Pimarane cyclooxygenase 2 (COX-2) inhibitor and its structure–activity relationship

Suh, Young‐Ger; Kim, Young‐Ho; Park, Mi-Hyoun; Choi, Younghoon; Lee, Hye Kyung; Moon, Joon‐Kwan; Min, Kyung Hoon; Shin, Dongyun; Cho, Jungsook; Park, Ok-Hui; Jeon, Raok; Park, Hyung-Sup; Kang, Soon-Ah

doi:10.1016/s0960-894x(01)00004-x

Cited by 28 publications

(13 citation statements)

References 10 publications

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“…Pimaric acid and levopimaric acid exerted inhibitory action on the aggregation of rabbit platelet [1] while salvipimarone showed antituberculous activity [2]. In addition, acanthoic acid and a series Tirapelli/Ambrosio/da Costa/de Oliveira of its analogues have been discovered as novel cyclooxygenase-2 inhibitors [3].…”

Section: Introductionmentioning

confidence: 99%

Evidence for the Mechanisms Underlying the Effects of Pimaradienoic Acid Isolated from the Roots of <i>Viguiera arenaria </i>on Rat Aorta

et al. 2003

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The present study examines the effects of the diterpene ent-pimara-8(14),15-dien-19-oic acid (PA) on rat thoracic aorta. PA (10^–5, 3 × 10^–5 and 10^–4 mol/l) caused concentration-dependent inhibition of phenylephrine (Phe)-induced contraction in either endothelium-intact or endothelium-denuded aortic rings. PA attenuated the contraction induced by CaCl₂ in Ca²⁺-free solution containing Phe (10^–7 mol/l) or KCl (30 mmol/l). This diterpene did not interfere with Ca²⁺ release from intracellular stores mediated by either Phe (10^–6 mol/l) or caffeine (30 mmol/l). PA (10^–6 to 3 × 10^–4 mol/l) concentration dependently relaxed Phe-pre-contracted rings with intact (92.64 ± 7.60%) or denuded endothelium (98.82 ± 1.56%). Pre-incubation of denuded aortic rings with N^G-nitro-L-arginine methyl ester (10^–4 mol/l), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (10^–6 mol/l) or indomethacin (10^–5 mol/l) reduced PA-induced relaxation (percentage of relaxation: 77.50 ± 3.95, 78.56 ± 2.81, 77.11 ± 6.22, respectively). However, the relaxant responses induced by PA on Phe-pre-contracted rings were unaffected by tetraethylammonium (1 and 5 mmol/l). PA also relaxed KCl-pre-contracted rings with intact (97.44 ± 3.66%) or denuded endothelium (95.95 ± 3.72%). Collectively, these results support the notion that the effects elicited by PA on vascular smooth muscle are endothelium-independent and involve extracellular Ca²⁺ influx blocked. In addition, PA effects are partly dependent on the release of nitric oxide from the vascular smooth muscle through an activation of guanylyl cyclase-dependent mechanism and are related to the release of metabolites derived from the arachidonic acid pathway. Finally, our results demonstrated that the PA relaxant action is not related with the opening of potassium (K⁺) channels.

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Section: Introductionmentioning

confidence: 99%

Evidence for the Mechanisms Underlying the Effects of Pimaradienoic Acid Isolated from the Roots of <i>Viguiera arenaria </i>on Rat Aorta

et al. 2003

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“…The structure‐activity studies of acanthoic acid (AA) have revealed that C4 modification provides significantly enhanced COX‐2 inhibitory activity and selectivity. ( 22 ) EAA has a more extended linker between C4 and the carboxyl group compared to AA. The in vitro COX inhibitory activities of AA and its analog, EAA, are summarized in Table 1.…”

Section: Resultsmentioning

confidence: 99%

“…( 20,21 ) Moreover, AA exhibits COX‐2 inhibitory activity, although the inhibitory potency was less than stellar. ( 22 ) To improve the biological activity of the parent molecule, a series of analogs has been developed on the basis of the structure‐activity relationship. Some of these analogs exhibited greater COX‐2 inhibitory activity and selectivity than AA.…”

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confidence: 99%

“…Some of these analogs exhibited greater COX‐2 inhibitory activity and selectivity than AA. ( 22 ) In the present study, we demonstrate that one of these new COX‐2 inhibitors, referred to as enoic acanthoic acid (EAA; 4‐[1,4a,7‐trimethyl‐7‐vinyl‐1,2,3,4,4a,6,7,8,8a,9,10,10a‐dodecahydro‐phenanthren‐1‐yl]‐but‐2‐enoic acid), exhibits potent antiangiogenic and antitumor activities in vivo .…”

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confidence: 99%

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Potent inhibition of in vivo angiogenesis and tumor growth by a novel cyclooxygenase‐2 inhibitor, enoic acanthoic acid

et al. 2007

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Recent studies have shown that cyclooxygenase-2 is crucially involved in angiogenesis. In fact, several specific cyclooxygenase-2 inhibitors suppress angiogenesis in vivo, suggesting that cyclooxygenase-2 is a promising target for the treatment of angiogenesis-related diseases. In the present study we investigate the activity of a new cyclooxygenase-2 inhibitor, enoic acanthoic acid (EAA), which was synthesized from the known natural cyclooxygenase-2 inhibitor, acanthoic acid ( C yclooxygenases (COXs) are key enzymes catalyzing the conversion of arachidonic acid to prostaglandins (PGs), which play a critical role in multiple physiological and pathological processes.(1,2) COX-1 is constitutively expressed in most tissues and is responsible for maintaining gastric and renal protection and platelet function. (3,4) In contrast, COX-2 is induced by various inflammatory and mitogenic stimuli such as growth factors, cytokines, and tumor promoters, and this enzyme is related to the formation of carcinogens, tumor promotion, apoptosis inhibition, angiogenesis development, and metastasis. (5)(6)(7)(8) In addition to these two enzymes, COX-3, which is a COX-1 splicing variant, was recently identified and plays a role in fever and pain processes. Recent studies suggest a critical role for COX-2 in angiogenesis. COX-2 induces the expression of angiogenic growth factors (vascular endothelial growth factor [VEGF] and basic fibroblast growth factor [bFGF]) and their receptors (KDR, Flt-1), and this enzyme regulates the expression of proteolytic enzymes (matrix metalloproteinase [MMP]) and adhesion molecules (E-cadherin). (10)(11)(12)(13) Furthermore, specific COX-2 inhibitors, including celecoxib, block both the production of angiogenic factors and the migration of vascular endothelial cells and thus decrease tumor growth.

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“…This natural product is biologically attractive because it has been shown to exhibit an excellent suppression of the major proinflammatory cytokines, interleukin-1 (IL-1␤) and tumor necrosis factor-␣ (TNF-␣), by human monocytes/macrophages and in the sera of silicosis, fulminant hepatitis, and cirrhosis models (Kang et al, 1996). Acanthoic acid has been reported to inhibit cyclooxygenase-2 and NOS-2 activity (Suh et al, 2001). In addition, oral administration of acanthoic acid to mice significantly reduced the granuloma formation Fig.…”

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Selective Activation of Liver X Receptors by Acanthoic Acid-Related Diterpenes

Través¹,

Hortelano²,

Zeini³

et al. 2007

Mol Pharmacol

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Terpenoids constitute a large family of natural steroids that are widely distributed in plants and insects. We investigated the effects of a series of diterpenes structurally related to acanthoic acid in macrophage functions. We found that diterpenes with different substitutions at the C4 position in ring A are potent activators of liver X receptors (LXR␣ and LXR␤) in both macrophage cell lines from human and mouse origin and primary murine macrophages. Activation of LXR by these diterpenes was evaluated in transient transfection assays and gene expression analysis of known LXR-target genes, including the cholesterol transporters ABCA1 and ABCG1, the sterol regulatory element-binding protein 1c, and the apoptosis inhibitor of macrophages (Sp␣). Moreover, active diterpenes greatly stimulated cholesterol efflux from macrophages. It is interesting that these diterpenes antagonize inflammatory gene expression mainly through LXR-dependent mechanisms, indicating that these compounds can activate both LXR activation and repression functions. Stimulation of macrophages with acanthoic acid diterpenes induced LXR-target gene expression and cholesterol efflux to similar levels observed with synthetic agonists

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Pimarane cyclooxygenase 2 (COX-2) inhibitor and its structure–activity relationship

Cited by 28 publications

References 10 publications

Evidence for the Mechanisms Underlying the Effects of Pimaradienoic Acid Isolated from the Roots of <i>Viguiera arenaria </i>on Rat Aorta

Evidence for the Mechanisms Underlying the Effects of Pimaradienoic Acid Isolated from the Roots of <i>Viguiera arenaria </i>on Rat Aorta

Potent inhibition of in vivo angiogenesis and tumor growth by a novel cyclooxygenase‐2 inhibitor, enoic acanthoic acid

Selective Activation of Liver X Receptors by Acanthoic Acid-Related Diterpenes

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