靶向LAT1的依达拉奉氨基酸衍生物的开发与评价  

Development and evaluation of edaravone amino acid derivatives targeting LAT1

作　　者：陈敏 伍雯 赵彩萍 冉茂婷 张雪梅[3] 邓庆华[2] CHEN Min;WU Wen;ZHAO Caiping(Department of Pharmacy,Chenjiaqiao Hospital of Shapingba District,The Affiliated Hospital of Chongqing Medical and Pharmaceutical College,Chongqing 401331,China;不详)

机构地区：[1]重庆市沙坪坝区陈家桥医院/重庆医药高等专科学校附属医院药剂科,重庆401331 [2]重庆医药高等专科学校药学院(中药学院),重庆401331 [3]昌吉职业技术学院药学与医学技术学院,新疆昌吉831100

出　　处：《中国处方药》2025年第3期17-20,共4页Journal of China Prescription Drug

基　　金：重庆市沙坪坝区科卫联合医学科研项目(2024SQKWLHMS027);重庆市自然科学基金项目(cstc2020jcyj-msxmX0675);“小组团”援疆团队项目(CQYGZXZTYJ02);重庆市沙坪坝区技术创新与应用发展项目(202347)。

摘　　要：目的本研究设计并合成了8种新型依达拉奉(EDA)氨基酸衍生物,旨在利用L型氨基酸转运蛋白(LAT1)的转运机制,实现EDA的脑靶向递送,进而增强其在急性脑卒中(AIS)治疗中的效能。方法本研究通过分子对接技术筛选出具有潜在脑靶向能力的EDA衍生物候选物,重点聚焦于亮氨酸、异亮氨酸、缬氨酸、苯丙氨酸、酪氨酸、色氨酸、甲硫氨酸和组氨酸等氨基酸与EDA的结合。采用酰基化和缩合反应策略合成了上述衍生物,并通过质谱和核磁共振光谱对其进行了结构表征。此外,通过细胞实验评估了所合成衍生物的生物相容性,包括对人肝正常细胞、肝癌细胞和乳腺癌细胞的影响。结果成功合成了5种EDA氨基酸衍生物,其中苯丙氨酸-EDA通过了核磁共振光谱的详细结构鉴定,且分子对接结果显示其对LAT1具有较高的亲和力(-9.5 kcal/mol))。生物安全性实验表明,这些衍生物在不同浓度下对三种细胞系均展现出良好的生物相容性,未观察到显著的细胞毒性。结论本研究首次开发了一系列具有潜在脑靶向能力的EDA氨基酸衍生物,其中部分衍生物展现出优异的生物相容性和合成效率,为AIS治疗提供了新的药物递送策略。未来研究将侧重于这些衍生物的体内药效学和药代动力学评价,以期推动其临床转化。Objective The study designed and synthesized eight novel edaravone(EDA)amino acid derivatives,aiming to leverage the transport mechanism of L-type amino acid transporter 1(LAT1)for targeted delivery of EDA to the brain,thereby enhancing its efficacy in AIS treatment.Methods The study employed molecular docking techniques to identify EDA derivative candidates with potential for brain targeting,focusing on the conjugation of edaravone with leucine,isoleucine,valine,phenylalanine,tyrosine,tryptophan,methionine,and histidine.The derivatives were synthesized via acylation and condensation reactions,and their structures were characterized using mass spectrometry and nuclear magnetic resonance spectroscopy.The biocompatibility of the synthesized derivatives was evaluated through cell experiments involving human normal liver cells,hepatocellular carcinoma cells,and breast cancer cells.Results Five of the EDA amino acid derivatives were successfully synthesized.Among them,phenylalanine-EDA underwent detailed structural confirmation by nuclear magnetic resonance spectroscopy,and molecular docking analysis revealed high affinity for LAT1(-9.5 kcal/mol).Biocompatibility assays confirmed that these derivatives exhibited favorable biocompatibility across various concentrations without inducing significant cytotoxicity against the three cell lines tested.Conclusion The study represents the first development of a series of EDA amino acid derivatives with potential for brain-targeted delivery,showcasing excellent biocompatibility and synthetic efficiency.These findings offer a novel drug delivery strategy for AIS treatment.Future research will focus on evaluating the pharmacodynamics and pharmacokinetics of these derivatives in vivo,with the goal of advancing their clinical translation.

关 键 词：急性脑卒中 依达拉奉 L型氨基酸转运蛋白 生物相容性 脑靶向递送 

分 类 号：R943[医药卫生—药剂学]