Design, synthesis and biological activity evaluation of water-soluble borneol phosphate prodrug
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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.
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Keywords:
- borneol /
- phosphate /
- ischemic stroke /
- improved water solubility
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Figure 4. Continuous administration of ice phosphate in the mice model of transient middle cerebral artery occlusion (tMCAO) ($ \bar{x} $± s, n = 6-10)
A: Schematic diagram of BP-3 administration in the tMCAO/R mouse model; B: Representative map of brain TTC staining in mice; C: Statistical analysis of brain infarct areas in mice *P < 0.05 vs vehicle group
Figure 6. BP-3 improved the motor ability of the mice model of tMCAO ($ \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
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