Novel Hybrid Conjugates with Dual Suppression of Estrogenic and Inflammatory Activities Display Significantly Improved Potency against Breast Cancer
| Autor: | Silong Zhang, Zhiye Hu, Hai-Bing Zhou, Chune Dong, Chu Tang, Lu Yang, Wentao Ning, Jian Huang |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Models
Molecular 0301 basic medicine Protein Conformation Anti-Inflammatory Agents Mice Nude Estrogen receptor Antineoplastic Agents Breast Neoplasms Resveratrol Ligands Mice Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine In vivo Drug Discovery medicine Animals Humans Structure–activity relationship Sulfones IC50 Cells Cultured Cell Proliferation Inflammation Mice Inbred BALB C Molecular Structure Macrophages Estrogen Receptor alpha NF-kappa B Biological activity 030104 developmental biology chemistry 030220 oncology & carcinogenesis Cancer research Molecular Medicine Female Estrogen Receptor Antagonists Signal transduction Tamoxifen Signal Transduction medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 61:8155-8173 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.8b00224 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|