Structure-activity relationship of novel (benzoylaminophenoxy)phenol derivatives as anti-prostate cancer agents
Structure-activity relationship of novel (benzoylaminophenoxy)phenol derivatives as anti-prostate cancer agents
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DOI：
10.1016/j.bmc.2018.09.008
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发表时间：
2018-10-01
影响因子：
3.5
通讯作者：
Tanatani, Aya
中科院分区：
文献类型：
--
作者：
Kazui, Yuko;Fujii, Shinya;Tanatani, Aya
雄激素受体（AR）是属于核受体超家族的配体诱导型转录因子，并且是用于开发治疗前列腺癌的药物的靶分子。然而，临床使用的AR拮抗剂，如氟替卡松（3a）和比卡鲁胺（4），在激素治疗数年后遇到耐药性，主要是由于AR突变。因此，尽管已经开发了一些新一代AR拮抗剂，但仍需要新型AR拮抗剂来治疗耐药前列腺癌。我们以前报道了一种新的（苯甲酰氨基苯氧基）苯酚衍生物10a，这是从传统的AR拮抗剂的结构不同。在这里，我们系统地研究了（苯甲酰氨基苯氧基）苯酚衍生物对前列腺癌细胞增殖的抑制活性的构效关系。我们发现4-[4（苯甲酰氨基）苯氧基]苯酚主链对于抗前列腺癌活性是重要的。在中心苯环（B环）的2位引入小取代基增加活性。在合成的化合物中，19 a和19 b对二氢睾酮诱导的几种雄激素依赖性细胞系SC-3（野生型AR）、LNCaP（T877 A AR）和22 Rv 1（H874 Y AR）的增殖表现出最有效的抑制活性，但有趣的是，它们也抑制AR非依赖性PC-3细胞的增殖。这些化合物具有与常规AR拮抗剂不同的药效团，是用于治疗前列腺癌的有希望的候选药物。
The androgen receptor(AR) is a ligand-inducible transcription factor belonging to the nuclear receptor superfamily, and is a target molecule for development of drugs to treat prostate cancer. However, AR antagonists in clinical use, such as flutamide(3a) and bicalutamide(4), encounter resistance after several years of hormone therapy, predominantly due to mutations of AR. Thus, although some new-generation AR antagonists have been developed, novel types of AR antagonists are still required to treat drug-resistant prostate cancer. We previously reported a novel(benzoylaminophenoxy) phenol derivative 10a, which is structurally distinct from conventional AR antagonists. Here, we systematically examined the structure-activity relationship of(benzoylaminophenoxy) phenol derivatives on the inhibitory activity on the prostate cancer cell proliferations. We found that the 4-[4( benzoylamino) phenoxy] phenol backbone is important for anti-prostate cancer activity. Introduction of a small substituent at the 2 position of the central benzene ring(B ring) increases the activity. Among the synthesized compounds, 19a and 19b exhibited the most potent inhibitory activity toward dihydrotestosterone-induced proliferation of several androgen-dependent cell lines, SC-3(wild-type AR), LNCaP(T877A AR), and 22Rv1(H874Y AR), but interestingly also inhibited proliferation of AR-independent PC-3 cells. These compounds, which have a different pharmacophore from conventional AR antagonists, are promising drug candidates for the treatment of prostate cancer.