Novotný J, Janůsová B, Novotný M, Hrabálek A, Vávrová K
Centre for New Antivirals and Antineoplastics, Department of Inorganic and Organic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic.
Skin Pharmacol Physiol. 2009;22(1):22-30. doi: 10.1159/000183923. Epub 2008 Dec 17.
Stratum corneum ceramides are major determinants of skin barrier function. Although their physiological and pathological role has been widely investigated, to date no structure-activity relationships have been established. In this study, a series of short-chain ceramide analogues with polar head structure identical to ceramide NS, a sphingosine length of 12 carbons and an acyl chain length of 2-12 carbons was synthesized. Their effect on skin permeability was evaluated using porcine skin and two model drugs, theophylline and indomethacin, and compared to that of a physiological ceramide NS. The results showed that the ceramide chain length was crucial for their barrier properties. Ceramides with a 4- to 8-carbon acyl chain were able to increase skin permeability for both drugs up to 10.8 times with maximum effect at a 6-carbon acyl chain. No increase in permeability was found for ceramide analogues with 2- and 12-carbon acyl chains and ceramide NS. The same relationships were obtained for skin concentrations of the model drugs. The relationship between ceramide acyl chain length and its ability to perturb skin barrier showed striking similarity to the behavior of short-chain ceramides in sphingomyelin/phospholipid membranes and confirmed that short-chain ceramides do not act as natural ceramides and their use as experimental tools should be cautious.
角质层神经酰胺是皮肤屏障功能的主要决定因素。尽管其生理和病理作用已得到广泛研究，但迄今为止尚未建立构效关系。在本研究中，合成了一系列短链神经酰胺类似物，其极性头部结构与神经酰胺NS相同，鞘氨醇长度为12个碳，酰基链长度为2至12个碳。使用猪皮和两种模型药物茶碱和吲哚美辛评估了它们对皮肤通透性的影响，并与生理性神经酰胺NS进行了比较。结果表明，神经酰胺的链长对其屏障特性至关重要。具有4至8个碳酰基链的神经酰胺能够使两种药物的皮肤通透性提高至10.8倍，在酰基链为6个碳时效果最佳。对于具有2个和12个碳酰基链的神经酰胺类似物以及神经酰胺NS，未发现通透性增加。模型药物的皮肤浓度也呈现相同的关系。神经酰胺酰基链长度与其扰乱皮肤屏障能力之间的关系与短链神经酰胺在鞘磷脂/磷脂膜中的行为表现出惊人的相似性，并证实短链神经酰胺并非天然神经酰胺，应谨慎将其用作实验工具。
