Jiangsu Key Laboratory of Drug Design & Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang Road, Nanjing 210009, China.
Department of Biochemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
Future Med Chem. 2017 Oct;9(16):1887-1898. doi: 10.4155/fmc-2017-0102. Epub 2017 Oct 27.
ASM, which hydrolyzes sphingomyelin into ceramide, is recognized as a therapeutic target for UV-induced skin damage. Direct inhibitors for this enzyme are rare. Here we synthesized several series of 1,3,6,7-tetrahydroxy-xanthone derivatives as novel ASM inhibitors.
Several compounds were more potent than the lead compound, among which 5b was found competitively inhibiting the enzyme and dose-dependently reducing ceramide generation. Furthermore, 5b and 5c showed excellent protective effect to skin keratinocytes against UV. Quantitative structure-activity relationship investigation revealed detail relationships between molecular structure and biological activity. Insight into the binding mode was precisely illuminated by molecule docking.
This work would provide fresh ideas and strong supports for further development of ASM inhibitors and drug candidates for skin damage.
ASM 可将神经鞘磷脂水解为神经酰胺，被认为是治疗 UV 诱导的皮肤损伤的一个有前途的治疗靶点。ASM 的直接抑制剂很少。在这里，我们合成了几系列 1,3,6,7-四羟基呫吨酮衍生物作为新型 ASM 抑制剂。
几个化合物比先导化合物具有更强的活性，其中 5b 被发现竞争性抑制酶并剂量依赖性地减少神经酰胺的产生。此外，5b 和 5c 对皮肤角质形成细胞具有优异的抗 UV 保护作用。定量构效关系研究揭示了分子结构与生物活性之间的详细关系。分子对接准确地阐明了结合模式。
这项工作将为 ASM 抑制剂的进一步开发以及皮肤损伤的药物候选物提供新的思路和有力支持。
