Jiangsu 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.
Department of Neurology and Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Drug Des Devel Ther. 2022 May 16;16:1441-1456. doi: 10.2147/DDDT.S356847. eCollection 2022.
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.
A series of silibinin derivatives with good biosafety and higher hepatoprotective activity were obtained by a safe, efficient and green chemical synthesis method.
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 (CCl)-induced acute liver injury model in C57BL/6J mice using silibinin as a control.
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 CCl.
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.
水飞蓟宾（Sil）是一种源自奶蓟种子的类黄酮木脂素类天然化合物，多年来一直用于治疗肝脏疾病，包括早期肝硬化和脂肪肝。然而，其较差的水溶性限制了其在胃肠道中的吸收和生物利用度。由于其作用缓慢，其临床应用受到限制。面对这一问题，对水飞蓟宾衍生物的研究受到了广泛关注。
采用安全、高效、绿色的化学合成方法，获得一系列生物安全性好、肝保护活性更高的水飞蓟宾衍生物。
首先，利用水飞蓟宾结构中的羰基与含硫氨基酸的羧基脱水缩合得到水飞蓟宾席夫碱衍生物。然后，对衍生物的结构、物理形态和溶解度进行相关实验。接着，在 LO-2 细胞和 SD 大鼠中进行衍生物的毒性试验，以评估其生物安全性。最后，以水飞蓟宾为对照，采用四氯化碳（CCl）诱导 C57BL/6J 小鼠急性肝损伤模型，观察其抗炎和抗凋亡活性。
研究表明，SS 和 ST 表现为无定形物质，与水飞蓟宾相比，溶解度有显著提高。这两种衍生物在生物安全性试验中表现出低毒性，对 CCl 诱导的急性肝损伤的生物活性（抗炎和抗凋亡）高于水飞蓟宾。
席夫碱反应得到的两种水飞蓟宾衍生物（SS 和 ST）在配体的亲水性和无定形形态的帮助下，提高了水飞蓟宾母体核在生物介质中的溶解度。体内外低毒性保证了衍生物的生物安全性。与水飞蓟宾相比，其肝保护活性（抗炎和抗凋亡）显著提高。
