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.
Wentao Ning  1 ,  Zhiye Hu  1 ,  Chu Tang  2 ,  Lu Yang  1 ,  Silong Zhang  1 ,  Chune Dong  1 ,  Jian Huang  3 ,  Hai-Bing Zhou  1
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.