2. Academic Validation
  3. Novel Hybrid Conjugates with Dual Suppression of Estrogenic and Inflammatory Activities Display Significantly Improved Potency against Breast Cancer

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

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.

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