An efficient synthesis of methyl 2-cyano-3,12-dioxoursol-1,9-dien-28-oate (CDDU-methyl ester): analogues, biological activities, and comparison with oleanolic acid derivatives

Fu, Liangfeng; Lin, Qian; Liby, Karen T.; Sporn, Michael B.; Gribble, Gordon W.

doi:10.1039/c4ob00679h

Cited by 12 publications

(6 citation statements)

References 32 publications

(50 reference statements)

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“…Acrylodan (Anaspec) was solubilized in acetonitrile, with the stock concentration determined by absorbance at 393 nm on dilution into methanol (ε = 18,483 M −1 cm −1 per manufacturer’s data sheet). Compounds were obtained as follows: compounds 1–5 , gift from Gordon Gribble and Michael Sporn (Dartmouth University); 45–50 compounds 6–8 and 15 were provided by the Developmental Therapeutics Program (DTP/NIH); compounds 9–14 and 16–17 were synthesized as described in the Supporting Information; estrone ( 15 ) was purchased from Cayman Chemical (Ann Arbor, MI); cyclohexenone ( 18 ) was purchased from Alfa Aesar (Ward Hill, MA). The GSSFLC NH2 peptide for fluorescent labeling with acrylodan was synthesized by Sigma–Genosys (The Woodlands, TX, USA) in the Pepscreen format.…”

Section: Methodsmentioning

confidence: 99%

Synthetic Triterpenoid Inhibition of Human Ghrelin O-Acyltransferase: The Involvement of a Functionally Required Cysteine Provides Mechanistic Insight into Ghrelin Acylation

et al. 2017

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The peptide hormone ghrelin plays a key role in regulating hunger and energy balance within the body. Ghrelin signaling presents a promising and unexploited target for development of small-molecule therapeutics to treat obesity, diabetes, and other health conditions. Inhibition of ghrelin O-acyltransferase (GOAT), which catalyzes an essential octanoylation step in ghrelin maturation, offers a potential avenue for controlling ghrelin signaling. Through screening a small molecule library, we have identified a class of synthetic triterpenoids that efficiently inhibit ghrelin acylation by the human isoform of GOAT (hGOAT). These compounds function as covalent reversible inhibitors of hGOAT, providing the first evidence for involvement of a nucleophilic cysteine residue in substrate acylation by a MBOAT family acyltransferase. Surprisingly, the mouse form of GOAT does not exhibit susceptibility to cysteine modifying electrophiles revealing an important distinction in the activity and behavior between these closely related GOAT isoforms. This study establishes these compounds as potent small molecule inhibitors of ghrelin acylation and provides a foundation for the development of novel hGOAT inhibitors as therapeutics targeting diabetes and obesity.

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Section: Methodsmentioning

confidence: 99%

Synthetic Triterpenoid Inhibition of Human Ghrelin O-Acyltransferase: The Involvement of a Functionally Required Cysteine Provides Mechanistic Insight into Ghrelin Acylation

et al. 2017

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“…For example, glycyrrhetinic acid has been used for the synthesis of CDDO analogs (soloxolones), which significantly improved cytotoxicity [ 11 , 12 , 13 ], and recently the effective inhibition by methyl soloxolone TGF-β-driven EMT of tumor cells was shown [ 14 ]. The same ursane-type analogs were obtained by an oxidative ozonolysis-mediated C-ring enone formation with a potency of approximately five-fold less than the corresponding oleanolic acid derivatives [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Novel A-Ring Chalcone Derivatives of Oleanolic and Ursolic Amides with Anti-Proliferative Effect Mediated through ROS-Triggered Apoptosis

Khusnutdinova

Petrova

Zileeva

et al. 2021

IJMS

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A series of A-ring modified oleanolic and ursolic acid derivatives including C28 amides (3-oxo-C2-nicotinoylidene/furfurylidene, 3β-hydroxy-C2-nicotinoylidene, 3β-nicotinoyloxy-, 2-cyano-3,4-seco-4(23)-ene, indolo-, lactame and azepane) were synthesized and screened for their cytotoxic activity against the NCI-60 cancer cell line panel. The results of the first assay of thirty-two tested compounds showed that eleven derivatives exhibited cytotoxicity against cancer cells, and six of them were selected for complete dose–response studies. A systematic study of local SARs has been carried out by comparative analysis of potency distributions and similarity relationships among the synthesized compounds using network-like similarity graphs. Among the oleanane type triterpenoids, C2-[4-pyridinylidene]-oleanonic C28-morpholinyl amide exhibited sub-micromolar potencies against 15 different tumor cell lines and revealed particular selectivity for non-small cell lung cancer (HOP-92) with a GI50 value of 0.0347 μM. On the other hand, superior results were observed for C2-[3-pyridinylidene]-ursonic N-methyl-piperazinyl amide 29, which exhibited a broad-spectrum inhibition activity with GI50 < 1 μM against 33 tumor cell lines and <2 μM against all 60 cell lines. This compound has been further evaluated for cell cycle analysis to decipher the mechanism of action. The data indicate that compound 29 could exhibit both cytostatic and cytotoxic activity, depending on the cell line evaluated. The cytostatic activity appears to be determined by induction of the cell cycle arrest at the S (MCF-7, SH-SY5Y cells) or G0/G1 phases (A549 cells), whereas cytotoxicity of the compound against normal cells is nonspecific and arises from apoptosis without significant alterations in cell cycle distribution (HEK293 cells). Our results suggest that the antiproliferative effect of compound 29 is mediated through ROS-triggered apoptosis that involves mitochondrial membrane potential depolarization and caspase activation.

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“…In recent reports, a large number of oleanolic acid derivatives were designed, synthesized, and evaluated for antitumor activity, in particular as potential anti-hepatic carcinoma and anti-fibrotic agents, which had made outstanding progresses [21,23]. The hepatoprotective activity of OA could be due to its anti-oxidant and anti-inflammatory effects, as well as its effect on drug-metabolizing enzymes [13].…”

Section: Discussionmentioning

confidence: 99%

“…Oleanolic acid (OA), an oleanane-type triterpenoid that belongs to the pentacyclic triterpene family, is well known for protective activity for the treatment of liver injury, chronic liver fibrosis, cirrhosis, and hepatic carcinoma [13]. In recent reports, due to its favorable properties, OA had been used as a base molecule for further synthetic modifications to develop lead compounds, in particular as potential anti-tumor and anti-fibrotic agents [14,15,16,17,18,19,20,21,22,23]. In the previous report, the lead compound TOA exhibited promising anticancer effects in vitro and in vivo [24,25,26].…”

Section: Introductionmentioning

confidence: 99%

Ligustrazine-Oleanolic Acid Glycine Derivative, G-TOA, Selectively Inhibited the Proliferation and Induced Apoptosis of Activated HSC-T6 Cells

et al. 2016

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Hepatic fibrosis is a naturally occurring wound-healing reaction, with an imbalance of extracellular matrix (ECM) during tissue repair response, which can further deteriorate to hepatocellular carcinoma without timely treatment. Inhibiting activated hepatic stellate cell (HSC) proliferation and inducing apoptosis are the main methods for the treatment of liver fibrosis. In our previous study, we found that the TOA-glycine derivative (G-TOA) had exhibited more significant inhibitory activity against HepG2 cells and better hydrophilicity than TOA, ligustrazine (TMP), and oleanolic acid (OA). However, inhibiting activated HSC proliferation and inducing apoptosis by G-TOA had not been reported. In this paper, the selective cytotoxicity of G-TOA was evaluated on HSC-T6 cells and L02 cells, and apoptosis mechanisms were explored. It was found that G-TOA could selectively inhibit the proliferation of activated HSC-T6 cells, induce morphological changes, early apoptosis, and mitochondrial membrane potential depolarization, increase intracellular free calcium levels, downregulate the expression of NF-κB/p65 and COX-2 protein, and decrease the ratio of Bcl-2/Bax, thereby inducing HSC-T6 cell apoptosis. Thence, G-TOA might be a potential antifibrosis agent for the therapy of hepatic fibrosis, provided that it exerts anti-fibrosis effects on activated HSC-T6 cells.

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An efficient synthesis of methyl 2-cyano-3,12-dioxoursol-1,9-dien-28-oate (CDDU-methyl ester): analogues, biological activities, and comparison with oleanolic acid derivatives

Cited by 12 publications

References 32 publications

Synthetic Triterpenoid Inhibition of Human Ghrelin O-Acyltransferase: The Involvement of a Functionally Required Cysteine Provides Mechanistic Insight into Ghrelin Acylation

Synthetic Triterpenoid Inhibition of Human Ghrelin O-Acyltransferase: The Involvement of a Functionally Required Cysteine Provides Mechanistic Insight into Ghrelin Acylation

Novel A-Ring Chalcone Derivatives of Oleanolic and Ursolic Amides with Anti-Proliferative Effect Mediated through ROS-Triggered Apoptosis

Ligustrazine-Oleanolic Acid Glycine Derivative, G-TOA, Selectively Inhibited the Proliferation and Induced Apoptosis of Activated HSC-T6 Cells

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