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Synthesis and biological evaluation of novel tamoxifen-1,2,4-triazole conjugates

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Abstract

A new class of compounds, structurally related to the breast cancer drug tamoxifen, was designed and synthesized. The McMurry coupling reaction was used as the key synthetic step in the preparation of these analogs, and the structural assignments were made on the basis of \(^{1}\hbox {H}\) NMR, \(^{13}\hbox {C}\) NMR, and HRMS studies. The absolute stereochemistry of E and Z isomers was unambiguously confirmed by a single-crystal X-ray diffraction analysis. Water was found to be an inexpensive nontoxic and effective medium for the C–N bond formation. Utilizing this protocol, various tamoxifen derivatives were synthesized in good yields. Environmental acceptability, low cost, and high yields are the important features of this protocol. These compounds were evaluated for their antiproliferative activity on five human tumor cell lines. Compound 4p (\(\mathrm{GI}_{50} = 0.23\,\upmu \hbox {M}\)) showed improved antiproliferative activity against breast cancer cell line (MDA-MB-231) compared to tamoxifen (\(\mathrm{GI}_{50} = 0.24 \,\upmu \hbox {M}\)), while the compound 4o (\(\mathrm{GI}_{50} = 0.12\,\upmu \mathrm{M}\)) exhibited similar activity against SiHa compared to the reference drug, tamoxifen (\(\mathrm{GI}_{50} = 0.12\,\upmu \mathrm{M}\)). In addition, these analogs were investigated for their antibacterial activity against six bacterial strains. Preliminary results indicate that some of the newly synthesized title compounds exhibited promising antibacterial activity compared with the standard drug, vancomycin.

Graphical Abstract

A new class of compounds were designed rationally by the replacement of a ethyl group in tamoxifen with a methylene (1H-1,2,4-triazole) group. The absolute stereochemistry of E and Z isomers were unambiguously confirmed by a single-crystal X-ray diffraction analysis. The title compounds were evaluated for their antiproliferative and antibacterial activities.

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References

  1. Bhandari PR (2015) Crocus sativus L. (saffron) for cancer chemoprevention: a mini review. J Tradit Complement Med 5:81–87. doi:10.1016/j.jtcme.2014.10.009

    Article  PubMed  PubMed Central  Google Scholar 

  2. Howell A (2001) Future use of selective estrogen receptor modulators and aromatase inhibitors. Clin Cancer Res 7:4402s–4410s

    CAS  PubMed  Google Scholar 

  3. Jordan VC (1993) A current view of tamoxifen for the treatment and prevention of breast cancer. Br J Pharmacol 110:507–517. doi:10.1111/j.1476-5381.1993.tb13840.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Cuzick J, Sestak I, Cawthorn S, Hamed H, Holli K, Howell A, Forbes JF (2015) Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial. Lancet Oncol 16:67–75. doi:10.1016/S1470-2045(14)71171-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Buzdar AU, Hortobagyi GN (1998) Tamoxifen and toremifene in breast cancer: comparison of safety and efficacy. J Clin Oncol 16:348–353

    CAS  PubMed  Google Scholar 

  6. Vogel CL, Johnston MA, Capers C, Braccia D (2014) Toremifene for breast cancer: a review of 20 years of data. Clin Breast Cancer 14:1–9. doi:10.1016/j.clbc.2013.10.014

    Article  CAS  PubMed  Google Scholar 

  7. Bonneterre J, Thürlimann B, Robertson JFR, Krzakowski M, Mauriac L, Koralewski P, Vergote I, Webster A, Steinberg M, von Euler M (2000) Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study. J Clin Oncol 18:3748–3757

    CAS  PubMed  Google Scholar 

  8. Mouridsen H, Gershanovich M, Sun Y, Pérez-Carrión R, Boni C, Monnier A, Apffelstaedt J, Smith R, Sleeboom HP, Jaenicke F, Pluzanska A, Dank M, Becquart D, Bapsy PP, Salminen E, Snyder R, Chaudri-Ross H, Lang R, Wyld P, Bhatnagar A (2003) A Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol 21:2101–2109. doi:10.1200/JCO.2003.04.194

    Article  CAS  PubMed  Google Scholar 

  9. Tanpure RP, Harkrider AR, Strecker TE, Hamel E, Trawick ML, Pinney KG (2009) Application of the McMurry coupling reaction in the synthesis of tri- and tetra-arylethylene analogues as potential cancer chemotherapeutic agents. Bioorg Med Chem 17:6993–7001. doi:10.1016/j.bmc.2009.08.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. MdUddin J, Rao PNP, McDonald R, Knaus EE (2004) A new class of acyclic 2-alkyl-1,1,2-triaryl \((Z)\)-olefins as selective cyclooxygenase-2 inhibitors. J Med Chem 47:6108–6111. doi:10.1021/jm049523y

    Article  Google Scholar 

  11. Christodoulou MS, Fokialakis N, Passarella D, Argaez ANG, Gia OM, Pongratz I, Via LD, Haroutounian SA (2013) Synthesis and biological evaluation of novel tamoxifen analogues. Bioorg Med Chem 21:4120–4131. doi:10.1016/j.bmc.2013.05.012

    Article  CAS  PubMed  Google Scholar 

  12. Abdellatif KRA, Belal A, Omar HA (2013) Design, synthesis and biological evaluation of novel triaryl \((Z)\)-olefins as tamoxifen analogues. Bioorg Med Chem Lett 23:4960–4963. doi:10.1016/j.bmcl.2013.06.056

    Article  CAS  PubMed  Google Scholar 

  13. Rey J, Hu H, Snyder JP, Barrett AGM (2012) Synthesis on novel tamoxifen derivatives. Tetrahedron 68:9211–9217. doi:10.1016/j.tet.2012.08.089

    Article  CAS  Google Scholar 

  14. Lednicer D, Lyster SC, Duncan GW (1967) Mammalian antifertility agents. IV. Basic 3,4-dihydronaphthalenes and 1,2,3,4-tetrahydro-1-naphthols. J Med Chem 10:78–84. doi:10.1021/jm00313a016

  15. Agouridas V, Laïos I, Cleeren A, Kizilian E, Magnier E, Blazejewskia JC, Leclercq G (2006) Loss of antagonistic activity of tamoxifen by replacement of one \(N\)-methyl of its side chain by fluorinated residues. Bioorg Med Chem Lett 14:7531–7538. doi:10.1016/j.bmc.2006.07.012

    Article  CAS  Google Scholar 

  16. Robertson DW, Katzenellenbogen JA, Hayes JR, Katzenellenbogen BS (1982) Antiestrogen basicity-activity relationships: a comparison of the estrogen receptor binding and antiuterotrophic potencies of several analogs of (Z)-1,2-diphenyl-1-[4-[2-(dimethylamino)ethoxy]phenyl]-1-butene (Tamoxifen, Nolvadex) having altered basicity. J Med Chem 25:167–171. doi:10.1021/jm00344a015

    Article  CAS  PubMed  Google Scholar 

  17. deMédina P, Favre G, Poirot M (2004) Multiple targeting by the antitumor drug tamoxifen: a structure-activity study. Curr Med Chem Anti Cancer Agents 4:491–508. doi:10.2174/1568011043352696

    Article  Google Scholar 

  18. Kangas L (1990) Review of the pharmacological properties of toremifene. J Steroid Biochem 36:191–195. doi:10.1016/0022-4731(90)90003-B

    Article  CAS  PubMed  Google Scholar 

  19. Yang DJ, Wallace S, Tansey W, Wright KC, Kuang LR, Tilbury RS, Diego I, Lim JL, Emran AM, Kim EE (1991) Synthesis and in vitro receptor binding studies of fluorotamoxifen analogues. Pharm Res 8:174–177. doi:10.1023/A:1015879717742

    Article  CAS  PubMed  Google Scholar 

  20. Forest BM, Landelle G, Roy JA, Lacroix J, Gaudreault RC, Paquin JF (2013) Synthesis and growth inhibition activity of fluorinated derivatives of tamoxifen. Bioorg Med Chem Lett 23:1712–1715. doi:10.1016/j.bmcl.2013.01.057

    Article  Google Scholar 

  21. Bariwal J, Van der Eycken E (2013) C-N bond forming cross-coupling reactions: an overview. Chem Soc Rev 42:9283–9303. doi:10.1039/C3CS60228A

    Article  CAS  PubMed  Google Scholar 

  22. Gawande MB, Bonifácio VDB, Luque R, Branco PS, Varma RS (2013) Benign by design: catalyst-free in-water, on-water green chemical methodologies in organic synthesis. Chem Soc Rev 42:5522–5551. doi:10.1039/C3CS60025D

    Article  CAS  PubMed  Google Scholar 

  23. Megid MA, Elnagdi MH, Negm AM (2002) Studies with 1-functionally substituted alkyl azoles: novel synthesis of functionally substituted azolylbenzimidazoles and functionally substituted azolyl-1,2,4-triazoles. J Heterocycl Chem 39:105–108. doi:10.1002/jhet.5570390115

    Article  Google Scholar 

  24. Coe PL, Scriven CE (1986) Crossed coupling of functionalised ketones by low valent titanium (the McMurry reaction): a new stereoselective synthesis of tamoxifen. J Chem Soc Perkin Trans 1:475–477. doi:10.1039/P19860000475

  25. Bedford GR, Richardson DN (1966) Preparation and identification of cis and trans isomers of a substituted triarylethylene. Nature 212:733–734. doi:10.1038/212733b0

    Article  CAS  Google Scholar 

  26. Shani J, Gazit A, Livshitz T, Biran S (1985) Synthesis and receptor-binding affinity of fluorotamoxifen, a possible estrogen-receptor imaging agent. J Med Chem 28:1504–1511. doi:10.1021/jm00148a022

    Article  CAS  PubMed  Google Scholar 

  27. McCague R, Leclercq G, Legros N, Goodman J, Blackburn GM, Jarman M, Foster AB (1989) Derivatives of tamoxifen. Dependence of antiestrogenicity on the 4-substituent. J Med Chem 32:2527–2533. doi:10.1021/jm00132a006

    Article  CAS  PubMed  Google Scholar 

  28. Harper MJK, Walpole AL (1966) Contrasting endocrine activities of cis and trans isomers in a series of substituted triphenylethylenes. Nature 212:87–87. doi:10.1038/212087a

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

MRK is thankful to the Council of Scientific & Industrial Research (CSIR), New Delhi, India, for the award of fellowships. We thank CSIR for the financial support under the 12th Five Year plan projects “Affordable Cancer Therapeutics (ACT)” (CSC 0301) and “Screening Molecules in Lead Exploration (SMiLE)” (CSC 0111).

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Authors and Affiliations

  1. Medicinal Chemistry & Pharmacology Division, Discovery Laboratory, CSIR–Indian Institute of Chemical Technology, Hyderabad, India

    M. S. R. Murty & Mohana Rao Katiki

  2. Centre for X-Ray Crystallography, CSIR–Indian Institute of Chemical Technology, Hyderabad, India

    Jagadeesh Babu Nanubolu

  3. Centre for Chemical Biology, CSIR–Indian Institute of Chemical Technology, Hyderabad, India

    Srujana Garimella, Sowjanya Polepalli & Nishant Jain

  4. Bioengineering & Environmental Sciences, CSIR–Indian Institute of Chemical Technology, Hyderabad, India

    Sudheer Kumar Buddana & R. S. Prakasham

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  1. M. S. R. Murty
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Correspondence to M. S. R. Murty.

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Murty, M.S.R., Katiki, M.R., Nanubolu, J.B. et al. Synthesis and biological evaluation of novel tamoxifen-1,2,4-triazole conjugates. Mol Divers 20, 687–703 (2016). https://doi.org/10.1007/s11030-016-9677-8

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