Vue Bao, Zhang Sheng, Zhang Xiaojie, Parisis Konstantinos, Zhang Qiang, Zheng Shilong, Wang Guangdi, Chen Qiao-Hong
Department of Chemistry, California State University, Fresno, 2555 E. San Ramon Avenue, M/S SB70, Fresno, CA 93740, USA.
RCMI Cancer Research Center Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA.
Eur J Med Chem. 2016 Feb 15;109:36-46. doi: 10.1016/j.ejmech.2015.12.041. Epub 2015 Dec 24.
This study aims to systematically explore the alkylation effect of 7-OH in silibinin and 2,3-dehydrosilibinin on the antiproliferative potency toward three prostate cancer cell lines. Eight 7-O-alkylsilibinins, eight 7-O-alkyl-2,3-dehydrosilibinins, and eight 3,7-O-dialkyl-2,3-dehydrosilibinins have been synthesized from commercially available silibinin for the in vitro cell-based evaluation. The WST-1 cell proliferation assay indicates that nineteen out of twenty-four silibinin derivatives have significantly improved antiproliferative potency when compared with silibinin. 7-O-Methylsilibinin (2) and 7-O-ethylsilibinin (3) have been identified as the most potent compounds with 98- and 123-fold enhanced potency against LNCaP human androgen-dependent prostate cancer cell line. Among 2,3-dehydrosilibinin derivatives, 7-O-methyl-2,3-dehydrosilibinin (10) and 7-O-ethyl-2,3-dehydrosilibinin (11) have been identified as the optimal compounds with the highest potency towards both androgen-dependent LNCaP and androgen-independent PC-3 prostate cancer cell lines. 7-O-Ethyl-2,3-dehydrosilibinin (11) was demonstrated to arrest PC-3 cell cycle at the G0/G1 phase and to induce PC-3 cell apoptosis. The findings in this study suggest that antiproliferative potency of silibinin and 2,3-dehydrosilibinin can be appreciably enhanced through suitable chemical modifications on the phenolic hydroxyl group at C-7 and that introduction of a chemical moiety with the potential to improve bioavailability through a linker to 7-OH in silibinin and 2,3-dehydrosilibinin would be a feasible strategy for the development of silibinin derivatives as anti-prostate cancer agents.
本研究旨在系统探索水飞蓟宾和2,3-脱氢水飞蓟宾中7-OH的烷基化作用对三种前列腺癌细胞系增殖抑制能力的影响。从市售水飞蓟宾合成了8种7-O-烷基水飞蓟宾、8种7-O-烷基-2,3-脱氢水飞蓟宾和8种3,7-O-二烷基-2,3-脱氢水飞蓟宾，用于基于细胞的体外评估。WST-1细胞增殖试验表明，与水飞蓟宾相比，24种水飞蓟宾衍生物中有19种的增殖抑制能力显著提高。7-O-甲基水飞蓟宾（2）和7-O-乙基水飞蓟宾（3）被确定为最有效的化合物，对LNCaP人雄激素依赖性前列腺癌细胞系的效力分别提高了98倍和123倍。在2,3-脱氢水飞蓟宾衍生物中，7-O-甲基-2,3-脱氢水飞蓟宾（10）和7-O-乙基-2,3-脱氢水飞蓟宾（11）被确定为对雄激素依赖性LNCaP和雄激素非依赖性PC-3前列腺癌细胞系效力最高的最佳化合物。7-O-乙基-2,3-脱氢水飞蓟宾（11）被证明可使PC-3细胞周期停滞在G0/G1期并诱导PC-3细胞凋亡。本研究结果表明，通过对C-7位酚羟基进行适当的化学修饰，可显著提高水飞蓟宾和2,3-脱氢水飞蓟宾 的增殖抑制能力，并且引入一个有可能通过连接子提高生物利用度的化学基团至水飞蓟宾和2,3-脱氢水飞蓟宾的7-OH上，将是开发水飞蓟宾衍生物作为抗前列腺癌药物的一种可行策略。
