Discovery of novel limonin derivatives as potent anti-inflammatory and analgesic agents

Wang, Shao-Chi; Yang, Yu-Chu; Liu, Jing; Jiang, Aidou; Chu, Zhaoxing; Chen, Siying; Gong, Guoqing; He, Guangwei; Xu, Yungen; Zhu, Qihua

doi:10.1016/s1875-5364(18)30052-9

Cited by 13 publications

(17 citation statements)

References 25 publications

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“…The Citrus reticulata semen (CRS) is the dry, mature seed of C. reticulata Blanco and its cultivated varieties and has been consumed as a traditional Chinese medicine for centuries with its properties including qi regulation, knot dispersion, pain relief, and so on. , However, compared with Citri Reticulatae Pericarpium, the chemical composition of CRS has not been fully studied; most Citrus seeds are discarded rather than being exploited, resulting in resource waste and environmental pollution. Therefore, the study of its chemical components is of great significance for its further utilization in medicine and raw materials.…”

Section: Introductionmentioning

confidence: 99%

Supercritical CO₂ Fluid Extraction for the Identification of Compounds from Citrus reticulata Semen by Ultra-High-Performance Liquid Chromatography Combined with Q-Exactive Orbitrap Tandem Mass Spectrometry

et al. 2020

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A rapid and simple method based on the coupling of supercritical fluid extraction and ultra-high-performance liquid chromatography combined with Q-Exactive Orbitrap tandem mass spectrometry (SFE-UHPLC-Q-Exactive Orbitrap-MS) detection for the identification of compounds from Citrus reticulata semen (CRS) was developed for the first time in this study. Through the optimization of the SFE parameters including extractive pressure, extractive temperature, and time, most of the compounds were successfully extracted at 50 °C, 33 MPa, and 2 h without an entraining agent, among which 32 compounds were successfully identified. Moreover, the operating conditions of UHPLC-Q-Exactive Orbitrap-MS were also optimized for the analysis of the SFE extracts, and the extracts in the CRS showed good separation performance in 20 min. A total of 28 compounds from the SFE extract were identified by comparing the standard sample together with full scan and related literature data, among which esters and flavonoids were the major compounds identified in the CRS extracts. In addition, 2 phenols, 2 aldehydes, 2 triterpenes, and 5 other compounds were identified. The SFE-UHPLC-Q-Exactive Orbitrap-MS method was successfully validated and applied for the identification of compounds from the CRS.

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Section: Introductionmentioning

confidence: 99%

Supercritical CO₂ Fluid Extraction for the Identification of Compounds from Citrus reticulata Semen by Ultra-High-Performance Liquid Chromatography Combined with Q-Exactive Orbitrap Tandem Mass Spectrometry

et al. 2020

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“…Moreover, subsequent research had found that 4-atom (-NH-CO-CH 2 -CH 2 -)-length linker between C(7)-position and tertiary nitrogen atom and the oxygen bridge between C(14) and C(15) of limonin were beneficial in their anti-inflammatory activity. Therefore, it was considered that the water-soluble derivatives of limonin modified by structure could play a better anti-inflammatory effect [51,52]. In addition, limonin glucoside can decrease several circulating markers of hepatic inflammation, and effectively reduce cell proliferation and inflammation [53].…”

Section: Pharmacologymentioning

confidence: 99%

Limonin: A Review of Its Pharmacology, Toxicity, and Pharmacokinetics

et al. 2019

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Limonin is a natural tetracyclic triterpenoid compound, which widely exists in Euodia rutaecarpa (Juss.) Benth., Phellodendron chinense Schneid., and Coptis chinensis Franch. Its extensive pharmacological effects have attracted considerable attention in recent years. However, there is no systematic review focusing on the pharmacology, toxicity, and pharmacokinetics of limonin. Therefore, this review aimed to provide the latest information on the pharmacology, toxicity, and pharmacokinetics of limonin, exploring the therapeutic potential of this compound and looking for ways to improve efficacy and bioavailability. Limonin has a wide spectrum of pharmacological effects, including anti-cancer, anti-inflammatory and analgesic, anti-bacterial and anti-virus, anti-oxidation, liver protection properties. However, limonin has also been shown to lead to hepatotoxicity, renal toxicity, and genetic damage. Moreover, limonin also has complex impacts on hepatic metabolic enzyme. Pharmacokinetic studies have demonstrated that limonin has poor bioavailability, and the reduction, hydrolysis, and methylation are the main metabolic pathways of limonin. We also found that the position and group of the substituents of limonin are key in affecting pharmacological activity and bioavailability. However, some issues still exist, such as the mechanism of antioxidant activity of limonin not being clear. In addition, there are few studies on the toxicity mechanism of limonin, and the effects of limonin concentration on pharmacological effects and toxicity are not clear, and no researchers have reported any ways in which to reduce the toxicity of limonin. Therefore, future research directions include the mechanism of antioxidant activity of limonin, how the concentration of limonin affects pharmacological effects and toxicity, finding ways to reduce the toxicity of limonin, and structural modification of limonin—one of the key methods necessary to enhance pharmacological activity and bioavailability.

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“…In order to improve its efficacy and water-solubility, the creation of novel limonin derivatives by structural modification has become one of the key focus areas. In our previous studies, analogues were obtained by introducing various tertiary amines onto the C (7)-position [ 10 , 19 ] A ring [ 20 , 21 ] of limonin or deoxylimonin, which possessed favorable physicochemical and water-soluble properties. Furthermore, some of them exhibited analgesic activities that were more potent than those of aspirin, and anti-inflammatory activities that were stronger than those of naproxen.…”

Section: Introductionmentioning

confidence: 99%

Preclinical Drug Pharmacokinetic, Tissue Distribution and Excretion Profiles of the Novel Limonin Derivate HY-071085 as an Anti-Inflammatory and Analgesic Candidate in Rats and Beagle Dogs

et al. 2022

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Limonin is one of the research hotspots in natural drug development. However, its low solubility in water leads to poor oral bioavailability, discouraging the further study of its potential as a candidate compound. In order to overcome this limitation, and to enhance its biological activities, a novel limonin derivative—HY-071085—was synthesized by structural modification, and has exhibited strong anti-inflammatory and analgesic activity. In order to achieve a thorough understanding of the biological actions of HY-071085 in vivo, this study evaluated the pharmacokinetics and bioavailability of HY-071085 in rats and beagle dogs, and the distribution and excretion in rats. Using ultra-high-performance liquid chromatography-tandem mass spectrometry, the kinetic profiles of HY-071085 in the plasma of healthy rats and beagle dogs after a single gavage, repeated gavages and the intravenous injection of HY-071085 were studied. The tissue distribution (heart, liver, spleen, lung, kidney, gastric tissue, intestine, brain, skin, testis, ovary and womb) and excretion of HY-071085 were also studied. These results showed that HY-071085 has nonlinear dynamic characteristics in rat and beagle dog plasma. It was found that the plasma concentrations of HY-071085 in female rats were significantly higher than those in male rats after a single oral administration. There were gender differences in the kinetic behavior of HY-071085 in rats; however, there was no difference identified in dogs. HY-071085 was mainly eliminated as metabolites in rats, and was distributed in most of the tissues except the brain, with the highest content being in the gastric tissue and intestinal arease, followed by the liver, spleen, fat, lung, kidney, ovary and heart. The bioavailability of HY-071085 in male and female rats was 2.8% and 10.8%, respectively, and was about 13.1% in beagle dogs. The plasma protein binding rate of HY-071085 in rats, beagle dogs and humans ranged from 32.9% to 100%, with obvious species differences. In conclusion, our study provides useful information regarding the absorption, distribution and excretion of HY-071085, which will provide a good base for the study of the mechanism of its biological effects.

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Discovery of novel limonin derivatives as potent anti-inflammatory and analgesic agents

Cited by 13 publications

References 25 publications

Supercritical CO₂ Fluid Extraction for the Identification of Compounds from Citrus reticulata Semen by Ultra-High-Performance Liquid Chromatography Combined with Q-Exactive Orbitrap Tandem Mass Spectrometry

Supercritical CO₂ Fluid Extraction for the Identification of Compounds from Citrus reticulata Semen by Ultra-High-Performance Liquid Chromatography Combined with Q-Exactive Orbitrap Tandem Mass Spectrometry

Limonin: A Review of Its Pharmacology, Toxicity, and Pharmacokinetics

Preclinical Drug Pharmacokinetic, Tissue Distribution and Excretion Profiles of the Novel Limonin Derivate HY-071085 as an Anti-Inflammatory and Analgesic Candidate in Rats and Beagle Dogs

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Discovery of novel limonin derivatives as potent anti-inflammatory and analgesic agents

Cited by 13 publications

References 25 publications

Supercritical CO2 Fluid Extraction for the Identification of Compounds from Citrus reticulata Semen by Ultra-High-Performance Liquid Chromatography Combined with Q-Exactive Orbitrap Tandem Mass Spectrometry

Supercritical CO2 Fluid Extraction for the Identification of Compounds from Citrus reticulata Semen by Ultra-High-Performance Liquid Chromatography Combined with Q-Exactive Orbitrap Tandem Mass Spectrometry

Limonin: A Review of Its Pharmacology, Toxicity, and Pharmacokinetics

Preclinical Drug Pharmacokinetic, Tissue Distribution and Excretion Profiles of the Novel Limonin Derivate HY-071085 as an Anti-Inflammatory and Analgesic Candidate in Rats and Beagle Dogs

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Supercritical CO₂ Fluid Extraction for the Identification of Compounds from Citrus reticulata Semen by Ultra-High-Performance Liquid Chromatography Combined with Q-Exactive Orbitrap Tandem Mass Spectrometry

Supercritical CO₂ Fluid Extraction for the Identification of Compounds from Citrus reticulata Semen by Ultra-High-Performance Liquid Chromatography Combined with Q-Exactive Orbitrap Tandem Mass Spectrometry