- 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
-
New derivatives with electron-withdrawing substituents at the C-2 position of 3-oxoolean-1-en-28-oic acid were synthesized. Among them, 2- cyano-3,12-dioxoleam-1,9-dien-28-oic acid (CDDO) was 400 times more potent than previous compounds we have made as an inhibitor of production of nitric oxide induced by interferon γ in mouse macrophages (IC50, 0.4 nM). The potency of CDDO was similar to that of dexamethasone, although CDDO does not act through the glucocorticoid receptor.
- Honda, Tadashi,Rounds, BarbieAnn V.,Gribble, Gordon W.,Suh, Nanjoo,Wang, Yongping,Sporn, Michael B.
-
-
Read Online
- C17 POLAR-SUBSTITUTED HETEROAROMATIC SYNTHETIC TRITERPENOIDS AND METHODS OF USE THEREOF
-
Disclosed herein are compounds of the formula: (I) wherein the variables are defined herein. Also provided are pharmaceutical compositions thereof. In some aspects, the compounds and compositions provided herein may be used as antioxidant inflammation modulators. In some aspects, the present disclosure provides methods wherein the compounds and composition described herein are used for the treatment of diseases and disorders, including those associated with inflammation and cancer.
- -
-
Page/Page column 58; 70; 98
(2021/01/29)
-
- Oleanolic acid derivative with conjugated diene structure C ring and preparation method and application thereof
-
The invention belongs to the field of medicinal chemistry, and particularly relates to an oleanolic acid derivative with a conjugated diene structure C ring and a preparation method and application thereof. In particular, the invention also provides a pharmaceutical composition comprising an effective amount of the derivative or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; moreover, the derivative or the pharmaceutically acceptable salt thereof can be used for treating inflammation-related diseases and has antitumor activity, and the safety of the compound is improved or equivalent.
- -
-
Paragraph 0105-0108
(2020/07/21)
-
- Improvement of synthesis method of 2-cyano-3,12-dioxo oleanane-1,9 (11)-diene-28-carboxylic acid
-
The invention discloses a synthesis technology of 2-cyano-3,12-dioxo oleanane-1,9 (11)-diene-28-carboxylic acid (CDDO), and relates to the technical field of medicines and chemical engineering. The CDDO compounds (CDDOs) are semisynthetic tritererpenoids with the highest known anticancer and anti-inflammatory activity at present and are compounds with broad development and application prospects. The synthesis method of the CDDO reported in the literature at present has the defects of being long in path, fussy in post-treatment, unfriendly to environment and high in cost. The method is a simplified six-step synthesis path, the post-treatment and purification processes are simple, the cost is relatively low, the yield is greatly improved and an important basis is provided for industrial production and subsequent scientific research. The formula is as shown in the specification.
- -
-
-
- Design and Synthesis of Irreversible Analogues of Bardoxolone Methyl for the Identification of Pharmacologically Relevant Targets and Interaction Sites
-
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.
- Wong, Michael H. L.,Bryan, Holly K.,Copple, Ian M.,Jenkins, Rosalind E.,Chiu, Pak Him,Bibby, Jaclyn,Berry, Neil G.,Kitteringham, Neil R.,Goldring, Christopher E.,O'Neill, Paul M.,Park, B. Kevin
-
p. 2396 - 2409
(2016/04/10)
-
- Therapeutic compounds and methods of use
-
Compounds and methods useful for chemopreventative treatment of diseases such as cancer, Alzheimer's disease, Parkinson's disease, inflammatory bowel diseases, and multiple sclerosis.
- -
-
-
- DDQ-promoted dehydrogenation from natural rigid polycyclic acids or flexible alkyl acids to generate lactones by a radical ion mechanism
-
A novel and facile DDQ-mediated dehydrogenation from natural rigid polycyclic acids or flexible alkyl acids to generate lactones is described. The formation of lactones proceeds by a radical ion mechanism, which has been established by DPPH?-mediated chemical identification, ESR spectroscopy and an enol intermediate trapping.
- Ding, Ye,Huang, Zhangjian,Yin, Jian,Lai, Yisheng,Zhang, Shibo,Zhang, Zhiguo,Fang, Lei,Peng, Sixun,Zhang, Yihua
-
supporting information; experimental part
p. 9495 - 9497
(2011/10/31)
-
- Synthetic oleanane and ursane triterpenoids with modified rings A and C: A series of highly active inhibitors of nitric oxide production in mouse macrophages
-
We have designed and synthesized 16 new olean- and urs-1-en-3-one triterpenoids with various modified rings C as potential antiinflammatory and cancer chemopreventive agents and evaluated their inhibitory activities against production of nitric oxide induced by interferon-γ in mouse macrophages. This investigation revealed that 9(11)-en-12-one and 12-en-11-one functionalities in ring C increase the potency by about 2-10 times compared with the original 12-ene. Subsequently, we have designed and synthesized novel olean- and urs-1-en-3-one derivatives with nitrile and carboxyl groups at C-2 in ring A and with 9(11)-en-12-one and 12-en-11-one functionalities in ring C. Among them, we have found that methyl 2-cyano-3, 12-dioxooleana-1,9(11)-dien-28-oate (25), 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) (26), and methyl 2-carboxy-3,12-dioxooleana-1,9(11)-dien-28-oate (29) have extremely high potency (IC50 = 0.1 nM level). Their potency is similar to that of dexamethasone although they do not act through the glucocorticoid receptor. Overall, the combination of modified rings A and C increases the potency by about 10 000 times compared with the lead compound, 3-oxooleana-1,12-dien-28-oic acid (8) (IC50 = 1 μM level). The selected oleanane triterpenoid, CDDO (26), was found to be a potent, multifunctional agent in various in vitro assays and to show antiinflammatory activity against thioglycollate-interferon-γ-induced mouse peritonitis.
- Honda,Rounds,Bore,Finlay,Favaloro Jr.,Suh,Wang,Sporn,Gribble
-
p. 4233 - 4246
(2007/10/03)
-
