Design and synthesis of 4-benzyl-1-(2H)-phthalazinone derivatives as novel androgen receptor antagonists
Design and synthesis of 4-benzyl-1-(2H)-phthalazinone derivatives as novel androgen receptor antagonists
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新型雄激素受体拮抗剂4-苄基-1-(2H)-二氮杂萘酮衍生物的设计与合成
DOI：
10.1016/j.ejmech.2015.08.002
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发表时间：
2015
影响因子：
6.7
通讯作者：
Aya Tanatani
中科院分区：
文献类型：
--
作者：
Kazumi Inoue;Ko Urushibara;Misae Kanai;Kei Yura;Shinya Fujii;Mari Ishigami-Yuasa;Yuichi Hashimoto;Shuichi Mori;Emiko Kawachi;Mio Matsumura;Tomoya Hirano;Hiroyuki Kagechika;Aya Tanatani
雄激素受体（AR）在多种生理功能中起重要作用，包括雄性生殖器官的分化、生长和维持，并且对毛发和皮肤也有影响。本文报道了具有4-苄基-1-（2 H）-二氮杂萘酮骨架的非甾体AR拮抗剂的合成。在合成的化合物中，苯基上具有两个邻位取代基的11 c可有效抑制SC-3细胞增殖（IC 50：0.18 μM），并显示出高wt AR结合亲和力（IC 50：10.9 μM），与羟基芴醇（3）相当。化合物11 c还抑制含有T877 A突变的AR的LNCaP细胞的增殖。11 c与AR配体结合结构域的对接研究表明，苄基在拮抗作用中是重要的。这些二氮杂萘酮衍生物可用于研究AR拮抗剂的潜在临床应用。
The androgen receptor (AR) plays important roles in multiple physiological functions, including differentiation, growth, and maintenance of male reproductive organs, and also has effects on hair and skin. In this paper, we report the synthesis of nonsteroidal AR antagonists having a 4-benzyl-1-(2H)-phthalazinone skeleton. Among the synthesized compounds, 11c with twoortho-substituents on the phenyl group potently inhibited SC-3 cell proliferation (IC50: 0.18 μM) and showed high wt AR-binding affinity (IC50: 10.9 μM), comparable to that of hydroxyflutamide (3). Compound11calso inhibited proliferation of LNCaP cells containing T877A-mutated AR. Docking study of11cwith the AR ligand-binding domain indicated that the benzyl group is important for the antagonism. These phthalazinone derivatives may be useful for investigating potential clinical applications of AR antagonists.