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

• Published in: Journal of medicinal chemistry Vol. 61; no. 18; pp. 8155 - 8173
• Main Authors: Ning, Wentao, Hu, Zhiye, Tang, Chu, Yang, Lu, Zhang, Silong, Dong, Chune, Huang, Jian, Zhou, Hai-Bing
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 27.09.2018; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; RESVERATROL; ACTIVATION; NITRIC-OXIDE PRODUCTION; ANTIESTROGENS; TAMOXIFEN; RECEPTOR LIGANDS; BIOLOGICAL EVALUATION; NF-KAPPA-B; TRANSCRIPTION FACTOR; MULTIFUNCTIONAL MEDICINES
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.8b00224

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.