Discovery of novel 2H-chromene-3-carbonyl derivatives as selective estrogen receptor degraders (SERDs): Design, synthesis and biological evaluation

Xiang Lu; Yu Teng; Xin Lin; Maoxu Xiao; Chenna Liu; Xinglong Chi; Yulan Zhang; Guoshun Luo; Hua Xiang

doi:10.1016/j.bioorg.2021.104714

Discovery of novel 2H-chromene-3-carbonyl derivatives as selective estrogen receptor degraders (SERDs): Design, synthesis and biological evaluation

Bioorg Chem. 2021 Apr:109:104714. doi: 10.1016/j.bioorg.2021.104714. Epub 2021 Feb 9.

Authors

Xiang Lu¹, Yu Teng¹, Xin Lin¹, Maoxu Xiao¹, Chenna Liu¹, Xinglong Chi¹, Yulan Zhang¹, Guoshun Luo², Hua Xiang³

Affiliations

¹ State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
² State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: gsluo@cpu.edu.cn.
³ State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: xianghua@cpu.edu.cn.

PMID: 33618254
DOI: 10.1016/j.bioorg.2021.104714

Abstract

Selective estrogen receptor degraders (SERDs) not only block ERα activity but degrade this receptor at the same time and are effective in relapsed ERα positive breast cancer patients who have accepted other endocrine therapies. Herein, through scaffold hopping of coumarin skeleton, a series of 2H-chromene-3-carbonyl-based SERDs with phenyl acrylic acid group as the side chain were designed and synthesized. Compound XH04 containing 7-hydroxy-2H-chromene-3-carbonyl skeleton exhibited the most potent activities in 2D (IC₅₀ = 0.8 μM) and 3D cells culture models (MCF-7) and had the best ERα binding affinity as well. Furthermore, the significant antiestrogen property of compound XH04 was confirmed by inhibiting the expression of progesterone receptor (PgR) mRNA in MCF-7 cells. On the other hand, the outgoing ERα degradation property of compound XH04 was qualitatively and quantificationally verified by immunofluorescence analysis and Western blot assay in MCF-7 cells. Besides, compound XH04 repressed the expression level of Ki67 in MCF-7 cells and induced the apoptosis increase of this tumor cells in a dose-dependent manner like approved-SERD fulvestrant (2), while compound XH04 exhibited better preliminary pharmacokinetics in human and rat liver microsomes in vitro and a lower LogD_7.4 value than fulvestrant. And further molecular docking study revealed that compound XH04 possessed a proverbial and typical binding model with ERα like other reported SERD. All these results confirmed that 7-hydroxy-2H-chromene-3-carbonyl structure could be a feasible skeleton for design of ERα antagonists including SERDs and compound XH04 is a promising candidate for further development of ERα + breast cancer therapy agents.

Keywords: 7-hydroxy-2H-chromene-3-carbonyl; Breast cancer; ERα; SERDs.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacology*
Breast Neoplasms
Drug Design*
Female
Gene Expression Regulation, Neoplastic
Humans
MCF-7 Cells
Models, Molecular
Molecular Docking Simulation
Molecular Structure
Protein Conformation
RNA, Messenger / genetics
RNA, Messenger / metabolism
Receptors, Progesterone / genetics
Receptors, Progesterone / metabolism
Selective Estrogen Receptor Modulators / chemical synthesis*
Selective Estrogen Receptor Modulators / pharmacology*

Substances

Antineoplastic Agents
RNA, Messenger
Receptors, Progesterone
Selective Estrogen Receptor Modulators