水溶性冰片磷酸酯前药的设计、合成及生物活性评价  

Design,synthesis and biological activity evaluation of water-soluble borneol phosphate prodrug

作　　者：张璐璐 孙美玲 秦亚娟[1] 厉廷有[1] ZHANG Lulu;SUN Meiling;QIN Yajuan;LI Tingyou(School of Pharmacy,Nanjing Medical University,Nanjing 211166;School of Basic Medical Sciences,Nanjing Medical University,Nanjing 211166,China)

机构地区：[1]南京医科大学药学院,南京211166 [2]南京医科大学基础医学院,南京211166

出　　处：《中国药科大学学报》2024年第3期375-380,共6页Journal of China Pharmaceutical University

基　　金：国家自然科学基金项目(No.81573280,No.81803349)。

摘　　要：对冰片进行结构优化,以改善冰片的溶解性,促进其在脑卒中治疗方面的进一步应用。利用磷酸酯修饰原理,设计并合成冰片前药BP-3。使用蒸发光散射检测器(ELSD)测定BP-3的溶解性,在小鼠血浆中测试原药释放的程度与速度,并在短暂性大脑中动脉闭塞(tMCAO)小鼠模型中评估BP-3的神经保护作用。结果显示,BP-3在20 mg/mL时可以完全溶解于生理盐水;在小鼠血浆中,2 h内释放约40%的冰片;在tMCAO小鼠模型中,TTC染色结果显示BP-3可以有效减少梗死面积;尼氏染色结果表明,BP-3可以改善神经元损伤;握力和抓力测试结果阐明,BP-3可以减少损伤带来的运动能力降低;转棒测试结果证明,BP-3可以促进小鼠运动能力的恢复。BP-3具有良好的水溶性、适宜的原药释放速率以及优异的神经保护作用,具备广阔的药物开发前景。In this study,structural optimization of borneol was carried out to improve their solubility and promote their further application in stroke therapy.BP-3,a prodrug of borneol,was designed and synthesized based on the principle of phosphate modification.The solubility of BP-3 was determined by evaporative light scattering detector(ELSD),and the degree and speed of drug release were tested in mouse plasma,and the neuroprotective effect of BP-3 was evaluated in mouse model of transient middle cerebral artery occlusion(tMCAO).According to the results,BP-3 was completely soluble in saline at 20 mg/mL;in mouse plasma,approximately 40%of the borneol were released within 2 h;in the tMCAO mouse model,TTC staining showed that BP-3 was effective in reducing the infarct area;Nissl staining showed that BP-3 ameliorated the neuronal injury;the grip and grasping strength tests elucidated that BP-3 reduced the damage of sports ability caused by injury;and the rotating rod test proved that BP-3 could promote the recovery of motor ability in mice.BP-3 has good water solubility,suitable drug release rate and excellent neuroprotective effects,and has broad prospects for drug development.

关 键 词：冰片 磷酸酯 缺血性脑卒中 水溶性改善 

分 类 号：R914.4[医药卫生—药物化学] R965[医药卫生—药学]