Skip to main content
SpringerLink
Log in

In vitro and in vivo antitumor effects of (4-methoxyphenyl)(3,4,5-trimethoxyphenyl)methanone

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

(4-Methoxyphenyl)(3,4,5-trimethoxyphenyl)methanone (PHT) is a phenstatin analog compound. PHT is a known tubulin inhibitor that has potent cytotoxic activity. In the present study, PHT was synthesized and its antitumor activity was determined using in vitro and in vivo experimental models.

Methods

The in vitro cytotoxic activity of the PHT was determined by the MTT assay. The antimitotic and hemolytic effects were determined based on the inhibition of sea urchin embryo development and lysis of mouse erythrocytes, respectively. In vivo antitumor activity was assessed in mice inoculated with sarcoma 180 cells.

Results

In vitro, PHT displayed cytotoxicity in tumor cell lines, showing IC50 values in the nanomolar range. In addition, it inhibited sea urchin embryo development during all phases examined, first and third cleavage and blastula stage. However, PHT did not induce hemolysis using mouse erythrocytes, suggesting that the cytotoxicity of PHT does not involve membrane damage. The in vivo study demonstrated tumor inhibition rates of 30.9 and 48.2% for PHT at doses of 20 and 40 mg/kg, respectively. In addition, PHT was also able to increase the response elicited by 5-fluorouracil (5-FU) from 33.3 to 55.7%. The histopathological analysis of liver, kidney, and spleen showed that they were just moderately affected by PHT treatment. Neither enzymatic activity of transaminases nor urea levels were significantly affected. Hematological analysis showed leukopenia after 5-FU treatment, but this effect was prevented when 5-FU was combined with PHT.

Conclusions

In conclusion, PHT exhibited in vitro and in vivo antitumor effects without substantial toxicity.

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

Similar content being viewed by others

References

  1. Vernon B, Powell S (2004) Localized delivery system for phenstatin using N-isopropylacrylamide, WO 2004009127

  2. Pettit GR, Grealish MP (2001) Synthesis of hydroxyphenstatin and the prodrugs thereof as anticancer and antimicrobial agents, WO 2001081288

  3. Alvarez C, Alvarez R, Corchete P, Pérez-Melero C, Peláez R, Medarde M (2008) Naphthylphenstatins as tubulin ligands: synthesis and biological evaluation. Bioorg Med Chem 16:8999–9008

    Article  PubMed  CAS  Google Scholar 

  4. Alvarez R, Alvarez C, Mollinedo F, Sierra BG, Medarde M, Peláez R (2009) Isocombretastatins A: 1,1-diarylethenes as potent inhibitors of tubulin polymerization and cytotoxic compounds. Bioorg Med Chem 17:6422–6431

    Article  PubMed  CAS  Google Scholar 

  5. Alvarez C, Alvarez R, Corchete P, Pérez-Melero C, Peláez R, Medarde M (2010) Exploring the effect of 2,3,4-trimethoxy-phenyl moiety as a component of indolephenstatins. Eur J Med Chem 45:588–597

    Article  PubMed  CAS  Google Scholar 

  6. Pettit GR, Toki B, Herald DL, Verdier-Pinard P, Boyd MR, Hamel E, Pettit RK (1998) Antineoplastic agents. 379. Synthesis of phenstatin phosphate. J Med Chem 41:1688–1695

    Article  PubMed  CAS  Google Scholar 

  7. Cushman M, Nagarathnam D, Gopal D, He HM, Lin CM, Hamel E (1992) Synthesis and evaluation of analogs of (Z)-1-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)ethene as potential cytotoxic and antimitotic agents. J Med Chem 35:2293–2306

    Article  PubMed  CAS  Google Scholar 

  8. Liou JP, Chang CW, Song JS, Yang YN, Yeh CF, Tseng HY, Lo YK, Chang YL, Chang CM, Hsieh HP (2002) Synthesis and structure-activity relationship of 2-aminobenzophenone derivatives as antimitotic agents. J Med Chem 45:2556–2562

    Article  PubMed  CAS  Google Scholar 

  9. Liou JP, Chang JY, Chang CW, Chang CY, Mahindroo N, Kuo FM, Hsieh HP (2004) Synthesis and structure-activity relationships of 3-aminobenzophenones as antimitotic agents. J Med Chem 47:2897–2905

    Article  PubMed  CAS  Google Scholar 

  10. Frank HR, Tarbell DS (1948) Friedel-Crafts reaction on highly methoxylated compounds. J Am Chem Soc 70:1276–1278

    Article  CAS  Google Scholar 

  11. Barbosa EG, Bega LAS, Beatriz A, Sarkar T, Hamel E, Amaral MS, Lima DP (2009) A diaryl sulfide, sulfoxide, and sulfone bearing structural similarities to combretastatin A-4. Eur J Med Chem 44:2685–2688

    Article  PubMed  CAS  Google Scholar 

  12. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 16:55–63

    Article  Google Scholar 

  13. Jimenez PC, Fortier SC, Lotufo TMC, Pessoa C, Moraes MEA, Moraes MO, Costa-Lotufo LV (2003) Biological activity in extracts of ascidians (Tunicata, Ascidiacea) from the northeastern Brazilian coast. J Exp Mar Biol Ecol 287:93–101

    Article  Google Scholar 

  14. Bezerra DP, Castro FO, Alves APNN, Pessoa C, Moraes MO, Silveira ER, Lima MAS, Elmiro FJM, Costa-Lotufo LV (2006) In vivo growth-inhibition of sarcoma 180 by piplartine and piperine, two alkaloid amides from Piper. Braz J Med Biol Res 39:801–807

    Article  PubMed  CAS  Google Scholar 

  15. Wu M, Sun Q, Yang C, Chen D, Ding J, Chen Y, Lin L, Xie Y (2007) Synthesis and activity of Combretastatin A-4 analogues: 1, 2, 3-thiadiazoles as potent antitumor agents. Bioorg Med Chem Lett 17:869–873

    Article  PubMed  CAS  Google Scholar 

  16. Bezerra DP, Pessoa C, Moraes MO, Alencar NM, Mesquita RO, Lima MW, Alves AP, Pessoa OD, Chaves JH, Silveira ER, Costa-Lotufo LV (2008) In vivo growth inhibition of sarcoma 180 by piperlonguminine, an alkaloid amide from the Piper species. J Appl Toxicol 28:599–607

    Article  PubMed  CAS  Google Scholar 

  17. Pessoa C, Silveira ER, Lemos TL, Wetmore LA, Moraes MO, Leyva A (2000) Antiproliferative effects of compounds derived from plants of Northeast Brazil. Phytother Res 14:187–191

    Article  PubMed  CAS  Google Scholar 

  18. Costa-Lotufo LV, Silveira ER, Barros MC, Lima MA, De Moraes ME, De Moraes MO, Pessoa C (2004) Antiproliferative effects of abietane diterpenes from Aegiphila lhotzkyana. Planta Med 70:180–182

    Article  PubMed  CAS  Google Scholar 

  19. Jacobs RS, White S, Wilson L (1981) Selective compounds derived from marine organisms: effects on cell division in fertilized sea urchin eggs. Fed Proc 40:26–29

    PubMed  CAS  Google Scholar 

  20. Alvarez C, Alvarez R, Corchete P, Pérez-Melero C, Peláez R, Medarde M (2007) Synthesis and biological activity of naphthalene analogues of phenstatins: naphthylphenstatins. Bioorg Med Chem Lett 17:3417–3420

    Article  PubMed  CAS  Google Scholar 

  21. Fusetani N (1987) Marine metabolites which inhibit development of echinoderm embryos. In: Scheur PJ (ed) Biorganic marine chemistry. Springer, Berlin, pp 61–92

    Google Scholar 

  22. Costa-Lotufo LV, Khan MT, Ather A, Wilke DV, Jimenez PC, Pessoa C, de Moraes ME, de Moraes MO (2005) Studies of the anticancer potential of plants used in Bangladeshi folk medicine. J Ethnopharmacol 99:21–30

    Article  PubMed  Google Scholar 

  23. Bezerra DP, Pessoa C, de Moraes MO, Silveira ER, Lima MA, Elmiro FJ, Costa-Lotufo LV (2005) Antiproliferative effects of two amides, piperine and piplartine, from Piper species. Z Naturforsch C 60:539–543

    PubMed  CAS  Google Scholar 

  24. Kaufman DC, Chabner BA (2001) Clinical strategies for cancer treatment: the role of drugs. In: Chabner BA, Longo DL (eds) Cancer chemotherapy & biotherapy. Lippincott Williams & Wilkins, Philadelphia, pp 1–16

    Google Scholar 

  25. Zamagni C, Martoni A, Cacciari N, Gentile A, Pannuti F (1998) The combination of paclitaxel and carboplatin as first-line chemotherapy in patients with stage III and stage IV ovarian cancer: a phase I-II study. Am J Clin Oncol 21:491–497

    Article  PubMed  CAS  Google Scholar 

  26. Cao X, Cai R, Ju DW, Tao Q, Yu Y, Wang J (1998) Augmentation of hematopoiesis by fibroblast-mediated interleukin-6 gene therapy in mice with chemotherapy. J Interferon Cytokine Res 18:227–233

    Article  PubMed  Google Scholar 

  27. Saif MW (2009) Secondary hepatic resection as a therapeutic goal in advanced colorectal cancer. World J Gastroenterol 15:3855–3864

    Article  PubMed  Google Scholar 

  28. McGee JOD, Isaacson PA, Wright NA (1992) Oxford textbook of pathology: pathology of systems. Oxford University Press, New York

    Google Scholar 

  29. Scheuer PJ, Lefkowitch JH (2000) Drugs and toxins. In: Scheuer PJ, Lefkowitch JH (eds) Liver biopsy interpretation, 6th edn. W. B. Saunders, London, pp 134–150

    Google Scholar 

  30. Kummar V, Abbas A, Fausto N (2004) Robbins and cotran pathologic basis of disease, 7th edn. W.B., Saunders

    Google Scholar 

  31. Curran RC (1990) Color atlas of histopathology. Oxford University Press, New York

    Google Scholar 

  32. Olsen S, Solez K (1994) Acute tubular necrosis and toxic renal injury. In: Tisher CC, Brenner BM (eds) Renal pathology: with clinical and functional correlations. JB Lippincott, Philadelphia, pp 769–809

    Google Scholar 

  33. Mitchell JA, Gillam EM, Stanley LA, Sim E (1990) Immunotoxic side-effects of drug therapy. Drug Saf 5:168–178

    Article  PubMed  CAS  Google Scholar 

  34. Takiguchi N, Saito N, Nunomura M, Kouda K, Oda K, Furuyama N, Nakajima N (2001) Use of 5-FU plus hyperbaric oxygen for treating malignant tumors: evaluation of antitumor effect and measurement of 5-FU in individual organs. Cancer Chemother Pharmacol 47:11–14

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We wish to thank CNPq, CAPES, Instituto Claude Bernard, FUNCAP and FINEP for their financial support in the form of grants and fellowship awards. The authors also thank the National Cancer Institute (Bethesda, MD, USA) for the donation of the tumor cell lines used in this study. The authors thank Silvana França dos Santos, Luciana França and Maria de Fátima Teixeira for technical assistance. Dr. A. Leyva helped with English editing of the manuscript.

Author information

Authors and Affiliations

  1. Departamento de Fisiologia e Farmacologia, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, Ceará, Brazil

    Hemerson Iury F. Magalhães, Bruno C. Cavalcanti, Diego V. Wilke, Flávio da S. Bitencourt, Ingrid S. T. de Figueiredo, Nylane M. N. Alencar, Letícia V. Costa-Lotufo, Manoel Odorico Moraes & Claudia Pessoa

  2. Departamento de Fisiologia, Universidade Federal de Sergipe, São Cristóvão, Sergipe, Brazil

    Daniel P. Bezerra

  3. Departamento de Química (Laboratório LP4), Universidade Federal do Mato Grosso do Sul, Campo Grande, Mato Grosso do Sul, Brazil

    Rodrigo Rotta, Dênis P. de Lima & Adilson Beatriz

  4. Departamento de Clínica Odontológica, Universidade Federal do Ceará, Fortaleza, Ceará, Brazil

    Ana Paula N. N. Alves

Authors
  1. Hemerson Iury F. Magalhães
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel P. Bezerra
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bruno C. Cavalcanti
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Diego V. Wilke
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rodrigo Rotta
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dênis P. de Lima
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Adilson Beatriz
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ana Paula N. N. Alves
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Flávio da S. Bitencourt
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ingrid S. T. de Figueiredo
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Nylane M. N. Alencar
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Letícia V. Costa-Lotufo
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Manoel Odorico Moraes
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Claudia Pessoa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Daniel P. Bezerra or Claudia Pessoa.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Magalhães, H.I.F., Bezerra, D.P., Cavalcanti, B.C. et al. In vitro and in vivo antitumor effects of (4-methoxyphenyl)(3,4,5-trimethoxyphenyl)methanone. Cancer Chemother Pharmacol 68, 45–52 (2011). https://doi.org/10.1007/s00280-010-1446-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-010-1446-2

Keywords

Search

Navigation