Xue Gui-Min, Xia Yuan-Zheng, Wang Zhi-Min, Li Ling-Nan, Luo Jian-Guang, Kong Ling-Yi
State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
Eur J Med Chem. 2016 Oct 4;121:238-249. doi: 10.1016/j.ejmech.2016.05.045. Epub 2016 May 24.
Ten new (1-10) and seventeen known (11-27) neo-clerodane diterpenoids substituted with nicotinoyloxyl were isolated from the plant Scutellaria barbata and their structures were established by extensive spectroscopic analysis. Chemoreversal effects of these neo-clerodane diterpenoids on multidrug resistance were evaluated in breast cancer multidrug-resistant MCF-7/ADR cells that overexpress P-glycoprotein. Four compounds (11, 14, 16, and 18) exhibited better chemoreversal abilities than the classical P-gp inhibitor verapamil and the most potent compound 11 reduced IC50 value of adriamycin in MCF-7/ADR cells from 58.8 μM to 1.3 μM. Mechanistic investigations showed that compound 11 reversed multidrug resistance through suppressing the activity of P-gp and restraining the expression of P-glycoprotein. In the present study, the structure-activity relationships of neo-clerodane diterpenoids were also discussed.
从半枝莲植物中分离出10个新的（1-10）和17个已知的（11-27）烟酰氧基取代的新克罗烷二萜类化合物，并通过广泛的光谱分析确定了它们的结构。在过表达P-糖蛋白的乳腺癌多药耐药MCF-7/ADR细胞中评估了这些新克罗烷二萜类化合物对多药耐药的化学逆转作用。四种化合物（11、14、16和18）表现出比经典P-糖蛋白抑制剂维拉帕米更好的化学逆转能力，最有效的化合物11将MCF-7/ADR细胞中阿霉素的IC50值从58.8 μM降低到1.3 μM。机制研究表明，化合物11通过抑制P-糖蛋白的活性和抑制P-糖蛋白的表达来逆转多药耐药。在本研究中，还讨论了新克罗烷二萜类化合物的构效关系。
