Design and synthesis of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid, a novel and highly active inhibitor of nitric oxide production in mouse macrophages

Honda, Tadashi; Rounds, Barbie Ann V.; Gribble, Gordon W.; Suh, Nanjoo; Wang, Yongping; Sporn, Michael B.

doi:10.1016/s0960-894x(98)00479-x

Cited by 177 publications

(170 citation statements)

References 9 publications

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“…Triterpenoids were synthesized as previously described (10,18,19). The various amide and imidazolide derivatives were synthesized by the condensation of CDDO acid chloride with the respective amines or imidazoles using previously published methods (10).…”

Section: Chemicalsmentioning

confidence: 99%

Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes

Yates

Tauchi

Katsuoka

et al. 2007

Molecular Cancer Therapeutics

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Synthetic triterpenoids have been developed, which are potent inducers of cytoprotective enzymes and inhibitors of inflammation, greatly improving on the weak activity of naturally occurring triterpenoids. An imidazolide triterpenoid derivative, 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im or TP235), has been previously shown to potently protect against hepatic tumorigenesis, acting in part by inducing cytoprotective genes through Keap1-Nrf2-antioxidant response element (ARE) signaling. In these studies, the pharmacodynamic activity of CDDO-Im is characterized in two distinct lines of ARE reporter mice and by measuring increases in Nqo1 transcript levels as a marker of cytoprotective gene induction. Oral administration of CDDO-Im induces AREregulated cytoprotective genes in many tissues in the mouse, including liver, lung, kidney, intestines, brain, heart, thymus, and salivary gland. CDDO-Im induces Nqo1 RNA transcripts in some organs at doses as low as 0.3 Mmol/kg body weight (orally). A structure activity evaluation of 15 additional triterpenoids (a) confirmed the importance of Michael acceptor groups on both the A and C rings, (b) showed the requirement for a nitrile group at C-2 of the A ring, and (c) indicated that substituents at C-17 dramatically affected pharmacodynamic action in vivo. In addition to CDDO-Im, other triterpenoids, particularly the methyl ester CDDO-Me (TP155) and the dinitrile TP225, are extremely potent inducers of cytoprotective genes in mouse liver, lung, small intestine mucosa, and cerebral cortex. This pharmacodynamic characterization highlights the chemopreventive promise of several synthetic triterpenoids in multiple target organs. [Mol Cancer Ther 2007;6(1):154 -62]

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Section: Chemicalsmentioning

confidence: 99%

Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes

Yates

Tauchi

Katsuoka

et al. 2007

Molecular Cancer Therapeutics

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265

232

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Kalra

Knatko

Zhang

et al. 2012

Cancer Prevention Research

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Chronic treatment with azathioprine, a highly effective anti-inflammatory and immunosuppressive agent, profoundly increases the risk for development of unusually aggressive cutaneous squamous cell carcinoma. Its ultimate metabolite, 6-thioguanine (6-TG) nucleotide, is incorporated in DNA of skin cells, and upon exposure to UVA radiation, causes oxidative stress, followed by damage of DNA and associated proteins. The acetylenic tricyclic bis(cyano enone) TBE-31 is a strong inhibitor of inflammation and a potent inducer of the Keap1/Nrf2/ARE pathway, which orchestrates the expression of a large network of cytoprotective genes. We now report that long-term (five days per week for four weeks) topical daily applications of small (200 nmol) quantities of TBE-31 cause a robust systemic induction of the Keap1/Nrf2/ ARE pathway and decreases the 6-TG incorporation in DNA of skin, blood, and liver of azathioprine-treated mice, indicating extraordinary bioavailability and efficacy. In addition, TBE-31, at nanomolar concentrations, protects cells with 6-TG in their genomic DNA against oxidative stress caused by UVA radiation through induction of the Keap1/Nrf2/ARE pathway. At the same 6-TG DNA levels, Keap1-knockout cells, in which the pathway is constitutively upregulated, are highly resistant to UVA radiation-induced oxidative stress. The protective effects of both the Keap1-knockout genotype and TBE-31 are completely lost in the absence of transcription factor Nrf2. Our findings suggest that compounds of this kind are excellent candidates for mechanism-based chemoprotective agents against conditions in which oxidative stress and inflammation underlie disease pathogenesis. Moreover, their potential skin patch incorporation for transdermal delivery is an exciting possibility. Cancer Prev Res; 5(7); 973-81. Ó2012 AACR.

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“…[1][2][3][4][5][6][7][8][9][10][11] Defects in apoptosis pathways make important contributions to chemoresistance, 1,2,10 suggesting a need to restore apoptosis sensitivity in AML or to identify alternative pathways for apoptosis induction. Most chemotherapeutic drugs currently available induce apoptosis via a pathway involving mitochondria, which release apoptogenic proteins into the cytosol, leading to activation of members of the caspase family of cell death proteases.…”

Section: Introductionmentioning

confidence: 99%

Synthetic triterpenoids activate a pathway for apoptosis in AML cells involving downregulation of FLIP and sensitization to TRAIL

et al. 2003

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Acute myelogenous leukemia (AML) remains a deadly disease for most adult patients, due primarily to the emergence of chemoresistant cells. Defects in apoptosis pathways make important contributions to chemoresistance, suggesting a need to restore apoptosis sensitivity or to identify alternative pathways for apoptosis induction. Triterpenoids represent a class of naturally occurring and synthetic compounds with demonstrated antitumor activity, including 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) and its methyl ester (CDDO-m). We explored the effects of CDDO and CDDO-m in vitro on established AML cell lines (HL-60, U937, AML-2) and on freshly isolated AML blasts. CDDO and CDDO-m reduced the viability of all AML cell lines tested in a dose-dependent manner, with effective doses for killing 50% of cells (ED 50 ) within 48 h of B1 and 0.5 lM, respectively. CDDO or CDDO-m also induced substantial increases in cell death in five out of 10 samples of primary AML blasts. Cell death induced by CDDO and CDDO-m was attributed to apoptosis, based on characteristic cell morphology and evidence of caspase activation. Immunoblot analysis demonstrated proteolytic processing of caspase-3, -7, and -8, but not caspase-9, suggesting the involvement of the 'extrinsic' pathway, linked to apoptosis induction by TNF-family death receptors. Accordingly, CDDO and CDDO-m induced concentration-dependent reductions in the levels of FLIP protein, an endogenous antagonist of caspase-8, without altering the levels of several other apoptosis-relevant proteins. Reductions in FLIP were rapid, detectable within 3 h after exposure of AML cell lines to CDDO or CDDO-m. CDDO and CDDO-m also sensitized two of four leukemia lines to TRAIL, a TNF-family death ligand. The findings suggest that synthetic triterpenoids warrant further investigation in the treatment of AML, alone or in combination with TRAIL or other immunebased therapies.

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Design and synthesis of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid, a novel and highly active inhibitor of nitric oxide production in mouse macrophages

Cited by 177 publications

References 9 publications

Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes

Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes

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

Synthetic triterpenoids activate a pathway for apoptosis in AML cells involving downregulation of FLIP and sensitization to TRAIL

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