Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno, Palackeho 1/3, 612 42 Brno, Czech Republic.
Bioorg Med Chem. 2010 Dec 15;18(24):8556-65. doi: 10.1016/j.bmc.2010.10.025. Epub 2010 Oct 15.
Skin penetration enhancers are used in the formulation of transdermal delivery systems for drugs that are otherwise not sufficiently skin-permeable. We generated two series of esters by multi-step synthesis with substituted 6-aminohexanoic acid as potential transdermal penetration enhancers by multi-step synthesis. The synthesis of all newly prepared compounds is presented here. Structure confirmation of all generated compounds was accomplished by (1)H NMR, (13)C NMR, IR and MS spectroscopy. All the prepared compounds were analyzed using RP-HPLC and their lipophilicity (logk) was determined. The hydrophobicity (logP/ClogP) of the studied compounds was also calculated using two commercially available programs and 3D structures of the selected compounds were investigated by means of ab initio calculations of geometry and molecular dynamic simulations. All the synthesized esters were tested for their in vitro transdermal penetration-enhancing activity and showed higher enhancement ratios than oleic acid. The highest enhancement ratios were exhibited by compound 5f (C((2)) substituted with piperidine-2-one, C(11) ester chain) and 5a (C((2)) substituted with piperidine-2-one, C(6) ester chain). The series with a ω-lactam ring (piperidin-2-one; 5a-g), showed slightly higher activities than those with morpholine (6a-6g). All of the agents showed minimal anti-proliferative activity (IC(50) >6.25μM), indicating they would have low cytotoxicity when administered as chemical penetration enhancers. The relationships between the lipophilicity and the chemical structure of the studied compounds, as well as the correlation between their chemical structure and transdermal penetration-enhancing activity, are discussed.
皮肤渗透增强剂用于药物的透皮给药系统的配方中，这些药物否则皮肤渗透性不足。我们通过多步合成，用取代的 6-氨基己酸作为潜在的透皮渗透增强剂，生成了两个系列的酯。所有新制备的化合物的合成都在这里呈现。通过 1H NMR、13C NMR、IR 和 MS 光谱对所有生成的化合物的结构进行了确认。所有制备的化合物均使用反相高效液相色谱法 (RP-HPLC) 进行分析，并测定其亲脂性 (logk)。还使用两个商业上可用的程序计算了研究化合物的疏水性 (logP/ClogP)，并通过几何结构的从头计算和所选化合物的分子动力学模拟研究了 3D 结构。所有合成的酯均进行了体外透皮渗透增强活性测试，其结果显示出比油酸更高的增强比。具有哌啶-2-酮取代基 (C((2))，C(11)酯链)的化合物 5f 和具有哌啶-2-酮取代基 (C((2))，C(6)酯链)的化合物 5a 表现出最高的增强比。具有 ω-内酰胺环 (哌啶-2-酮；5a-g) 的系列，其活性略高于具有吗啉 (6a-6g) 的系列。所有这些试剂的抗增殖活性都很小 (IC50 >6.25μM)，表明它们作为化学渗透增强剂给药时，细胞毒性低。讨论了研究化合物的亲脂性与化学结构之间的关系，以及它们的化学结构与透皮渗透增强活性之间的相关性。
