Synthetic Oleanane and Ursane Triterpenoids with Modified Rings A and C:  A Series of Highly Active Inhibitors of Nitric Oxide Production in Mouse Macrophages

Honda, Tadashi; Rounds, BarbieAnn V.; Bore, Lothar; Finlay, Heather J.; Favaloro, Frank G.; Suh, Nanjoo; Wang, Yongping; Sporn, Michael B.; Gribble, Gordon W.

doi:10.1021/jm0002230

Cited by 218 publications

(166 citation statements)

References 22 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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508

471

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“…The cytotoxicity and antiinflammatory activity of CDDO-Me and related compounds are due to the 2-cyano group and the 1-en-3-one and 9-en-12-one functionalities in the A-and C-rings, respectively. 7, 8 We also showed that the glycyrrhetinic acid analog methyl 2-cyano-3,11-dioxo-18β-olean-1,12-dien-30-oate (β-CDODA-Me) and the corresponding 18α derivative (α-CDODA-Me) which contain 2-cyano-1-en-3-one and 12-en-11-one functionalities in their A-and C-rings, respectively, activated PPARγ and were also highly cytotoxic in colon cancer cells. 10 Similar results were obtained for the betulinic acid derivatives containing a 2-cyano-1 en-3-one function.…”

Section: Abstract Glycyrrhetinate Analogs; Growth Inhibition; Bladdermentioning

confidence: 99%

Structure-dependent inhibition of bladder and pancreatic cancer cell growth by 2-substituted glycyrrhetinic and ursolic acid derivatives

Chadalapaka

Jutooru

McAlees³

et al. 2008

Bioorganic & Medicinal Chemistry Letters

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Derivatives of oleanolic acid, ursolic acid and glycyrrhetinic acid substituted with electron withdrawing groups at the 2-position in the A-ring which also contains a 1-en-3-one structure are potent inhibitors of cancer cell growth. In this study, we have compared the effects of several 2-substituted analogs of triterpenoid acid methyl esters derived from ursolic and glycyrrhetinic acid on proliferation of KU7 and 253JB-V bladder and Panc-1 and Panc-28 pancreatic cancer cells. The results show that the 2-cyano and 2-trifluoromethyl derivatives were the most active compounds. The glycyrrhetinic acid derivatives with the rearranged C-ring containing the 9(11)-en-12-one structure were generally more active than the corresponding 12-en-11-one isomers. However, differences in growth inhibitory IC 50 values were highly variable and dependent on the 2-substitutent (CN vs. CF 3 ) and cancer cell context. Keywords glycyrrhetinate analogs; growth inhibition; bladder cancer; pancreatic cancerPentacyclic triterpenoid acids such as betulinic acid, oleanolic acid, ursolic acid, and glycyrrhetinic acid are phytochemicals that have been extensively used in traditional medicines for treatment of a wide variety of human ailments. 1-4 Most of these compounds exhibit antiinflammatory and anticarcinogenic activities as well as a large number of compound-specific effects. For example, the major bioactive component of licorice extracts is glycyrrhizic acid glycoside which is readily hydrolyzed to glycyrrhetinic acid and these extracts/compounds possess anti-inflammatory, antiviral and endocrine activities. 4 All of these triterpenoid acids have been used as building blocks for the synthesis of more active analogs. Oleanolic acid has been converted into 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO), the Corresponding author: Stephen Safe, Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX , Email: ssafe@cvm.tamu.edu. * Both the authors contributed equally to this study.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. corresponding methyl ester (CDDO-Me) and other structurally-related analogs, and these compounds are potent anticancer agents. 5-9 These synthetic triterpenoids activate the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) 9 and also induce several other responses including apoptosis in various cancer cell lines. The cytotoxicity and antiinflammatory activity of CDDO-Me and related compounds are due to the 2-cyano group and the 1-en-3-one and 9-en-12-one functionalities in the A-and C-rings, respectively....

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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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Synthetic Oleanane and Ursane Triterpenoids with Modified Rings A and C: A Series of Highly Active Inhibitors of Nitric Oxide Production in Mouse Macrophages

Cited by 218 publications

References 22 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

Structure-dependent inhibition of bladder and pancreatic cancer cell growth by 2-substituted glycyrrhetinic and ursolic acid derivatives

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

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