Skip to main content
SpringerLink
Log in

Synthesis of a radioiodinated antiestrogen glucuronide compound (TAM-G)

  • Published:
Journal of Radioanalytical and Nuclear Chemistry Aims and scope Submit manuscript

Abstract

Tamoxifen [TAM; ([Z]-2-[4-(1,2-diphenyl-1-di-butenyl)-phenoxy]-N,N-dimethylethanamine) has been used as an antiestrogen drug for treatment and prevention of human breast cancer. The aim of this study is conjugation of hydrophilic glucuronic acid to the starting substance TAM and labeling with 131I using iodogen as oxidizing agent. The reactions are completed in three steps, including enzymatic reaction, with the following sub-steps; preparation of microsomal fraction from rat liver and subsequent purification of UDP-glucuronyl transferase (UDPGT), estimation of protein amount in microsomal samples and glucuronidation reaction. Synthesized glucuronide derivative (TAM-G) was purified using high performance liquid chromatography (HPLC). Mass spectroscopy of cold standard showed that the labeling most probably occurs in ortho position to the aromatic ring containing the ether group of TAM-G as expected. Radiochemical yield of the 131I labeled TAM-G ([131I]TAM-G) is determined by using Thin Layer Radio Chromatography (TLRC). The radiopharmaceutical potential of [131I]TAM-G is examined by biodistribution studies that is run on normal female Albino Wistar rats. According to biodistribution results 131I labeled TAM-G may be proposed as a new antiestrogen glucuronide imaging agent for breast and uterus.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Martin EA, Brown K, Gaskell M, Al-Azzawi F, Garner RC, Boocock DJ et al (2003) Tamoxifen DNA damage deteted in human endometrium using accelerator mass spectrometry. Cancer Res 63:8461–8465

    CAS  Google Scholar 

  2. Musa MA, Khan MOF, Cooperwood JS (2007) Medicinal chemistry and emerging strategies applied to the development of selective estrogen receptor modulators (SERMs). Curr Med Chem 14:1249–1261

    Article  CAS  Google Scholar 

  3. Marcsek Z, Kocsis Z, Jakab M, Szende B, Tompa A (2004) The efficacy of tamoxifen in estrogen receptor-positive breast cancer cells is enhanced by a medical nutriment. Cancer Biother Radiopharm 19:746–753

    Article  CAS  Google Scholar 

  4. Sperker B, Backman JT, Kroemer HK (1997) The role of beta-glucuronidase in drug disposition and drug targeting in humans. J Clin Pharmacol 33:18–31

    CAS  Google Scholar 

  5. Houba PHJ, Leenders RGG, Boven E, Scheeren JW, Pinedo HM, Haisma HJ (1996) Characterization of novel anthracycline prodrugs activated by human β-glucuronidase for use in antibody-directed enzyme prodrug therapy. Biochem Pharmacol 9:455–463

    Article  Google Scholar 

  6. Kamal A, Tekumalla V, Raju P, Naidu VGM, Diwan PV, Sistla R (2008) Pyrrolo[2,1-c][1,4]benzodiazepine-β-glucuronide prodrugs with a potential for selective therapy of solid tumors by PMT and ADEPT strategies. Bioorg Med Chem Lett 18:3769–3773

    Article  CAS  Google Scholar 

  7. Starkey DE, Han A, Bao JJ, Ahn CH, Wehmeyer KR, Prenger MC et al (2001) Fluorogenic assay for β-glucuronidase using microchip-based capillary electrophorrsis. J Chromatogr 762:33–41

    Article  CAS  Google Scholar 

  8. Minton JP, Walaszek Z, Schooley W, Hanausek WM, Webb TE (1986) Beta-Glucuronidase levels in patients with fibrocystic breast disease. Breast Cancer Res Treat 8:217–222

    Article  CAS  Google Scholar 

  9. Delpassand SE, Yang JD, Wallace S, Cherıf A, Quadrı MS, Price J et al (1996) Synthesis, biodistribution and estrogen receptor scintigraphy of Indium-111-diethylenetriamine pentaacetic acid-tamoxifen analogue. J Pharm Sci 85:553–559

    Article  CAS  Google Scholar 

  10. Yurt A, Biber Muftuler FZ, Unak P, Enginar H, Yolcular S, Acar C (2009) Synthesis of a novel anti estrogen radioligand (99mTc-TOR-DTPA). Cancer Biother Radiopharm 24:707–716

    Article  CAS  Google Scholar 

  11. Zihnioglu FEU (1992) Graduate school of natural and applied sciences chemistry department biochemistry. Doctorate Thesis; 169

  12. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  CAS  Google Scholar 

  13. Alkharfy KM, Frye RF (2002) Sensitive liquid chromatographic method using fluorescence detection for the determination of estradiol 3- and 17-glucuronides in rat and human liver microsomal incubations: formation kinetics. J Chromatogr B Analyt Technol Biomed Life Sci 1:33–38

    Article  Google Scholar 

  14. Stevenson DE, Hubl U (1999) Optimization of β-glucuronide synthesis using UDP-glucuronyl transferase. Enzyme Microbial Technol 24:388–396

    Article  CAS  Google Scholar 

  15. Stevenson DE (1999) Optimisation of UDP-glucuronyl transferase-catalysed synthesis of testosterone-β-D-glucuronide by inhibition of contaminating ß-glucuronidase. Biotechnol Tech 13:17–21

    Article  CAS  Google Scholar 

  16. Mihailescu R, Aboul-Enein HY, Efstatide MD (2000) Identification of tamoxifen and metabolites in human male urine by GC/MS. Biomed Chromatogr 14:180–183

    Article  CAS  Google Scholar 

  17. Ünak T, Akgün Y, Duman Y, Erenel G (2001) Self-radioiodination of iodogen. Appl Radiat Isot 54:749–752

    Article  Google Scholar 

  18. Biber Muftuler FZ, Unak P, Teksoz S, Acar C, Yolcular S, Yürekli Y (2008) 131I labeling of tamoxifen and biodistribution studies in rats. Appl Radiat Isot 66:178–187

    Article  CAS  Google Scholar 

  19. Biber FZ, Unak P, Ertay T, Medine EI, Zihnioglu F, Tascı C et al (2006) Synthesis of an estradiol glucuronide derivative and investigation of its radiopharmaceutical potential. Appl Radiat Isot 64:778–788

    Article  CAS  Google Scholar 

  20. Biber Muftuler FZ, Unak P, Yolcular S, Yurt Kilcar A, Ichedef C, Enginar H, Sakarya S (2010) Synthesis, radiolabeling and in vivo tissue distribution of an anti-oestrogen glucuronide compound, 99mTc-TOR-G. Anticancer Res 30:1249–1256

    Google Scholar 

  21. Delpassand ES, Yang DG, Wallace S, Cherif A, Quadri SM, Price G et al (1996) Synthesis, biodistribution, and estrogen receptor scintigraphy of indium-111-diethyleneaminpentaacetic acid-tamoxifen analogue. J Pharm Sci 85:553–559

    Article  CAS  Google Scholar 

  22. Kon OL (1983) An antiestrogen binding protein in human tissues. J Biol Chem 258:3173–3177

    CAS  Google Scholar 

  23. Winborn WB, Sheridan PJ, McGill HC (1987) Sex steroid in the stomach, liver, pancreas, and gastrointestinal tract of the baboon. Gastroenterology 92:23–32

    CAS  Google Scholar 

  24. Ciocca DR, Vargas LM (1995) Estrogen receptors in human nontarget tissues: biological and clinical implications. Endocr Rev 16:35–62

    CAS  Google Scholar 

  25. Enginar H, Unak P, Lambrecht FY, Biber FZ, Medine IE, Çetinkaya B (2005) Synthesis of I-131 labeled estrone derivatives and biodistribution studies on rats. J Radioanal Nucl Chem 264:535–539

    Article  CAS  Google Scholar 

  26. Unak T, Avcıbaşı U, Yıldırım Y, Cetinkaya B (2003) Attempts to develop a new nuclear measurement technique of β-glucuronidase levels in biological samples. Czechoslovak J Phys 53:A797–A802

    Article  CAS  Google Scholar 

  27. Fabian C, Sternson L, El-serafi M, Cain L, Hearne E (1981) Clinical pharmacology of Tamoxifen in patients with breast cancer: correlation with clinical data. Cancer 48:876–882

    Article  CAS  Google Scholar 

  28. Silva MC, Luciana P, Gano L, SáMelo ML, Inohae E, Shuntaro M et al (2001) Synthesis and biological evaluation of two new radiolabelled estrogens: (125I)(E)-3-methoxy-17α-iodovinylestra-1,3,5(10),6-tetraen-17β-ol and (125I)(Z)-3-methoxy-17α-iodovinylestra-1,3,5(10),6-tetraen-17β-ol. Appl Radiat Isot 54:227–239

    Article  Google Scholar 

  29. Strickland LA, Ponce YZ, Hunter DH, Zabel PL, Powe JE, Morrissey G et al (1990) Amino and iodotamoxifens: synthesis estrogen receptor affinity and biodistribution. Drug Des Deliv 6:195–212

    CAS  Google Scholar 

Download references

Acknowledgements

The authors thank Prof. Dr. Tamerkan OZGEN and Research Assistant Murat ERDOGAN for GS/MS/MS measurements and Assoc. Prof. Cavit KAZAZ and Dr. Murat ACAR for NMR spectra and MSc. Feriha TOKSOZ and Research Assistant Ayfer YURT KILCAR for technical helping.

Disclosure

This work financially supported by T.R. Prime Ministry State Planning Organization Contract No 06 DPT 06 and Ege University Research Fund contact no 2007 NBE 006.

Author information

Authors and Affiliations

  1. Department of Nuclear Applications, Institute of Nuclear Sciences, Ege University, Bornova, Izmir, 35100, Turkey

    Fazilet Zumrut Biber Muftuler, Perihan Unak, Çigdem Içhedef & Ilknur Demir

Authors
  1. Fazilet Zumrut Biber Muftuler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Perihan Unak
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Çigdem Içhedef
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ilknur Demir
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fazilet Zumrut Biber Muftuler.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Cite this article

Muftuler, F.Z.B., Unak, P., Içhedef, Ç. et al. Synthesis of a radioiodinated antiestrogen glucuronide compound (TAM-G). J Radioanal Nucl Chem 287, 679–689 (2011). https://doi.org/10.1007/s10967-010-0932-7

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10967-010-0932-7

Keywords

Search

Navigation