Jiao Wei, Wan Zhongmin, Chen Shuang, Lu Runhua, Chen Xiaozhen, Fang Dongmei, Wang Jiufeng, Pu Shengcai, Huang Xin, Gao Haixiang, Shao Huawu
†Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.
‡Department of Applied Chemistry, China Agricultural University, Beijing 100194, China.
J Med Chem. 2015 May 14;58(9):3720-38. doi: 10.1021/acs.jmedchem.5b00058. Epub 2015 Apr 22.
Five series of 37 new acylate and epoxide derivatives (3-39) of Euphorbia factor L3, a lathyrol diterpene isolated from Euphorbia lathyris, were designed by modifying the hydroxyl moiety of C-3, C-5, or C-15. Chemoreversal effects of the acylates on multidrug resistance (MDR) were evaluated in breast cancer multidrug-resistant MCF-7/ADR cells that overexpress P-glycoprotein (P-gp). Eight derivatives exhibited greater chemoreversal ability than verapamil (VRP) against adriamycin (ADR) resistance. Compounds 19 and 25 exhibited 4.8 and 4.0 times, respectively, more effective reversal ability than VRP against ADR resistance. To determine the key characteristics of Euphorbia factor L3 derivatives that contribute to MDR reversal, we conducted a structure-activity relationship study of these compounds. The simulation studies indicated different possible mechanisms and revealed the important influence of hydrophobic interactions and hydrogen bonds in the flexible cavity of P-gp.
通过修饰大戟因子L3（一种从续随子中分离得到的瑞香烷二萜）的C-3、C-5或C-15位的羟基，设计了五组共37种新的酰化物和环氧化物衍生物（3-39）。在过表达P-糖蛋白（P-gp）的乳腺癌多药耐药MCF-7/ADR细胞中评估了这些酰化物对多药耐药（MDR）的化学逆转作用。八种衍生物对阿霉素（ADR）耐药的化学逆转能力比维拉帕米（VRP）更强。化合物19和25对ADR耐药的逆转能力分别比VRP高4.8倍和4.0倍。为了确定大戟因子L3衍生物中有助于MDR逆转的关键特征，我们对这些化合物进行了构效关系研究。模拟研究表明了不同的可能机制，并揭示了疏水相互作用和氢键在P-gp柔性腔内的重要影响。
