase II clinical trials for the treatment of severe chronic kidney disease in diabetic patients. Most of the TCEs having two different kinds of non-enolizable cyano enones in rings A and C are highly potent suppressors of induction of inducible nitric oxide synthase stimulated with interferon-γ, and highly potent inducers of the cytoprotective enzymes heme oxygenase-1 and NAD(P)H:quinone oxidoreductase-1. Among these compounds, (±)-(4bS,8aR,10aS)-10a-ethynyl-4b,8,8-trimethyl-3,7-dioxo-3,4b,7,8,8a,9,10,10a-octahydrophenanthrene-2,6-dicarbonitrile ((±)-31) is the most potent in these bioassays in our pool of drug candidates including semisynthetic triterpenoids and synthetic tricycles. These facts strongly suggest that an essential factor for potency is not a triterpenoid skeleton, but the cyano enone functionality. Notably, TCE 31 reduces hepatic tumorigenesis induced with aflatoxin in rats. Further preclinical studies and detailed mechanism studies on 31 are in progress.

Highly Potent Activation of Nrf2 by Topical Tricyclic Bis(Cyano Enone): Implications for Protection against UV Radiation during Thiopurine Therapy

“…Inducers are also antiinflammatory agents, and there is a linear correlation between these two biologic activities that spans 6 orders of magnitude of inducer concentrations (7,8). Semisynthetic pentacyclic triterpenoids (9)(10)(11) and related synthetic tricyclic compounds (12)(13)(14)(15) which contain Michael acceptors are the most potent inducers known to date, activating Nrf2 and inhibiting proinflammatory responses at sub-to low nanomolar concentrations (7,16,17). Furthermore, they show remarkable protective efficacy in a number of preclinical animal models of chronic disease, including carcinogenesis, cardiovascular disease, and neurodegeneration, and in early clinical trials (reviewed in refs.…”

Electron affinity of tricyclic, bicyclic, and monocyclic compounds containing cyanoenones correlates with their potency as inducers of a cytoprotective enzyme

“…During the development of bardoxolone methyl and its analogues, tri-, bi-, and monocyclic compounds with cyanoenones have been designed and explored. 9,10,14 They are also highly potent Nrf2 activators and reversible covalent drugs. Amongst them, tricyclic compound 1 (TBE-31, Figure 1 and Table 1) is the most potent Nrf2 activator.…”

“…The potency of tri-, bi-, and monocyclic compounds containing cyanoenones as Nrf2 activators was evaluated using a prototypic cytoprotective enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1) in Hepa1c1c7 murine hepatoma cells by CD values (the concentration required to double the specific enzyme activity of NQO1). 9,10,14 For this study, the pCD values (logarithm of the reciprocal of CD values expressed in M (mol/L) units) are employed for inducer potency. NQO1 is the prototypical Nrf2 target gene, and the NQO1 bioassay is widely recognized as a highly quantitative readout for Nrf2 activity.…”

“…We have previously shown that cyanoenones react with cysteine residues in Keap1, the main negative regulator of Nrf2. 6,7,14 In a variety of cell lines and animal tissues, we have demonstrated that Nrf2 activation by cyanoenones leads to the coordinate transcriptional upregulation of NQO1 together with other Nrf2-target genes, such as multiple isoforms of glutathione S-transferase (GST), heme oxygenase 1, -glutamyl cysteine ligase catalytic (GCLC) subunit, as well as an ARE-luciferase reporter, a direct readout of Nrf2-mediated transcription. 6,7,14 Furthermore, Nrf2 is required for the NQO1 inducer activity of cyanoenones as NQO1 induction is not observed in Nrf2-deficient cells.…”

“…6,7,14 In a variety of cell lines and animal tissues, we have demonstrated that Nrf2 activation by cyanoenones leads to the coordinate transcriptional upregulation of NQO1 together with other Nrf2-target genes, such as multiple isoforms of glutathione S-transferase (GST), heme oxygenase 1, -glutamyl cysteine ligase catalytic (GCLC) subunit, as well as an ARE-luciferase reporter, a direct readout of Nrf2-mediated transcription. 6,7,14 Furthermore, Nrf2 is required for the NQO1 inducer activity of cyanoenones as NQO1 induction is not observed in Nrf2-deficient cells. 6,7 The electron affinity of these new compounds can be calculated via the energy of their lowest unoccupied molecular orbital, E (LUMO) in eV, and was quantified at two quantum mechanical levels: the semiempirical AM1, 16 and the density functional theory (DFT) 17 (see Table 1).…”