Novel Hybrid Conjugates with Dual Suppression of Estrogenic and Inflammatory Activities Display Significantly Improved Potency against Breast Cancer

Wentao Ning; Zhiye Hu; Chu Tang; Lu Yang; Silong Zhang; Chune Dong; Jian Huang; Hai-Bing Zhou

doi:10.1021/acs.jmedchem.8b00224

Novel Hybrid Conjugates with Dual Suppression of Estrogenic and Inflammatory Activities Display Significantly Improved Potency against Breast Cancer

J Med Chem. 2018 Sep 27;61(18):8155-8173. doi: 10.1021/acs.jmedchem.8b00224. Epub 2018 Aug 16.

Authors

Wentao Ning¹, Zhiye Hu¹, Chu Tang², Lu Yang¹, Silong Zhang¹, Chune Dong¹, Jian Huang³, Hai-Bing Zhou¹

Affiliations

¹ State Key Laboratory of Virology, 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 Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education, School of Life Science and Technology , Xidian University , Xi'an 710126 , Shaanxi , China.
³ College of Life Sciences , Wuhan University , Wuhan 430072 , China.

PMID: 30053783
DOI: 10.1021/acs.jmedchem.8b00224

Abstract

In this work, we developed a small library of novel OBHS-RES hybrid compounds with dual inhibition activities targeting both the estrogen receptor α (ERα) and NF-κB by incorporating resveratrol (RES), a known inhibitor of NF-κB, into a privileged indirect antagonism structural motif (OBHS, oxabicycloheptene sulfonate) of estrogen receptor (ER). The OBHS-RES conjugates could bind well to ER and showed remarkable ERα antagonistic activity, and they also exhibited excellent NO inhibition in macrophage RAW 264.7 cells. Compared with 4-hydroxytamoxifen, some of them showed better antiproliferative efficacy in MCF-7 cell lines with IC₅₀ up to 3.7 μM. In vivo experiments in a MCF-7 breast cancer model in Balb/c nude mice indicated that compound 26a was more potent than tamoxifen. Exploration of the compliancy of the structure against ER specificity utilizing these types of isomeric three-dimensional ligands indicated that one enantiomer had much better biological activity than the other.

Publication types

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

MeSH terms

Animals
Anti-Inflammatory Agents / chemistry
Anti-Inflammatory Agents / pharmacology*
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Breast Neoplasms / drug therapy*
Breast Neoplasms / metabolism
Breast Neoplasms / pathology
Cell Proliferation / drug effects*
Cells, Cultured
Estrogen Receptor Antagonists / chemistry
Estrogen Receptor Antagonists / pharmacology
Estrogen Receptor alpha / antagonists & inhibitors*
Female
Humans
Inflammation / drug therapy*
Inflammation / metabolism
Inflammation / pathology
Ligands
Macrophages / cytology
Macrophages / drug effects
Macrophages / metabolism
Mice
Mice, Inbred BALB C
Mice, Nude
Models, Molecular
Molecular Structure
NF-kappa B / antagonists & inhibitors*
Protein Conformation
Resveratrol / chemistry
Signal Transduction
Structure-Activity Relationship
Sulfones / chemistry

Substances

Anti-Inflammatory Agents
Antineoplastic Agents
Estrogen Receptor Antagonists
Estrogen Receptor alpha
Ligands
NF-kappa B
Sulfones
Resveratrol