Novel class of 7-Oxabicyclo[2.2.1]heptene sulfonamides with long alkyl chains displaying improved estrogen receptor α degradation activity

Eur J Med Chem. 2019 Nov 15:182:111605. doi: 10.1016/j.ejmech.2019.111605.

Zhiye Hu ¹, Yuanyuan Li ¹, Baohua Xie ¹, Wentao Ning ¹, Yuan Xiao ¹, Yuan Huang ¹, Chenxi Zhao ², Jian Huang ³, Chune Dong ⁴, Hai-Bing Zhou ⁵

Affiliations

1 State Key Laboratory of Virology, Hubei Provincial Key Laboratory of Developmentally Originated Disease, Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan, 430071, China.
2 Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, China.
3 Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, China. Electronic address: [email protected].
4 State Key Laboratory of Virology, Hubei Provincial Key Laboratory of Developmentally Originated Disease, Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan, 430071, China. Electronic address: [email protected].
5 State Key Laboratory of Virology, Hubei Provincial Key Laboratory of Developmentally Originated Disease, Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan, 430071, China. Electronic address: [email protected].

PMID: 31437778 DOI: 10.1016/j.ejmech.2019.111605

Abstract

Hormone therapy is widely used in clinic for breast Cancer treatment, such as tamoxifen, but long-term use can cause drug resistance. In this regard, a strategy based on small molecule-induced protein degradation, i.e. selective Estrogen receptor downregulator (SERD), might be an effective alternative to hormone therapy for breast Cancer. However, most of the SERD candidates involve very limited scaffolds and are still in clinical trials, and none of them has been approved for marketing. In this study, a series of novel 7-oxabicyclo[2.2.1]heptene sulfonamide (OBHSA) derivatives with long alkyl chains were identified as novel SERDs. We found that the position and the length of alkyl side chain have significant effect on the biological activity of the SERD compounds and with the six-carbon side chain was the best. Among them, compounds 23a and 36 displayed potent inhibitory activity against MCF-7 breast Cancer cell line with IC₅₀ values of 0.84 μM and 0.77 μM, respectively, as well as excellent ERα degradation activity. Primary mechanism study indicated that the degradation of ERα is mediated through proteasome-mediated process. Flow cytometry analysis of Apoptosis of 36 suggested that the effect of this type compounds on MCF-7 cells is associated with Apoptosis. As such, these compounds have shown potential to become promising leads for the development of highly efficient SERDs for drug-resistance breast Cancer therapies.

Keywords

Breast cancer; Estrogen receptor; Long alkyl chains; Selective estrogen receptor downregulators; Structure-activity relationships.

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