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. 2016 Dec 8;8(1):239-246.
doi: 10.1039/c6md00553e. eCollection 2017 Jan 1.

Design and synthesis of novel selective estrogen receptor degradation inducers based on the diphenylheptane skeleton

Takashi Misawa  1 , Takuma Fujisato  1 , Yasunari Kanda  1 , Nobumichi Ohoka  1 , Takuji Shoda  1 , Momoko Yorioka  1 , Makoto Makishima  2 , Yuko Sekino  1 , Mikihiko Naito  1 , Yosuke Demizu  1 , Masaaki Kurihara  1
Affiliations

Design and synthesis of novel selective estrogen receptor degradation inducers based on the diphenylheptane skeleton

Takashi Misawa et al. Medchemcomm. .

Abstract

Estrogen receptors (ERs) are a family of nuclear receptors (NRs) that regulate physiological effects such as reproduction and bone homeostasis. It has been reported that approximately 70% of human breast cancers are hormone-dependent and ERα-positive. Recently, novel anti-breast cancer drugs based on different mechanisms of action have received significant attention. In this article, we have designed and synthesized a selective ER degradation inducer based on the diphenylheptane skeleton. Western blotting analysis revealed that PBP-NC10 degraded ERα through the ubiquitin-proteasome system. We also performed computational docking analysis to predict the binding mode of PBP-NC10 to ERα.

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Figures

Fig. 1
Fig. 1. (a) Chemical structures of 17β-estradiol, anti-estrogenic compounds and (b) selective estrogen receptor downregulators.
Fig. 2
Fig. 2. Chemical structures of the diphenylheptane skeleton (PBP) and designed compounds PBP-NH2, PBP-tam, PBP-C2 to PBP-C12, and PBP-NC6 to PBP-NC16 in this study.
Scheme 1
Scheme 1. Synthesis of compounds PBP-NH2, PBP-tam, PBP-C2 to PBP-C12, and PBP-NC6 to PBP-NC16. Reagents and conditions: (a) MsOH, rt, 3 days, 59%; (b) R-I (R = ethyl, n-hexyl, n-octyl, n-decyl, n-dodecyl), K2CO3, MeCN, 60–100 °C, 16–47%; (c) 1,2-dichloroethane, K2CO3, MeCN, 48 h, 19%; (d) R-NH2 (R = n-hexyl, n-octyl, n-decyl, n-dodecyl, n-hexadecyl), MeCN, microwave, 120 °C, 4 h, 20–42%; (e) benzyl (2-bromoethyl)carbamate or 2-chloro-N,N-dimethylethylamine Cs2CO3, NaI, DMF, 100 °C, 21 h, 6%; (f) Pd(OH)2, H2, MeOH, rt, 26 h, 25%.
Fig. 3
Fig. 3. (a and b) Western blotting analysis of estrogen receptor (ER) α levels in MCF-7 cells after 6 h of incubation with the synthesized compounds. (c) Quantification of the levels of ERα is provided in a histogram. Data are expressed as means ± S.E. of three independent experiments (*P < 0.05 versus control).
Fig. 4
Fig. 4. The effects of PBP-NC10 on nuclear receptor levels in MCF-7 cells with or without proteasome inhibitor MG132. ER, estrogen receptor; AR, androgen receptor; VDR, vitamin D receptor; AhR, aryl hydrocarbon receptor.
Fig. 5
Fig. 5. ERα antagonistic activity of PBP, PBP-C12 and PBP-NC10 in HEK293 cells. Data are expressed as means ± S.E. of three independent experiments.
Fig. 6
Fig. 6. Computational model of the estrogen receptor (ER) α ligand binding domain and PBP-NC10, ICI164,384. The hydrophobic region is colored orange, PBP-NC10 is colored green, and ICI164,384 is colored blue.
See this image and copyright information in PMC

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