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

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.

本研究通过将已知核因子κB（NF-κB）抑制剂白藜芦醇（RES）引入雌激素受体（ER）的优势间接拮抗结构基序——氧双环庚烯磺酸酯（OBHS, oxabicycloheptene sulfonate），构建了一类兼具雌激素受体α（ERα）与NF-κB双重抑制活性的新型OBHS-RES杂合化合物小型文库。该类OBHS-RES共轭化合物可与ER高效结合，展现出显著的ERα拮抗活性，同时在巨噬细胞RAW 264.7中表现出优异的一氧化氮（NO）抑制效果。与4-羟基他莫昔芬相比，部分化合物在MCF-7细胞系中展现出更优的抗增殖活性，半数抑制浓度（IC50）低至3.7 μM。在Balb/c裸鼠MCF-7乳腺癌模型中的体内实验表明，化合物26a的活性优于他莫昔芬。利用这类异构三维配体探究结构对ER特异性的适配性时发现，其中一种对映异构体的生物活性远优于另一种。