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Design, synthesis and biological evaluation of novel indone derivatives as selective ERβ modulators

  • Xi-Xi Liu
  • Mei-Lin Tang
  • Chen Zhong
  • Yun Tang
  • Jian-Ming Yu
  • Xun SunEmail author
Original Research
  • 18 Downloads

Abstract

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.

Keywords

Resveratrol oligomer ERβ Breast cancer SERM 

Notes

Acknowledgements

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).

Funding

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.

Author contributions

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.

Supplementary material

44_2019_2355_MOESM1_ESM.doc (1 mb)
Supplementary Information

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Xi-Xi Liu
    • 1
  • Mei-Lin Tang
    • 1
    • 4
  • Chen Zhong
    • 1
  • Yun Tang
    • 3
  • Jian-Ming Yu
    • 1
  • Xun Sun
    • 1
    • 2
    Email author
  1. 1.Department of Natural Products Chemistry, School of PharmacyFudan UniversityShanghaiChina
  2. 2.The Institutes of Integrative Medicine of Fudan UniversityShanghaiChina
  3. 3.Shanghai Key Laboratory of New Drug Design, School of PharmacyEast China University of Science and TechnologyShanghaiChina
  4. 4.State Key Laboratory of Molecular Engineering and Institutes of Biomedical SciencesFudan UniversityShanghaiChina

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