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Design, synthesis and apoptosis inducing activity of nonsteroidal flavone-methanesulfonate derivatives on MCF-7 cell line as potential sulfatase inhibitor

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Abstract

In recent years, focusing on new potent anticancer agents with selective activity is one of the greatest challenges in cancer therapy. Breast cancer is the most common cancer and the main cause of cancer deaths in women. The sulfatase enzyme plays an important role in converting the sulfated steroids into non-sulfate steroid hormones, which increases the growth and development of many hormone-dependent cancers, such as breast cancer. In this regard, structure-based optimization was conducted to design novel flavone-sulfonates pharmacophore as a new steroid sulfatase inhibitor. In the present work, the conventional methods for the synthesis of 4-oxo-2-phenyl-4H-chromen-7-yl methanesulfonate derivatives were reported. Their cytotoxicity was evaluated with MTT assay against a breast cancer cell line (MCF-7). The apoptosis inducing activity of the most cytotoxic compound 3c with an IC50 value of 0.615 µM was evaluated in comparison to docetaxel in the presence of estradiol which is a crucial growth factor to survive the cancerous cells. The results of double staining Annexin V-FITC/PI analysis suggested that the cytotoxic activity of this compound 3c in MCF-7 cells occurs via apoptosis. Molecular docking studies were conducted to clarify the inhibition mode of the most promising compound (3c) over the sulfatase (1P49) binding site. The analysis revealed the role of hydrogen bond interaction with Gly181 and hydrophobic interactions through the 1P49 active site in the ligand-receptor complex as significant descriptors to rationalize the potential inhibition activity.

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References

  1. American Cancer Society. Cancer Facts & Figures 2018. Atlanta: American Cancer Society; 2018.

  2. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–917.

  3. Pasqualini JR. The selective estrogen enzyme modulators in breast cancer: a review. Biochim Biophys Acta. 2004;1654:123–43..

  4. Deroo BJ, Korach KS. Estrogen receptors and human disease. J Clin Investig. 2006;116:561–70.

    Article  CAS  Google Scholar 

  5. Saha T, Makar S, Swetha R, Gutti G, Singh SK. Estrogen signaling: an emanating therapeutic target for breast cancer treatment. Eur J Med Chem. 2019;177:116–43.

    Article  CAS  Google Scholar 

  6. Ireson CR, Chander SK, Purohit A, Parish DC, Woo LWL, Potter BVL. Pharmacokinetics of the nonsteroidal steroid sulphatase inhibitor 667 COUMATE and its sequestration into red blood cells in rats. Br J Cancer. 2004;91:1399–404.

    Article  CAS  Google Scholar 

  7. Reed MJ, Purohit A, Woo LWL, Newman SP, Potter BVL. Steroid sulfatase: molecular biology, regulation, and inhibition. Endocr Rev 2005;26:171–202.

    Article  CAS  Google Scholar 

  8. Rižner TL. The Important Roles of Steroid Sulfatase and Sulfotransferases in Gynecological Diseases. Front Pharmacol 2016;7:30.

    Article  Google Scholar 

  9. Geisler J, Sasano H, Chen S, Purohit A. Steroid sulfatase inhibitors: Promising new tools for breast cancer therapy? J Steroid Biochem Mol Biol 2011;125:39–45.

    Article  CAS  Google Scholar 

  10. Thakur A, Singla R, Jaitak V. Coumarins as anticancer agents: a review on synthetic strategies, mechanism of action and SAR studies. Eur J Med Chem. 2015;101:476–95.

    Article  CAS  Google Scholar 

  11. Maltais R, Ngueta Djiemeny A, Roy J, Barbeau X, Lambert JP, Poirier D. Design and synthesis of dansyl-labeled inhibitors of steroid sulfatase for optical imaging. Bioorg Med Chem. 2020;28:115368.

    Article  CAS  Google Scholar 

  12. Hng Y, Lin MH, Lin TS, Liu IC, Lin IC, Lu YL, et al. Design and synthesis of 3-benzylaminocoumarin-7-O-sulfamate derivatives as steroid sulfatase inhibitors. Bioorg Chem 2020;96:103618.

    Article  CAS  Google Scholar 

  13. Moi D, Foster PA, Rimmer LG, Jaffri A, Deplano A, Balboni G, et al. Synthesis and in vitro evaluation of piperazinyl-ureido sulfamates as steroid sulfatase inhibitors. Eur J Med Chem. 2019;182:111614.

    Article  CAS  Google Scholar 

  14. Grienke U, Kaserer T, Kirchweger B, Lambrinidis G, Kandel RT, Foster PA, et al. Steroid sulfatase inhibiting lanostane triterpenes – Structure activity relationship and in silico insights. Bioorg Chem 2020;95:103495.

    Article  CAS  Google Scholar 

  15. Purohit A, Dauvois S, Parker MG, Potter BVL, Williams GJ, Reed MJ. The hydrolysis of oestrone sulphate and dehydroepiandrosterone sulphate by human steroid sulphatase expressed in transfected COS-1 cells. J Steroid Biochem Mol Biol 1994;50:101–4.

    Article  CAS  Google Scholar 

  16. Purohit A, Williams GJ, Howarth NM, Potter BV, Reed MJ. Inactivation of steroid sulfatase by an active site-directed inhibitor, estrone-3-O-sulfamate. Biochemistry. 1995;34:11508–14.

  17. Thomas MP, Potter BV. Discovery and Development of the Aryl O-Sulfamate Pharmacophore for Oncology and Women’s Health. J Med Chem. 2015;58:7634–58..

  18. Kozak W, Daśko M, Masłyk M, Pieczykolan JS, Gielniewski B, Rachon J, et al. Phosphate tricyclic coumarin analogs as steroid sulfatase inhibitors: synthesis and biological activity. RSC Adv. 2014;5:44350–44358.

    Article  Google Scholar 

  19. Demkowicz S, Kozak W, Daśko M, Masłyk M, Gielniewski B, Rachon J. Synthesis of bicoumarin thiophosphate derivatives assteroid sulfatase inhibitors. Eur J Med Chem. 2015;101:358–66.

  20. Nussbaumer P, Billich A. Steroid sulfatase inhibitors. Med Res Rev. 2004;24:529–76.

    Article  CAS  Google Scholar 

  21. Reed MJ, Potter BVL. Compounds that inhibit oestrone sulphatase and/or aromatase and methods for making and using, 2003;US6506792B1.

  22. Nussbaumer P, Lehr P, Billich A. 2-Substituted 4-(thio)chromenone 6-O-sulfamates: potent inhibitors of human steroid sulfatase. J Med Chem. 2002;45:4310–20.

  23. Nussbaumer P, Winiski AP, Billich A. Estrogenic potential of 2-alkyl-4-(thio) chromenone 6-O-sulfamates: potent inhibitors of human steroid sulfatase. J Med Chem. 2003;46:5091–5094.

    Article  CAS  Google Scholar 

  24. Ouellet C, Maltais R, Ouellet E, Barbeau X, Lagüe P, Poirier D. Discovery of a sulfamate-based steroid sulfatase inhibitor with intrinsic selective estrogen receptor modulator properties. Eur J Med Chem. 2016;119:169–82.

    Article  CAS  Google Scholar 

  25. Edraki N, Iraji A, Firuzi O, Fattahi Y, Mahdavi M, Foroumadi A, et al. 2-Imino 2H-chromene and 2-(phenylimino) 2H-chromene 3-aryl carboxamide derivatives as novel cytotoxic agents: synthesis, biological assay, and molecular docking study. J Iran Chem Soc. 2016;13:2163–71.

    Article  CAS  Google Scholar 

  26. Saeedi M, Maleki A, Iraji A, Hariri R, Akbarzadeh T, Edraki N, et al. Synthesis and bio-evaluation of new multifunctional methylindolinone-1,2,3-triazole hybrids as anti-Alzheimer’s agents. J Mol Struct. 2021;1229:129828.

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Authors and Affiliations

  1. Department of Chemistry, North Tehran Branch, Islamic Azad University, Tehran, Iran

    Mahdiyeh H. S. Javadi

  2. Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

    Aida Iraji

  3. Central Research Laboratory, Shiraz University of Medical Sciences, Shiraz, Iran

    Aida Iraji

  4. Department of Biotechnology, Iranian Research Organization for Science and Technology, Tehran, Iran

    Maliheh Safavi

  5. Department of Pharmacognosy and Pharmaceutical Biotechnology, School of Pharmacy, Iran University of Medical Sciences, Tehran, Iran

    Hamed Montazeri

  6. Department of Medical biotechnology, Faculty of allied medicine, Iran university of Medical sciences, Tehran, Iran

    Parastoo Tarighi & Samane Eftekhari

  7. Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

    Latifeh Navidpour

  8. Department of Medicinal Chemistry, School of Pharmacy, Iran University of Medical Sciences, Tehran, Iran

    Seyedeh Sara Mirfazli

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  1. Mahdiyeh H. S. Javadi
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  2. Aida Iraji
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Correspondence to Latifeh Navidpour or Seyedeh Sara Mirfazli.

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Javadi, M.H.S., Iraji, A., Safavi, M. et al. Design, synthesis and apoptosis inducing activity of nonsteroidal flavone-methanesulfonate derivatives on MCF-7 cell line as potential sulfatase inhibitor. Med Chem Res 30, 1677–1687 (2021). https://doi.org/10.1007/s00044-021-02767-w

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  • DOI: https://doi.org/10.1007/s00044-021-02767-w

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