高级检索

水溶性冰片磷酸酯前药的设计、合成及生物活性评价

张璐璐, 孙美玲, 秦亚娟, 厉廷有

张璐璐,孙美玲,秦亚娟,等. 水溶性冰片磷酸酯前药的设计、合成及生物活性评价[J]. 中国药科大学学报,2024,55(3):375 − 380. DOI: 10.11665/j.issn.1000-5048.2023060703
引用本文: 张璐璐,孙美玲,秦亚娟,等. 水溶性冰片磷酸酯前药的设计、合成及生物活性评价[J]. 中国药科大学学报,2024,55(3):375 − 380. DOI: 10.11665/j.issn.1000-5048.2023060703
ZHANG Lulu, SUN Meiling, QIN Yajuan, et al. Design, synthesis and biological activity evaluation of water-soluble borneol phosphate prodrug[J]. J China Pharm Univ, 2024, 55(3): 375 − 380. DOI: 10.11665/j.issn.1000-5048.2023060703
Citation: ZHANG Lulu, SUN Meiling, QIN Yajuan, et al. Design, synthesis and biological activity evaluation of water-soluble borneol phosphate prodrug[J]. J China Pharm Univ, 2024, 55(3): 375 − 380. DOI: 10.11665/j.issn.1000-5048.2023060703

水溶性冰片磷酸酯前药的设计、合成及生物活性评价

基金项目: 国家自然科学基金项目 (No.81573280; No.81803349)
详细信息
    通讯作者:

    厉廷有: Tel:025-86868474 E-mail:l_tingyou@njmu.edu.cn

  • 中图分类号: R914.4;R965

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

Funds: This study was supported by the National Natural Science Foundation of China (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。

    Abstract:

    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.

  • Figure  1.   Chemical structure of BP-3

    Figure  2.   Synthetic route of compound BP-3

    Figure  3.   Percentages of borneol released from BP-3 into mouse plasma ($ \bar{x} $± sn = 3)

    Figure  4.   Continuous administration of ice phosphate in the mice model of transient middle cerebral artery occlusion (tMCAO) ($ \bar{x} $± s, n = 6-10)

    A: Schematic diagram of BP-3 administration in the tMCAO/R mouse model; B: Representative map of brain TTC staining in mice; C: Statistical analysis of brain infarct areas in mice *P < 0.05 vs vehicle group

    Figure  5.   BP-3 reversed the loss of Nissl bodies in the mice model of tMCAO(Nissl staining)

    A: 10×plain optical imaging image of the striatal region on the left, magnified on the right; B: 10×plain optical imaging image of the cortical region on the left, magnified on the right

    Figure  6.   BP-3 improved the motor ability of the mice model of tMCAO ($ \bar{x} $± s, n = 6-10)

    A: Statistical analysis of grip strength ; B: Statistical analysis of residence time of mice on the swivel bar; C: Statistical analysis of grip strength test of mice; D: Statistical analysis of residence time of mice on the swivel bar#P<0.05 vs sham group;*P<0.05,**P<0.001,***P<0.001 vs vehicle group

  • [1]

    Wu SM, Wu B, Liu M, et al. Stroke in China: advances and challenges in epidemiology, prevention, and management[J]. Lancet Neurol, 2019, 18(4): 394-405.

    [2]

    Xu J, Wang AX, Meng X, et al. Edaravone dexborneol versus edaravone alone for the treatment of acute ischemic stroke: a phase Ⅲ, randomized, double-blind, comparative trial[J]. Stroke, 2021, 52(3): 772-780.

    [3]

    Yu B, Yao Y, Zhang XF, et al. Synergic neuroprotection between Ligusticum chuanxiong hort and borneol against ischemic stroke by neurogenesis via modulating reactive astrogliosis and maintaining the blood-brain barrier[J]. Front Pharmacol, 2021, 12: 666790.

    [4]

    Xu J, Wang YL, Wang AX, et al. Safety and efficacy of Edaravone Dexborneol versus edaravone for patients with acute ischaemic stroke: a phase Ⅱ, multicentre, randomised, double-blind, multiple-dose, active-controlled clinical trial[J]. Stroke Vasc Neurol, 2019, 4(3): 109-114.

    [5]

    Ji X, Wang J, Zhang L, et al. Application of phosphates and phosphonates prodrugs in drug research and development[J]. Acta Pharm Sin, 2013, 48(5): 621-634.

    [6] Li ZL, Zheng ZJ, Li XD, et al. Study on the effect of borneol on scutellarin permeabilization in vitro blood-retinal barrier[J]. Mod Tradit Chin Med Mater Med World Sci Technol(世界科学技术 中医药现代化), 2022, 24(11): 4260-4268.
    [7]

    Zhang SS, Asghar S, Yang L, et al. Borneol and poly (ethylene glycol) dual modified BSA nanoparticles as an itraconazole vehicle for brain targeting[J]. Int J Pharm, 2020, 575: 119002.

    [8]

    Li Y, Ren MH, Wang JJ, et al. Progress in borneol intervention for ischemic stroke: a systematic review[J]. Front Pharmacol, 2021, 12: 606682.

    [9]

    Wang JY, Dong XY, Yu ZW, et al. Borneol inhibits CD4+T cells proliferation by down-regulating miR-26a and miR-142-3p to attenuate asthma[J]. Int Immunopharmacol, 2021, 90: 107223.

    [10]

    Liu SY, Long Y, Yu S, et al. Borneol in cardio-cerebrovascular diseases: pharmacological actions, mechanisms, and therapeutics[J]. Pharmacol Res, 2021, 169: 105627.

    [11]

    Dong TW, Chen N, Ma X, et al. The protective roles of L-borneolum, D-borneolum and synthetic borneol in cerebral ischaemia via modulation of the neurovascular unit[J]. Biomedecine Pharmacother, 2018, 102: 874-883.

    [12]

    Zhang WW, Wen JX, Jiang YX, et al. L-Borneol ameliorates cerebral ischaemia by downregulating the mitochondrial calcium uniporter-induced apoptosis cascade in pMCAO rats[J]. J Pharm Pharmacol, 2021, 73(2): 272-280.

    [13]

    Xie Q, Li JX, Dong TW, et al. Neuroprotective effects of synthetic borneol and natural borneol based on the neurovascular unit against cerebral ischaemic injury[J]. J Pharm Pharmacol, 2022, 74(2): 236-249.

    [14]

    Zhang YL, Liu SY, Wan JY, et al. Preparation, characterization and in vivo study of borneol-baicalin-liposomes for treatment of cerebral ischemia-reperfusion injury[J]. Int J Nanomedicine, 2020, 15: 5977-5989.

图(6)
计量
  • 文章访问数:  95
  • HTML全文浏览量:  21
  • PDF下载量:  22
  • 被引次数: 0
出版历程
  • 收稿日期:  2023-06-06
  • 网络出版日期:  2024-06-24
  • 刊出日期:  2024-06-24

目录

    /

    返回文章
    返回
    x 关闭 永久关闭