Department of Chemistry, Faculty of Science, Kyushu University, Motooka 744, Nishi-ku, Fukuoka, 819-0395, Japan; Department of Applied Microbial Technology, Faculty of Biotechnology and Life Sciences, Sojo University, Kumamoto, 860-0082, Japan.
Department of Chemistry, Faculty of Science, Kyushu University, Motooka 744, Nishi-ku, Fukuoka, 819-0395, Japan.
Toxicol Lett. 2021 Jul 1;345:24-33. doi: 10.1016/j.toxlet.2021.04.001. Epub 2021 Apr 12.
As demonstrated for bisphenol AF (BPAF), the electrostatic halogen bond based on the London dispersion force of halogen atoms was found to be a major driving force of their bifunctional ERα-agonist and ERβ-antagonist activities. Because similar electronic effects are anticipated for hydrocarbon groups (alkyl or aryl groups), we hypothesized that bisphenol compounds consisting of such groups also work bifunctionally. In the present study, we examined bisphenol AP (BPAP), B (BPB), and Z (BPZ). After recognizing their considerably strong receptor binding affinities, we evaluated the abilities of BPAP, BPB, and BPZ to activate ERα and ERβ in a luciferase reporter gene assay. These bisphenols were fully active for ERα but completely inactive for ERβ. When we examined their inhibitory activities for 17β-estradiol in ERβ by two different qualitative and quantitative analytical methods, we found that those bisphenols worked as definite antagonists. Consequently, they were established as bifunctional ERα-agonists and ERβ-antagonists. The present structure-activity analyses revealed that the dispersion force works not only on the halogens but also on the hydrocarbon groups, and that it is a major driving force of bifunctional ERα-agonist and ERβ-antagonist activities.
如双酚 AF（BPAF）所示，基于卤素原子伦敦色散力的静电卤键被发现是其双功能 ERα 激动剂和 ERβ 拮抗剂活性的主要驱动力。由于预计烃基（烷基或芳基）也具有类似的电子效应，我们假设由这些基团组成的双酚化合物也具有双功能。在本研究中，我们检查了双酚 AP（BPAP）、B（BPB）和 Z（BPZ）。在认识到它们具有相当强的受体结合亲和力后，我们评估了 BPAP、BPB 和 BPZ 在荧光素酶报告基因测定中激活 ERα 和 ERβ 的能力。这些双酚化合物对 ERα 完全有效，但对 ERβ 完全无效。当我们用两种不同的定性和定量分析方法检查它们对 ERβ 中 17β-雌二醇的抑制活性时，发现这些双酚化合物作为确定的拮抗剂起作用。因此，它们被确立为双功能 ERα 激动剂和 ERβ 拮抗剂。目前的结构-活性分析表明，色散力不仅作用于卤素，而且作用于烃基，是双功能 ERα 激动剂和 ERβ 拮抗剂活性的主要驱动力。
