Fenchone Derivatives as a Novel Class of CB2 Selective Ligands: Design, Synthesis, X-ray Structure and Therapeutic Potential

Smoum, Reem; Haj, Christeene; Hirsch, Shira; Nemirovski, Alina; Yekhtin, Zhannah; Bogoslavsky, Benny; Bakshi, Gaganjyot Kaur; Chourasia, Mukesh; Gallily, Ruth; Tam, Joseph; Mechoulam, Raphael

doi:10.3390/molecules27041382

Cited by 6 publications

(3 citation statements)

References 30 publications

(51 reference statements)

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“…CB2R are predominantly located in the periphery, and their stimulation has beneficial effects in chronic inflammatory and neuropathic pain. Following CB2R stimulation, an increase in the production of IL-10, a cytokine with anti-inflammatory action, was observed [ 33 , 34 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

Fennel Essential Oil as a Complementary Therapy in the Management of Diabetes

Ștefănescu,

Ősz,

Pintea

et al. 2023

Pharmaceutics

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Diabetes is a serious pathology that affects a significant number of people worldwide. Its progression is rapid and leads to serious complications if glycemic control is missing. The micro and macrovascular complications of diabetes produce disabilities over time that affect the daily lives of patients. The major challenge of diabetes therapy is to reach a stable glycemic state and to delay the onset of specific complications. Aromatherapy is considered an alternative or complementary therapy, but in recent years, there has been a tendency to overuse essential oils. The present study was designed to evaluate and compare the effects produced by the topical and oral administration of fennel essential oil to diabetic rats. Eighteen compounds in fennel essential oil were identified by gas chromatography–mass spectrometry (GC-MS) analysis. The major compounds were trans-anethole (64.6%) and fenchone (24.5%). The in vivo study revealed that after a four-week treatment with fennel essential oil, the rats’ glycemic levels were significantly reduced (p ≤ 0.05). Furthermore, there were no differences between the two routes of administration. In addition, an ex vivo study underlined the potential effect of this essential oil in the prevention of cataract formation.

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Section: Discussionmentioning

confidence: 99%

Fennel Essential Oil as a Complementary Therapy in the Management of Diabetes

Ștefănescu,

Ősz,

Pintea

et al. 2023

Pharmaceutics

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“…HU308, fenchones 1D and 1B were synthesized and characterized as previously reported [ 8 , 9 ] and formulated fresh before use in a solvent comprised of ethanol, cremophor (Kolliphor EL, Sigma-Aldrich, St Louis, MI, USA), and saline at 1:1:18 ratio, respectively. Initially, the required amount of 1D/1B was dissolved in ethanol, followed by the addition of cremophor with vigorous mechanical agitation to form a viscous micelle solution.…”

Section: Methodsmentioning

confidence: 99%

A Fenchone Derivative Effectively Abrogates Joint Damage Following Post-Traumatic Osteoarthritis in Lewis Rats

Carmon

Smoum

Farhat

et al. 2022

Cells

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Background: In a previous report, we have identified the CB2 agonist HU308 to possess a beneficial effect in preventing age and trauma-induced osteoarthritis (OA) in mice. The effects of HU308 were largely related to the capacity of this compound to induce cartilage anabolism which was largely related to the CREB/SOX9 axis, as well as to pro-survival and pro-proliferative hallmarks of articular cartilage. Here, we utilized novel cannabinoid-fenchone CB2 agonists (1B, 1D), which were previously reported to render anti-inflammatory effects in a zymosan model. Methods: Initially, we assessed the selectivity of CB2 using a Gs-protein receptor cAMP potency assay, which was also validated for any antagonistic effects to the Gi-protein receptor cAMP pathway. Based on EC50 values, 1D was selected for a zymosan inflammatory pain model. Next, 1D was administered in two doses intra-articularly (IA), in a post-traumatic medial meniscal tear (MMT, Lewis rats) model, and compared to sham, vehicle, and fibroblast growth factor (FGF18) positive controls. The histopathological assessment was carried out according to the Osteoarthritis Research Society International (OARSI) guidelines for rat models following 28 days post-MMT. Results: The G protein receptor assays confirmed that both 1B and 1D possess CB2 agonistic effects in cell lines and in chondrocytes. Administering CB2 antagonists to 25 mg/kg 1D in a paw inflammatory pain model abolished its anti-swelling effect while partially abolishing its analgesic effects. Using an MMT model, 24 µg 1D, when administered IA, exhibited reduced cartilage damage. Similarly, this dose of 1D exhibited a 30% improvement in cartilage degeneration (zonal/total tibial scores) and lesion depth ratios (44%), comparable to the FGF18 positive control. Synovitis scores remained unaffected and histopathologic evaluation of subchondral bone damage did not suggest that this treatment changed the load-bearing ability of the rats. Contrary to the anabolic effect of FGF18, synovial inflammation was observed and accompanied by increased osteophyte size. Conclusion: The structural histopathological analysis supports a disease-modifying effect of IA-administered 1D compound without any deleterious effects on the joint structure.

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“…According to other studies, essential fennel oil is rich in chemicals, including α-pinene, fenchone, anethole, and estragol [ 12 , 21 , 22 , 23 ]. Fenchone is an aromatic mono-terpene [ 24 ] with a medicinal function for treating tuberculosis after some chemical modifications [ 25 ]. In addition, essential fennel oil has antifungal and acaricidal activity [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

Phenolics and Volatile Compounds of Fennel (Foeniculum vulgare) Seeds and Their Sprouts Prevent Oxidative DNA Damage and Ameliorates CCl4-Induced Hepatotoxicity and Oxidative Stress in Rats

et al. 2022

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Researchers recently focused on studying the nutritional and functional qualities of sprouts generated from seeds. The current study investigated the total phenolic content (TPC), total flavonoids (TF), total flavonols (TFL), antioxidant activity (AOA), specific phenolic acids, and volatile chemicals in fennel seeds (FS) and fennel seed sprouts (FSS). The oxidative DNA damage prevention activity of selected FS and FSS extracts against DNA was examined. Consequently, the antioxidative stress potential of FS and FSS extracts at 300 and 600 mg kg−1 on CCl4-induced hepatotoxicity and oxidative stress in rats weas investigated. The liver’s functions and oxidative stress biomarkers in rat blood were examined. FSS exhibited rich phytochemical content such as TPC, TF, TFL, and AOA with altered phenolics and volatiles. HPLC identified nineteen compounds of phenolic acids and their derivatives in FS. Thirteen phenolics and six flavonoids were predominantly identified as Vanillic acid and Kaempferol, respectively. GC-MS analysis identified fifty and fifty-one components in FS and FSS, respectively. The predominant component was Benzene, [1-(2-propenyloxy)-3-butenyl] (trans-Anethole) (38.41%), followed by trans-Anethole (Benzene, 1-methoxy-4-(2-propenyl)) (23.65%), Fenchone (11.18%), and 1,7-Octadiene, 2-methyl-6-methylene- Cyclohexene (7.17%). Interestingly, α-Pinene, Fenchone, trans-Anethole (Benzene, 1-methoxy-4-(2-propenyl)), 4-Methoxybenzaldehyde (4-Anisaldehyde), Benzeneacetic acid, α-hydroxy-4-methoxy, and Nonacosane contents were increased. While Dillapiole, 7-Octadecenoic acid, and methyl ester were newly identified and quantified in FSS. The oxidative DNA damage prevention capability of FSS and FS extracts indicated remarkable DNA protection. Administrating FS and FSS extracts at 300 and 600 mg kg−1 ameliorated AST, ALT, and ALP, as well as GSH, CAT, MDA, and SOD, in a dose-dependent manner. The most efficient treatment of FS or FSS was using a dose of 600 mg Kg−1, which recorded an improvement rate of 20.77 and 24.17, 20.36 and 24.92, and 37.49 and 37.90% for ALT, AST, and ALP, respectively. While an improvement rate of 40.08 and 37.87%, 37.17 and 46.52%, 114.56 and 154.13%, and 66.05 and 69.69% for GSH, DMA, CAT, and SOD compared to the CCl4-group, respectively. The observed protection is associated with increased phenolics and volatiles in F. vulgare. Therefore, FS and FSS are recommended as functional foods with bioactive functionality, health-promoting properties, and desired prevention capabilities that may help prevent oxidative stress-related diseases.

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Fenchone Derivatives as a Novel Class of CB2 Selective Ligands: Design, Synthesis, X-ray Structure and Therapeutic Potential

Cited by 6 publications

References 30 publications

Fennel Essential Oil as a Complementary Therapy in the Management of Diabetes

Fennel Essential Oil as a Complementary Therapy in the Management of Diabetes

A Fenchone Derivative Effectively Abrogates Joint Damage Following Post-Traumatic Osteoarthritis in Lewis Rats

Phenolics and Volatile Compounds of Fennel (Foeniculum vulgare) Seeds and Their Sprouts Prevent Oxidative DNA Damage and Ameliorates CCl4-Induced Hepatotoxicity and Oxidative Stress in Rats

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