Dobričić Vladimir, Marković Bojan, Nikolic Katarina, Savić Vladimir, Vladimirov Sote, Čudina Olivera
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11000 Belgrade, Serbia.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11000 Belgrade, Serbia.
Eur J Pharm Sci. 2014 Feb 14;52:95-108. doi: 10.1016/j.ejps.2013.10.017. Epub 2013 Nov 12.
In this paper, twenty-two 17β-carboxamide steroids were synthesized from five corticosteroids (hydrocortisone, prednisolone, methylprednisolone, dexamethasone and betamethasone) in two steps. The first step was periodic acid oxydation of these corticosteroids to corresponding cortienic acids and the second step was amidation of thus obtained cortienic acids with esterified l-amino acids. These compounds are potential soft corticosteroids with local anti-inflammatory activity in the skin. Parallel artificial membrane permeability assay (PAMPA) was applied in order to predict permeability and retention of these compounds in human skin. Comparison of permeability and retention parameters between 17β-carboxamide steroids and corresponding corticosteroids was performed. Compounds with significantly higher retention were identified and the derivative that does not have significantly higher permeability was underlined. Molecular structures of all compounds were optimized by use of Gaussian semiempirical/PM3 method. Geometrical, thermodynamic, physicochemical and electronical molecular parameters of the optimized structures were calculated and quantitative structure-property relationship (QSPR) analysis was performed in order to explain permeability and retention of these compounds. ANN-, PLS- and MLR-QSPR models were created. Quality of these models was evaluated by commonly used statistical parameters and the most reliable models were selected. Analyzing descriptors in the selected models, main molecular properties that influence permeability and retention in the PAMPA artificial membrane were identified. Based on these data, further structural modifications could be applied in order to increase retention without significant increase of permeability, which can positively affect potential local anti-inflammatory activity of these compounds. Selected QSPR models could be used as in silico tool for predicting human skin permeability and retention of novel 17β-carboxamide steroids without performing PAMPA experiments.
本文通过两步反应，从五种皮质类固醇（氢化可的松、泼尼松龙、甲泼尼龙、地塞米松和倍他米松）合成了二十二种17β - 羧酰胺类固醇。第一步是将这些皮质类固醇用高碘酸氧化为相应的皮质烯酸，第二步是将所得的皮质烯酸与酯化的L - 氨基酸进行酰胺化反应。这些化合物是具有皮肤局部抗炎活性的潜在软性皮质类固醇。应用平行人工膜通透性测定法（PAMPA）来预测这些化合物在人皮肤中的通透性和滞留性。对17β - 羧酰胺类固醇与相应皮质类固醇之间的通透性和滞留参数进行了比较。鉴定出具有显著更高滞留性的化合物，并强调了通透性没有显著提高的衍生物。所有化合物的分子结构均使用高斯半经验/PM3方法进行了优化。计算了优化结构的几何、热力学、物理化学和电子分子参数，并进行了定量构效关系（QSPR）分析，以解释这些化合物的通透性和滞留性。创建了人工神经网络（ANN）、偏最小二乘法（PLS）和多元线性回归（MLR）-QSPR模型。通过常用统计参数评估这些模型的质量，并选择了最可靠的模型。分析所选模型中的描述符，确定了影响PAMPA人工膜中通透性和滞留性的主要分子性质。基于这些数据，可以进行进一步的结构修饰，以在不显著增加通透性的情况下提高滞留性，这可能会对这些化合物潜在的局部抗炎活性产生积极影响。所选的QSPR模型可作为一种计算机模拟工具，用于预测新型17β - 羧酰胺类固醇在人皮肤中的通透性和滞留性，而无需进行PAMPA实验。
