雄激素受体N末端结构域抑制剂的设计、合成与活性评价

Design,synthesis and evaluation of the activity of androgen receptor N-terminal domain inhibitors

目的以EPI-002为先导化合物,设计合成其衍生物并进行活性评价。方法以双酚A为起始原料,通过取代、Lewis酸催化开环等反应合成EPI-002衍生物,并进行前列腺癌细胞增殖抑制活性以及免疫印迹测试。结果合成共计5个EPI-002衍生物a~e,部分化合物对前列腺癌细胞增殖抑制活性优于EPI-002与恩杂鲁胺。同时,免疫印迹实验显示出化合物b与c能够下调AR-FL、AR-V7以及下游蛋白FKBP51与TMPRSS2。

Objective A series of androgen receptor N-terminal domain antagonist were designed and synthesized with EPI-002 as the lead compound,and their activities were evaluated.Methods EPI-002 derivatives were synthesized by substitution,Lewis acid catalyzed ring opening,and their anti-tumor cell proliferation and immunoblotting were tested.Results EPI-002 derivatives a-e were synthesized,which showed better anti-tumor activity than EPI-002 and enzalutamide.Western blot showed that b and c could down regulate the expression of AR-FL,AR-V7 and AR downstream proteins FKBP51 and TMPRSS2.