Silibinin Schiff Base Derivatives Counteract CCl4-Induced Acute Liver Injury by Enhancing Anti-Inflammatory and Antiapoptotic Bioactivities
Rong Xu,1,* Siyan Qiu,1,* Jie Zhang,1 Xiaoli Liu,1 Ling Zhang,1 Haizhu Xing,1 Min You,1 Man Wang,1 Yuting Lu,1 Peng Zhang,1 Jing Zhu1,2 1Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine...
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| Format: | Article |
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Dove Medical Press
2022-05-01
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| Series: | Drug Design, Development and Therapy |
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| Online Access: | https://www.dovepress.com/silibinin-schiff-base-derivatives-counteract-ccl4-induced-acute-liver--peer-reviewed-fulltext-article-DDDT |
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| author | Xu R Qiu S Zhang J Liu X Zhang L Xing H You M Wang M Lu Y Zhang P Zhu J |
| author_facet | Xu R Qiu S Zhang J Liu X Zhang L Xing H You M Wang M Lu Y Zhang P Zhu J |
| author_sort | Xu R |
| collection | DOAJ |
| description | Rong Xu,1,* Siyan Qiu,1,* Jie Zhang,1 Xiaoli Liu,1 Ling Zhang,1 Haizhu Xing,1 Min You,1 Man Wang,1 Yuting Lu,1 Peng Zhang,1 Jing Zhu1,2 1Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China; 2Department of Neurology and Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA*These authors contributed equally to this workCorrespondence: Jing Zhu, Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Department of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, People’s Republic of China, Tel +86-15895975410, Email 830640@njucm.edu.cnBackground: Silibinin (Sil), a flavonoid lignan-like natural compound derived from milk thistle seeds, has been used to treat hepatic diseases, including early-phase hepatocirrhosis and fatty liver, for many years. However, its poor water solubility limits its gastrointestinal absorption and bioavailability. It clinical use has been limited due to its slow onset of action. Faced with this problem, research on the derivatives of silibinin has been receiving much attention.Purpose: A series of silibinin derivatives with good biosafety and higher hepatoprotective activity were obtained by a safe, efficient and green chemical synthesis method.Patients and Methods: First, the carbonyl group in the structure of silibinin was used to obtain silibinin Schiff base derivatives by dehydration condensation with the carboxyl group in the sulfur-containing amino acid. Next, relevant experiments were performed to characterize the structure, physical form and solubility of the derivatives. Then, toxicity tests of the derivatives were performed in LO-2 cells and SD rats to evaluate their biosafety. Finally, the anti-inflammatory and antiapoptotic activities were observed using a carbon tetrachloride (CCl4)-induced acute liver injury model in C57BL/6J mice using silibinin as a control.Results: The studies showed that SS and ST behaved as amorphous substances and showed a significant increase in solubility compared to silibinin. These two derivatives showed low toxicity in biosafety tests and higher bioactivity (anti-inflammatory and anti-apoptotic) than silibinin against acute liver injury induced by CCl4.Conclusion: Two silibinin derivatives (SS and ST) obtained by the Schiff base reaction improved the solubility of the silibinin parent nucleus in biological media with the help of the hydrophilic and amorphous morphology of the ligand. The low toxicity in vivo and in vitro ensures the biosafety of the derivatives. The hepatoprotective activity (anti-inflammatory and anti-apoptotic) was significantly improved compared to silibinin.Keywords: silibinin, sulfur-containing amino acid, Schiff base, solubility, inflammation, apoptosis |
| first_indexed | 2024-04-12T15:33:49Z |
| format | Article |
| id | doaj.art-c57a5838fedc4c678758629394967fdd |
| institution | Directory Open Access Journal |
| issn | 1177-8881 |
| language | English |
| last_indexed | 2024-04-12T15:33:49Z |
| publishDate | 2022-05-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | Drug Design, Development and Therapy |
| spelling | doaj.art-c57a5838fedc4c678758629394967fdd2022-12-22T03:27:00ZengDove Medical PressDrug Design, Development and Therapy1177-88812022-05-01Volume 161441145675305Silibinin Schiff Base Derivatives Counteract CCl4-Induced Acute Liver Injury by Enhancing Anti-Inflammatory and Antiapoptotic BioactivitiesXu RQiu SZhang JLiu XZhang LXing HYou MWang MLu YZhang PZhu JRong Xu,1,* Siyan Qiu,1,* Jie Zhang,1 Xiaoli Liu,1 Ling Zhang,1 Haizhu Xing,1 Min You,1 Man Wang,1 Yuting Lu,1 Peng Zhang,1 Jing Zhu1,2 1Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China; 2Department of Neurology and Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA*These authors contributed equally to this workCorrespondence: Jing Zhu, Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Department of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, People’s Republic of China, Tel +86-15895975410, Email 830640@njucm.edu.cnBackground: Silibinin (Sil), a flavonoid lignan-like natural compound derived from milk thistle seeds, has been used to treat hepatic diseases, including early-phase hepatocirrhosis and fatty liver, for many years. However, its poor water solubility limits its gastrointestinal absorption and bioavailability. It clinical use has been limited due to its slow onset of action. Faced with this problem, research on the derivatives of silibinin has been receiving much attention.Purpose: A series of silibinin derivatives with good biosafety and higher hepatoprotective activity were obtained by a safe, efficient and green chemical synthesis method.Patients and Methods: First, the carbonyl group in the structure of silibinin was used to obtain silibinin Schiff base derivatives by dehydration condensation with the carboxyl group in the sulfur-containing amino acid. Next, relevant experiments were performed to characterize the structure, physical form and solubility of the derivatives. Then, toxicity tests of the derivatives were performed in LO-2 cells and SD rats to evaluate their biosafety. Finally, the anti-inflammatory and antiapoptotic activities were observed using a carbon tetrachloride (CCl4)-induced acute liver injury model in C57BL/6J mice using silibinin as a control.Results: The studies showed that SS and ST behaved as amorphous substances and showed a significant increase in solubility compared to silibinin. These two derivatives showed low toxicity in biosafety tests and higher bioactivity (anti-inflammatory and anti-apoptotic) than silibinin against acute liver injury induced by CCl4.Conclusion: Two silibinin derivatives (SS and ST) obtained by the Schiff base reaction improved the solubility of the silibinin parent nucleus in biological media with the help of the hydrophilic and amorphous morphology of the ligand. The low toxicity in vivo and in vitro ensures the biosafety of the derivatives. The hepatoprotective activity (anti-inflammatory and anti-apoptotic) was significantly improved compared to silibinin.Keywords: silibinin, sulfur-containing amino acid, Schiff base, solubility, inflammation, apoptosishttps://www.dovepress.com/silibinin-schiff-base-derivatives-counteract-ccl4-induced-acute-liver--peer-reviewed-fulltext-article-DDDTsilibininsulfur-containing amino acidschiff basesolubilityinflammationapoptosis |
| spellingShingle | Xu R Qiu S Zhang J Liu X Zhang L Xing H You M Wang M Lu Y Zhang P Zhu J Silibinin Schiff Base Derivatives Counteract CCl4-Induced Acute Liver Injury by Enhancing Anti-Inflammatory and Antiapoptotic Bioactivities Drug Design, Development and Therapy silibinin sulfur-containing amino acid schiff base solubility inflammation apoptosis |
| title | Silibinin Schiff Base Derivatives Counteract CCl4-Induced Acute Liver Injury by Enhancing Anti-Inflammatory and Antiapoptotic Bioactivities |
| title_full | Silibinin Schiff Base Derivatives Counteract CCl4-Induced Acute Liver Injury by Enhancing Anti-Inflammatory and Antiapoptotic Bioactivities |
| title_fullStr | Silibinin Schiff Base Derivatives Counteract CCl4-Induced Acute Liver Injury by Enhancing Anti-Inflammatory and Antiapoptotic Bioactivities |
| title_full_unstemmed | Silibinin Schiff Base Derivatives Counteract CCl4-Induced Acute Liver Injury by Enhancing Anti-Inflammatory and Antiapoptotic Bioactivities |
| title_short | Silibinin Schiff Base Derivatives Counteract CCl4-Induced Acute Liver Injury by Enhancing Anti-Inflammatory and Antiapoptotic Bioactivities |
| title_sort | silibinin schiff base derivatives counteract ccl4 induced acute liver injury by enhancing anti inflammatory and antiapoptotic bioactivities |
| topic | silibinin sulfur-containing amino acid schiff base solubility inflammation apoptosis |
| url | https://www.dovepress.com/silibinin-schiff-base-derivatives-counteract-ccl4-induced-acute-liver--peer-reviewed-fulltext-article-DDDT |
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