Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, PR China; The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, 210029, PR China.
Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, PR China; School of Chemical and Material Engineering, Jiangnan University, Wuxi, 214122, PR China.
Eur J Med Chem. 2019 Nov 1;181:111582. doi: 10.1016/j.ejmech.2019.111582. Epub 2019 Aug 1.
5-Aminolevulinic acid (5-ALA) and its two ester derivatives (5-ALA-OMe and 5-ALA-OHex) have been approved for photodiagnosis and photodynamic therapy (PDT) of tumors in the clinical. However, their pharmacological activities are limited by their instability under physiological conditions and lack of tumor selectivity. With the aim to overcome these shortcomings, a glutathione-responsive 5-ALA derivative (SA) was designed based on the fact that many types of tumor cells have higher intracellular glutathione level than normal cells. SA was synthesized by masking the 5-amion group of 5-ALA methyl ester (5-ALA-OMe) with a self-immolative disulfide linker. Compared with 5-ALA and 5-ALA-OMe, SA exhibited higher stability under physiological conditions, and it can efficiently release the parent compound 5-ALA-OMe in response to glutathione. In tumor cells, SA displayed excellent protoporphyrin IX (PpIX) production activity at low concentrations while 5-ALA and 5-ALA-OMe were ineffective at the same concentration. The SA-induced PpIX production was positively correlated with the intracellular glutathione level, and SA exhibited enhanced phototoxicity due to its excellent PpIX generation activity. This study indicates that modification of the amino group in 5-ALA derivatives with a self-immolative disulfide linker is an effective strategy to improve their chemical stability and pharmacological activities, and SA is a potential photosensitizer for photodiagnosis and PDT of tumors.
5-氨基酮戊酸（5-ALA）及其两种酯衍生物（5-ALA-OME 和 5-ALA-OHex）已被批准用于肿瘤的光诊断和光动力治疗（PDT）。然而，它们的药理学活性受到其在生理条件下的不稳定性和缺乏肿瘤选择性的限制。为了克服这些缺点，根据许多类型的肿瘤细胞内谷胱甘肽水平高于正常细胞的事实，设计了一种谷胱甘肽响应性 5-ALA 衍生物（SA）。SA 通过用自毁性二硫键连接物掩蔽 5-ALA 甲酯（5-ALA-OME）的 5-氨基基团来合成。与 5-ALA 和 5-ALA-OME 相比，SA 在生理条件下表现出更高的稳定性，并且能够有效地响应谷胱甘肽释放母体化合物 5-ALA-OME。在肿瘤细胞中，SA 在低浓度下表现出优异的原卟啉 IX（PpIX）产生活性，而相同浓度下的 5-ALA 和 5-ALA-OME 则无效。SA 诱导的 PpIX 产生与细胞内谷胱甘肽水平呈正相关，并且由于其优异的 PpIX 生成活性，SA 表现出增强的光毒性。这项研究表明，用自毁性二硫键连接物修饰 5-ALA 衍生物中的氨基是提高其化学稳定性和药理学活性的有效策略，并且 SA 是用于肿瘤光诊断和 PDT 的潜在光敏剂。
