A novel dicyanotriterpenoid, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-onitrile, active at picomolar concentrations for inhibition of nitric oxide production

Honda, Tadashi; Honda, Yukiko; Favaloro, Frank G.; Gribble, Gordon W.; Suh, Nanjoo; Place, Andrew E.; Rendi, Mara H.; Sporn, Michael B.

doi:10.1016/s0960-894x(02)00105-1

Cited by 134 publications

(128 citation statements)

References 13 publications

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“…This potency correlation extends over 6 orders of magnitude of concentration in a number of cell lines. Design of structural modifications of these TP was intended to optimize potency in suppressing inflammatory responses (1)(2)(3). The most successful modifications involved introduction of an activated Michael acceptor (enone) group in ring A and a second Michael acceptor group at a critical distance from the first in ring C. These structural modifications were precisely the same as found earlier to be important for high potency of phase 2 gene induction (7,8).…”

Section: Discussionmentioning

confidence: 99%

“…This unexpected correlation was disclosed as follows. We synthesized many analogues of oleanolic acid with the goal of maximizing antiinflammatory activity, guided by their ability to block the IFN-␥-dependent induction of inducible nitric oxide synthase (iNOS) in mouse macrophages (1)(2)(3). These studies showed that the presence of Michael acceptor groups at critical positions was essential not only for antiinflammatory activity, but also for inhibition of proliferation, promotion of differentiation, and induction of apoptosis in various cell lines (4)(5)(6).…”

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confidence: 99%

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Extremely potent triterpenoid inducers of the phase 2 response: Correlations of protection against oxidant and inflammatory stress

Dinkova‐Kostova

Liby

Stephenson

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Extremely potent triterpenoid inducers of the phase 2 response: Correlations of protection against oxidant and inflammatory stress

Dinkova‐Kostova

Liby

Stephenson

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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510

471

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“…Drugs CDDO-Im, LG100268, and vorinostat were synthesized as previously described (21)(22)(23)(24), and LG101506 was synthesized by J-Star Research. Carboplatin and paclitaxel (C/P) were provided by the Drug Synthesis and Chemistry Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis of the NCI.…”

Section: Methodsmentioning

confidence: 99%

The Rexinoids LG100268 and LG101506 Inhibit Inflammation and Suppress Lung Carcinogenesis in A/J Mice

Cao

Royce

Risingsong

et al. 2016

Cancer Prevention Research

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LG101506 was originally synthesized to overcome some of the undesirable side effects of rexinoids. We compared the anticarcinogenic action of LG101506 and LG100268 and for the first time showed that both drugs are useful for prevention of lung cancer in A/J mice. These molecules markedly reduced tumor number, tumor size, and total tumor burden, when chronically administered to A/J mice that had been initiated with the mutagenic carcinogen, vinyl carbamate. Moreover, LG100268 synergized with the histone deacetylase inhibitor, vorinostat, for prevention of experimental lung cancer and enhanced the effect of carboplatin/paclitaxel for treatment of experimental lung cancer. Both rexinoids diminished the percentage of high-grade, highly malignant adenocarcinomas found at autopsy. In cell culture studies, the rexinoids exhibited potent anti-inflammatory properties at nanoMolar concentrations. These drugs suppressed the ability of lipopolysaccharide to stimulate the synthesis and secretion of nitric oxide and inflammatory cytokines and chemokines, such as IL6, IL1b, CXCL2, and CSF3, in macrophage-like RAW264.7 cells. The present results suggest that LG100268, LG101506, or a related rexinoid may have useful clinical applications in the field of oncology. Cancer Prev Res; 9(1);

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“…Based on our earlier structure-activity relationship studies showing that a cyano enone in ring A and an enone in ring C are essential for the extremely high potency of CDDO (15)(16)(17), we hypothesized that the entire triterpenoid skeleton may not be necessary for inducer potency. Therefore, we designed and synthesized tricyclic compounds having the same A, B, and C rings as CDDO (27,28).…”

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An Exceptionally Potent Inducer of Cytoprotective Enzymes

Dinkova‐Kostova

Talalay

Sharkey

et al. 2010

Journal of Biological Chemistry

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The Keap1/Nrf2/ARE pathway controls a network of cytoprotective genes that defend against the damaging effects of oxidative and electrophilic stress, and inflammation. Induction of this pathway is a highly effective strategy in combating the risk of cancer and chronic degenerative diseases, including atherosclerosis and neurodegeneration. An acetylenic tricyclic bis(cyano enone) bearing two highly electrophilic Michael acceptors is an extremely potent inducer in cells and in vivo. We demonstrate spectroscopically that both cyano enone functions of the tricyclic molecule react with cysteine residues of Keap1 and activate transcription of cytoprotective genes. Novel monocyclic cyano enones, representing fragments of rings A and C of the tricyclic compound, reveal that the contribution to inducer potency of the ring C Michael acceptor is much greater than that of ring A, and that potency is further enhanced by spatial proximity of an acetylenic function. Critically, the simultaneous presence of two cyano enone functions in rings A and C within a rigid three-ring system results in exceptionally high inducer potency. Detailed understanding of the structural elements that contribute to the reactivity with the protein sensor Keap1 and to high potency of induction is essential for the development of specific and selective lead compounds as clinically relevant chemoprotective agents.

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A novel dicyanotriterpenoid, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-onitrile, active at picomolar concentrations for inhibition of nitric oxide production

Cited by 134 publications

References 13 publications

Extremely potent triterpenoid inducers of the phase 2 response: Correlations of protection against oxidant and inflammatory stress

Extremely potent triterpenoid inducers of the phase 2 response: Correlations of protection against oxidant and inflammatory stress

The Rexinoids LG100268 and LG101506 Inhibit Inflammation and Suppress Lung Carcinogenesis in A/J Mice

An Exceptionally Potent Inducer of Cytoprotective Enzymes

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