Methylation and Esterification of Magnolol for Ameliorating Cutaneous Targeting and Therapeutic Index by Topical Application
Methylation and Esterification of Magnolol for Ameliorating Cutaneous Targeting and Therapeutic Index by Topical Application
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DOI：
10.1007/s11095-016-1953-x
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发表时间：
2016-09-01
影响因子：
3.7
通讯作者：
Fang, Jia-You
中科院分区：
文献类型：
--
作者：
Lin, Chwan-Fwu;Hung, Chi-Feng;Fang, Jia-You
作为阐明结构修饰对皮肤吸收行为影响的持续努力，我们尝试通过甲基化和乙酰化评估厚朴酚的皮肤渗透性。本研究设计并合成了二乙酰厚朴酚和2-O-乙酰基-2'-O-甲基厚朴酚（AMM）。评估针对受刺激的中性粒细胞和角质形成细胞的抗炎活性，以检查类似物的生物活性。使用裸鼠和猪皮肤模型以等摩尔和饱和剂量研究体外皮肤吸收。厚朴酚通常表现出最强的抗炎潜力，其次是二乙酰厚朴酚和AMM。观察到厚朴酚和二乙酰厚朴酚的抗菌活性，但未观察到 AMM 的抗菌活性。二乙酰厚朴酚和AMM进入皮肤后可部分水解为厚朴酚和2-O-甲基厚朴酚。二乙酰厚朴酚的水解速度比AMM快。亲脂性在皮肤吸收中发挥着至关重要的作用，其中AMM表现出最高的皮肤沉积性。 AMM 在裸鼠皮肤内的积累量比厚朴酚和二乙酰厚朴酚高约 2.5 倍。另一方面，甲基化和酯化减少了皮肤的透皮渗透。这导致 AMM 具有卓越的皮肤靶向性。尽管AMM的药理活性较低，但与其他药物相比，AMM的高皮肤吸收和生物转化为2-O-甲基厚朴酚导致了更高的治疗指数（TI，皮肤沉积x炎症抑制百分比）。 AMM在毛囊中的累积量为77.12 nmol/cm(2)，显着高于厚朴酚(44.84 nmol/cm(2))和二乙酰厚朴酚(26.96 nmol/cm(2))。合成类似物对裸鼠皮肤具有耐受性。根据实验结果，我们建议局部应用 AMM 作为治疗皮肤炎症的有效且安全的候选药物。
As a continuing effort to elucidate the impact of structure modification upon cutaneous absorption behavior, we attempted to assess the skin permeation of magnolol by methylation and acetylation.Diacetylmagnolol and 2-O-acetyl-2'-O-methylmagnolol (AMM) were designed and synthesized in this study. The anti-inflammatory activity against stimulated neutrophils and keratinocytes was evaluated to check the bioactivity of the analogues. In vitro skin absorption was investigated using nude mouse and pig skin models at both equimolar and saturated doses.Magnolol generally showed the strongest anti-inflammatory potential, followed by diacetylmagnolol and AMM. The antibacterial activity was observed for magnolol and diacetylmagnolol but not AMM. Diacetylmagnolol and AMM could be partly hydrolyzed to magnolol and 2-O-methylmagnolol after entering the skin. The hydrolysis rate of diacetylmagnolol was faster than that of AMM. The lipophilicity played a crucial role in cutaneous absorption, with AMM exhibiting the highest skin deposition. AMM accumulation within nude mouse skin was about 2.5-fold greater than that of magnolol and diacetylmagnolol. On the other hand, the transdermal penetration across the skin was lessened by methylation and esterification. This led to a superior skin targeting of AMM. Although the pharmacological activity of AMM was low, the high skin uptake and bioconversion into 2-O-methylmagnolol in the skin contributed to a greater therapeutic index (TI, skin deposition x inflammatory inhibition percentage) compared to the others. The accumulation of AMM in the hair follicles was 77.12 nmol/cm(2), which was significantly greater than that with magnolol (44.84 nmol/cm(2)) and diacetylmagnolol (26.96 nmol/cm(2)). The synthetic analogues were tolerable to the nude mouse skin.Based on the experimental results, we may suggest topically applied AMM as a potent and safe candidate for the treatment of cutaneous inflammation.