Design, synthesis and biological evaluation of novel indone derivatives as selective ERβ modulators
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To reduce the endometrial toxicity and improve the efficacy of current selective estrogen receptor modulators used in breast cancer treatment by enhancing ERβ selectivity, inspired by active resveratrol oligomer, a series of analogs (5a–f, 6a–b, 7a–d, 8a–d) were designed, synthesized and biologically evaluated. Among them, the chiral indone analog (2R,3R)-8a exhibited best antiproliferative activity against both breast cancer cell lines (MDA-MB-231 and MCF-7) and better safety profile on uterus than tamoxifen. Analog (2R,3R)-8a demonstrated good binding affinity and selectivity toward ERβ, which was further proved by both molecular docking and radiometric competitive binding assay. Other studies for (2R,3R)-8a also have been explored including cell cycle and apoptosis evaluation and in vitro metabolic stability studies. These results demonstrated that (2R,3R)-8a could be a promising lead compound for future exploration of selective ERβ anti-breast cancer agents.
KeywordsResveratrol oligomer ERβ Breast cancer SERM
This work was supported by the National Natural Science Foundation of China (No: 81673297), Shanghai Municipal Committee of Science and Technology (No: 17JC1400200, 17431902500), and China Postdoctoral Science Foundation (BX20180065).
The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
Conceptualization and methodology, X.S., C.Z., and X.-X.L.; software, X.-X.L. and Y.T.; validation, X.-X.L.; formal analysis, X.-X.L.; investigation, X.-X.L.; resources, X.S.; data curation, X.-X.L.; writing—original draft preparation, X.-X.L.; writing—review and editing, X.S., J.-M.Y. and M.-L.T.; supervision, X.S.; project administration, X.-X.L.; funding acquisition, X.S.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
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