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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Bishayee A. (2009) Cancer prevention and treatment with resveratrol: from rodent studies to clinical trials. Cancer Prev Res (Phila). 2:409–418
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424
Dotzlaq H (1997) Expression of estrogen receptor in human breast tumors. J Clin Endocrinol Metab. 82:2371–2374
Ellis AJ, Hendrick VM, Williams R, Komm BS (2015) Selective estrogen receptor modulators in clinical practice: a safety overview. Expert Opin Drug Saf. 14:921–934
Figueroa-Magalhães MC, Jelovac D, Connolly R, Wolff AC (2014) Treatment of HER2-positive breast cancer. Breast (Edinburgh, Scotland). 23:128–136
Fong CJ, Burgoon LD, Williams KJ, Forgacs AL, Zacharewski TR (2007) Comparative temporal and dose-dependent morphological and transcriptional uterine effects elicited by tamoxifen and ethynylestradiol in immature, ovariectomized mice. BMC Genomics. 8:151
Fox EM, Davis RJ, Shupnik MA (2008) ERbeta in breast cancer-onlooker, passive player, or active protector? Steroids. 73:1039–1051
Gim HJ, Li H, Jung SR, Park YJ, Ryu JH, Chung KH, Jeon R (2014) Design and synthesis of azaisoflavone analogs as phytoestrogen mimetics. Eur J Med Chem. 85:107–118
Grese TA, Sluka JP, Bryant HU, Cullinan GJ, Glasebrook AL, Jones CD, Matsumoto K, Palkowitz AD, Sato M, Termine JD, Winter MA, Yang NN, Dodge JA. 1997 Molecular determinants of tissue selectivity in estrogen receptor modulators. Proc Natl Acad Sci USA. 94:14105–14110
Hao XD, Chang J, Qin BY, Zhong C, Chu ZB, Huang J, Zhou WJ, Sun X (2015) Synthesis, estrogenic activity, and anti-osteoporosis effects in ovariectomized rats of resveratrol oligomer derivatives. Eur J Med Chem. 102:26–38
Hartman J, Strom A, Gustafsson JA (2009) Estrogen receptor beta in breast cancer-diagnostic and therapeutic implications. Steroids. 74:635–641
Howell A, Evans DG (2013) Breast cancer prevention: SERMs come of age. Lancet. 381:1795–1797
Jordan VC (2004) Selective estrogen receptor modulation: concept and consequences in cancer. Cancer Cell. 5:207–213
Khamis AAA, Ali EMM, El-Moneim MAA, Abd-Alhaseeb MM, El-Magd MA, Salim EI (2018) Hesperidin, piperine and bee venom synergistically potentiate the anticancer effect of tamoxifen against breast cancer cells. Biomed Pharmacother. 105:1335–1343
Li HY, Sun J, He ZG (2007) In vitro prediction of in vivo hepatic metabolic clearance of drugs in human. Chin J New Drugs and Clin Remedies. 26:702–707
Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (2001) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 46:3–26
Luo HF, Zhang LP, Hu CQ (2001) Five novel oligostilbenes from the roots of Caragana sinica. Tetrahedron. 57:4849–4854
Ma DY, Luo HF, Hu CQ (2010) Three stilbene tetramers from the roots of Caragana sinica. Chin J Chem. 22:207–211
Mak P, Leung YK, Tang WY, Harwood C, Ho SM (2006) Apigenin suppresses cancer cell growth through ERbeta. Neoplasia. 8:896–904
Meri De Angelis FS, Kathryn AC, Benita S, Katzenellenbogen BS, Katzenellenbogen JA(2005) Indazole estrogens: highly selective ligands for the estrogen receptor beta J Med Chem. 48:1132–1144
Mosselman S, Polman J, Dijkema R (1996) ERβ: Identification and characterization of a novel human estrogen receptor. FEBS Lett 392:49–53
Paterni I, Granchi C, Katzenellenbogen JA, Minutolo F (2014) Estrogen receptors alpha (ERalpha) and beta (ERbeta): subtype-selective ligands and clinical potential. Steroids. 90:13–29
Skliris GP, Leygue E, Watson PH, Murphy LC (2008) Estrogen receptor alpha negative breast cancer patients: estrogen receptor beta as a therapeutic target. J Steroid Biochem Mol Biol. 109:1–10
Ström A, Hartman J, Foster JS, Kietz S, Wimalasena J, Gustafsson JÅ (2004) Estrogen receptor β inhibits 17β-estradiol-stimulated proliferation of the breast cancer cell line T47D. Proc Natl Acad Sci USA 101:1566–1571
Sun X, Izumi KJ, Hu CQ, Lin GQ (2006) Convenient synthesis of indene derivatives via intramolecular friedel—crafts cyclization of tetraaryl substituted 1,3-butadienes. Cheminform. 37:430–434
Sun X, Zhu J, Zhong C et al. (2007) A concise and convenient synthesis of stilbenes via benzils and arylmethyldiphenylphosphine oxides. Chin J Chem 25:1866–1870
Tang ML, Peng P, Liu ZY, Zhang J, Yu JM, Sun X (2016) Sulfoxide-based enantioselective nazarov cyclization: divergent syntheses of (+)-Isopaucifloral F, (+)-Quadrangularin A, and (+)-Pallidol. Chemistry. 22:14535–14539
Tang ML, Zhong C, Liu ZY, Peng P, Liu XH, Sun X (2016) Discovery of novel sesquistilbene indanone analogues as potent anti-inflammatory agents. Eur J Med Chem 113:63–74
Wang M, Liu X, Zhou L, Zhu J, Sun X (2015) Fluorination of 2-substituted benzo[b]furans with Selectfluor™. Org Biomol Chem. 13:3190–3193
Zhong C, Liu XH, Hao XD, Chang J, Sun X (2013) Synthesis and biological evaluation of novel neuroprotective agents for paraquat-induced apoptosis in human neuronal SH-SY5Y cells. Eur J Med Chem. 62:187–198
Zhong C, Zhu J, Chang J, Sun X (2011) Concise total syntheses of (±)isopaucifloral F, (±)quadrangularin A, and (±)pallidol. Tetrahedron Lett 52:2815–2817
Zhu J, Zhong C, Lu HF, Li GY, Sun X (2008) Toward the synthesis of caraphenol C: substituent effect on the nazarov cyclization of 2-arylchalcones. Synlett 2008:458–462
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 information
Authors and Affiliations
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.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Rights and permissions
About this article
Cite this article
Liu, XX., Tang, ML., Zhong, C. et al. Design, synthesis and biological evaluation of novel indone derivatives as selective ERβ modulators. Med Chem Res 28, 1010–1026 (2019). https://doi.org/10.1007/s00044-019-02355-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00044-019-02355-z