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Pharmaceutical Research

, Volume 23, Issue 1, pp 70–81 | Cite as

Evaluation of Cancer-Preventive Activity and Structure–Activity Relationships of 3-Demethylubiquinone Q2, Isolated from the Ascidian Aplidium glabrum, and its Synthetic Analogs

  • Sergey N. Fedorov
  • Oleg S. Radchenko
  • Larisa K. Shubina
  • Nadezhda N. Balaneva
  • Ann M. Bode
  • Valentin A. Stonik
  • Zigang Dong
Research Paper

Purpose

3-Demethylubiquinone Q2 (1) was isolated from the ascidian Aplidium glabrum. The cancer-preventive properties and the structure–activity relationship for 3-demethylubiquinone Q2 (1) and 12 of its synthetic analogs (314) are reported.

Methods

Compounds 314, having one or several di- or triprenyl substitutions and quinone moieties with methoxyls in different positions, were synthesized. The cancer-preventive properties of compounds 1 and 314 were tested in JB6 Cl41 mouse skin cells, using a variety of assessments, including the methanethiosulfonate (MTS) assay, flow cytometry, and soft agar assay. Statistical nonparametric methods were used to confirm statistical significance.

Results

All quinones tested were shown to inhibit JB6 Cl41 cell transformation, to induce apoptosis, AP-1, and NF-κB activity, and to inhibit p53 activity. The most promising effects were indicated for compounds containing two isoprene units in a side chain and a methoxyl group at the para-position to a polyprenyl substitution.

Conclusions

Quinones 1 and 314 demonstrated cancer-preventive activity in JB6 Cl41 cells, which may be attributed to the induction of p53-independent apoptosis. These activities depended on the length of side chains and on the positions of the methoxyl groups in the quinone part of the molecule.

Key Words

apoptosis cancer prevention marine prenylated quinones nuclear factor structure–activity relationship 

Abbreviations

3-demethylubiquinone Q2

2,3-dimethoxy-5-(3′,7′-dimethyl-octa-2′(E),6′-dienyl)-[1,4]benzoquinone (1)

EGF

epidermal growth factor

FBS

fetal bovine serum

MEM

minimum essential medium

TPA

12-O-tetradecanoyl-phorbol-13-acetate

Notes

Acknowledgments

This work was supported in part by The Hormel Foundation and National Institutes of Health grants CA81064, CA77646, and CA88961. The Russian co-authors are grateful for financial support by the RFFI Grant no. 05-04-48246, Russian Federation President Grant no. 725.2003.4, Program of Presidium of RAS “Molecular and Cell Biology” Grant no. 05-I-05-005, and FEB Grant no. 05-III-A-05-129.

References

  1. 1.
    Herskind, C., Fleckenstein, K., Lohr, J., Li, C. Y., Wenz, F., Lohr, F. 2004Antitumoral action of interferons and interleukins in combination with radiotherapy. Part I: immunologic basisStrahlenther. Onkol.180187193PubMedGoogle Scholar
  2. 2.
    Rogozin, E. A., Urazova, L. N., Serebrov, V. Yu 2003Influence of vaccines of Venezuelan equine encephalitis, influenza and mumps viruses on morphological pattern and vitality of human tumor cells in vitro J. BUON83943PubMedGoogle Scholar
  3. 3.
    Hersey, P. 1993Evaluation of vaccinia viral lysates as therapeutic vaccines in the treatment of melanomaAnn. N.Y. Acad. Sci.690167177PubMedGoogle Scholar
  4. 4.
    Davis, I. D., Jefford, M., Parente, P., Cebon, J. 2003Rational approaches to human cancer immunotherapyJ. Leukoc. Biol.73329CrossRefPubMedGoogle Scholar
  5. 5.
    Rinehart, K. L. 2000Antitumor compounds from tunicatesMed. Res. Rev.20127CrossRefPubMedGoogle Scholar
  6. 6.
    Haefner, B. 2003Drugs from the deep: marine natural products as drug candidatesDrug Discov. Today8536544PubMedGoogle Scholar
  7. 7.
    Mayer, A. M., Lehmann, V. K. 2001Marine pharmacology in 1999: antitumor and cytotoxic compoundsAnticancer Res2124892500PubMedGoogle Scholar
  8. 8.
    Thomson, R. H. 1971Naturally Occurring QuinonesAcademic PressLondonGoogle Scholar
  9. 9.
    Pennock, J. F. 1967The chemistry of isoprenoid quinonesPridham, J. B. eds. Terpenoids in PlantsAcademic PressLondon129146Google Scholar
  10. 10.
    Faulkner, D. J. 1986Marine natural productsNat. Prod. Rep.3133CrossRefPubMedGoogle Scholar
  11. 11.
    M. Ochi, H. Kotsuki, S. Inoue, M. Taniguchi, and T. Tokoroyama. Isolation of 2-(3,7,11-trimethyl-2,6,10-dodecatrienyl) hydroquinone from the brown seaweed Dictyopteris unulata. Chem. Lett. 831–832 (1979).Google Scholar
  12. 12.
    Capon, R. J., Ghisalberti, E. L., Jefferies, P. R. 1981Isoprenoid dihydroquinones from a brown alga, Cystophora spPhytochemistry2025982600CrossRefGoogle Scholar
  13. 13.
    Gerwick, W. H., Fenical, W. 1981Ichthyotoxic and cytotoxic metabolites of the tropical brown alga Stypopodium zonale (Lamouroux) PapenfussJ. Org. Chem.462227Google Scholar
  14. 14.
    Fenical, W. 1978DiterpenoidsScheuer, P. J. eds. Marine Natural Products, Chemical and Biological Perspectives, Vol. 2Academic PressNew York238245Google Scholar
  15. 15.
    Minale, L. 1978Terpenoids from marine spongesScheuer, P. J. eds. Marine Natural Products, Chemical and Biological Perspectives, Vol. 1Academic PressNew York220240Google Scholar
  16. 16.
    Rosa, S., Crispino, A., Giulio, A., Iodice, C., Milone, A. 1995Sulfated polyprenylhydroquinones from the sponge Ircinia spinulosa J. Nat. Prod.5814501454Google Scholar
  17. 17.
    Bifulco, G., Bruno, I., Minale, L., Riccio, R. 1995Bioactive prenylhydroquinone sulfates and a novel, C31 furanoterpene alcohol sulfate from the marine sponge, Ircinia spJ. Nat. Prod.5814441449Google Scholar
  18. 18.
    Bowden, B. F., Coll, J. C. 1981Studies of Australian soft corals. XXVI tetraprenylbenzoquinone derivatives from a Nephthea species of soft coral (Octocorallia, Alcyonacea)Aust. J. Chem.3426772681Google Scholar
  19. 19.
    Ravi, B. N., Wells, R. J. 1982Lipid and terpenoid metabolites of the gorgonian Plexaura flava Aust. J. Chem.35105112Google Scholar
  20. 20.
    Howard, B. M., Clarkson, K., Bernstein, R. L. 1979Simple prenylated hydroquinone derivatives from the marine urochordate Aplidium californicum Tetrahedron Lett.2044494452Google Scholar
  21. 21.
    Targett, N. M., Keeran, W. S. 1984A terpenehydroquinone from the marine ascidian Aplidium constellatum J. Nat. Prod.47556557CrossRefPubMedGoogle Scholar
  22. 22.
    Guella, G., Mancini, I., Pietra, F. 1987Verapliquinones: novel diprenylquinones from an Aplidium sp. (Ascidiacea) of the Ile-Verte waters, BrittanyHelv. Chim. Acta70621626Google Scholar
  23. 23.
    Faulkner, D. J. 1993Marine natural productsNat. Prod. Rep.10497539CrossRefPubMedGoogle Scholar
  24. 24.
    Fu, X., Bilayet Hossain, M., Helm, D., Schmitz, F. 1994Longithorone A: unprecedented dimeric prenylated quinone from the tunicate Aplidium longithorax J. Am. Chem. Soc.1161212512126Google Scholar
  25. 25.
    Fu, X., Bilayet Hossain, M., Schmitz, F., Helm, D. 1997Longithorones, unique prenylated para- and metacyclopropane type quinones from the tunicate Aplidium longithorax J. Org. Chem.6238103819CrossRefGoogle Scholar
  26. 26.
    Shubina, L. K., Fedorov, S. N., Radchenko, O. S., Balaneva, N. N., Kolexnikova, S. A., Dmitrenok, P. S., Bode, A. M., Dong, Z., Stonik, V. A. 2005Desmethylubiquinone Q2 from the Far-eastern ascidian Aplidium glabrum: structure and synthesisTetrahedron Lett.46559562CrossRefGoogle Scholar
  27. 27.
    Rosa, S., Giulio, A., Iodice, C. 1994Biological effects of prenylated hydroquinones: structure–activity relationship studies in antimicrobial, brine shrimp, and fish lethality assaysJ. Nat. Prod.5717111716PubMedGoogle Scholar
  28. 28.
    Misiti, D., Moore, H. W., Folkers, K. 1965Identification of plastoquionone-2 from chloroplastsJ. Am. Chem. Soc.8714021403CrossRefGoogle Scholar
  29. 29.
    Sakamoto, K., Miyoshi, H., Takegami, K., Mogi, T., Anraku, Y., Iwamura, H. 1996Probing substrate binding site of the Escherichia coli quinol oxidases using synthetic ubiquinol analoguesJ. Biol. Chem.2712989729902PubMedGoogle Scholar
  30. 30.
    Colburn, N. H., Former, B. F., Nelson, K. A., Yuspa, S. H. 1979Tumour promoter induces anchorage independence irreversiblyNature281589591CrossRefPubMedGoogle Scholar
  31. 31.
    Colburn, N. H., Wendel, E. J., Abruzzo, G. 1981Dissociation of mitogenesis and late-stage promotion of tumor cell phenotype by phorbol esters: mitogen-resistant variants are sensitive to promotionProc. Natl. Acad. Sci. USA7869126916PubMedGoogle Scholar
  32. 32.
    Dong, Z., Cmarik, J. L., Wendel, E. J., Colburn, N. H. 1994Differential transformation efficiency but not AP-1 induction under anchorage-dependent and -independent conditionsCarcinogenesis1510011004PubMedGoogle Scholar
  33. 33.
    Dong, Z., Birrer, M. J., Watts, R. G., Matrisian, L. M., Colburn, N. H. 1994Blocking of tumor promoter-induced AP-1 activity inhibits induced transformation in JB6 mouse epidermal cellsProc. Natl. Acad. Sci. USA91609613PubMedGoogle Scholar
  34. 34.
    Dong, Z., Watts, S. G., Sun, Y., Colburn, N. H. 1995Progressive elevation of AP-1 activity during preneoplastic-to neoplastic progression as modeled in mouse JB6 cell variantsInt. J. Oncol.7359364Google Scholar
  35. 35.
    Dong, Z., Lavrovsky, V., Colburn, N. H. 1995Transformation reversion induced in JB6 RT101 cells by AP-1 inhibitorsCarcinogenesis16749756PubMedGoogle Scholar
  36. 36.
    Dong, Z., Cmarik, J. L. 2002Harvesting cells under anchorage-independent cell transformation conditions for biochemical analysesSci. STKE2002PL7PubMedCrossRefGoogle Scholar
  37. 37.
    Lavrovsky, V., Dong, Z., Ma, W. Y., Colburn, N. 1996Drug-induced reversion of progression phenotype is accompanied by reversion of AP-1 phenotype in JB6 cellsIn Vitro Cell. Dev. Biol., Anim.32234237Google Scholar
  38. 38.
    Strickland, J., Sun, Y., Dong, Z., Colburn, N. H. 1997Grafting assay distinguishes promotion sensitive from promotion resistant JB6 cellsCarcinogenesis1811351138CrossRefPubMedGoogle Scholar
  39. 39.
    Sun, Y., Nakamura, K., Hegamyer, G., Dong, Z., Colburn, N. 1993No point mutation of Ha-ras or p53 genes expressed in preneoplastic-to-neoplastic progression as modeled in mouse JB6 cell variantsMol Carcinog84957PubMedGoogle Scholar
  40. 40.
    Ames, B. N., McCann, J., Yamasaki, E. 1975Methods for detecting carcinogens and mutagens with the Salmonella/mammalian-microsome mutagenicity testMutat. Res.31347364PubMedGoogle Scholar
  41. 41.
    Fedorov, S. N., Bode, A. M., Stonik, V. A., Gorshkova, I. A., Schmid, P. C., Radchenko, O. S., Berdyshev, E. V., Dong, Z. 2004Marine alkaloid polycarpine and its synthetic derivative dimethylpolycarpine induce apoptosis in JB6 cells through p53- and caspase 3-dependent pathwaysPharm. Res.2123072319CrossRefPubMedGoogle Scholar
  42. 42.
    Huang, C., Ma, W. Y., Goranson, A., Dong, Z. 1999Resveratrol suppresses cell transformation and induces apoptosis through a p53-dependent pathwayCarcinogenesis20237242PubMedGoogle Scholar
  43. 43.
    Nomura, M., Kaji, A., Ma, W., Miyamoto, K., Dong, Z. 2001Suppression of cell transformation and induction of apoptosis by caffeic acid phenethyl esterMol. Carcinog.318389CrossRefPubMedGoogle Scholar
  44. 44.
    Huang, C., Ma, W. Y., Li, J., Hecht, S. S., Dong, Z. 1998Essential role of p53 in phenethyl isothiocyanate-induced apoptosisCancer Res.5841024106PubMedGoogle Scholar
  45. 45.
    He, Z., Ma, W. Y., Hashimoto, T., Bode, A. M., Yang, C. S., Dong, Z. 2003Induction of apoptosis by caffeine is mediated by the p53, Bax, and caspase 3 pathwaysCancer Res.6343964401PubMedGoogle Scholar
  46. 46.
    Bernstein, L. R., Colburn, N. H. 1989AP1/jun function is differentially induced in promotion-sensitive and resistant JB6 cellsScience244566569PubMedGoogle Scholar
  47. 47.
    Young, M. R., Li, J. J., Rincon, M., Flavell, R. A., Sathyanarayana, B. K., Hunziker, R., Colburn, N. 1999Transgenic mice demonstrate AP-1 (activator protein-1) transactivation is required for tumor promotionProc. Natl. Acad. Sci. USA9698279832PubMedGoogle Scholar
  48. 48.
    Chiu, R., Angel, P., Karin, M. 1989Jun-B differs in its biological properties from, and is a negative regulator of, c-JunCell59979986CrossRefPubMedGoogle Scholar
  49. 49.
    Passegue, E., Jochum, W., Schorpp-Kistner, M., Mohle-Steinlein, U., Wagner, E. F. 2001Chronic myeloid leukemia with increased granulocyte progenitors in mice lacking junB expression in the myeloid lineageCell1042132CrossRefPubMedGoogle Scholar
  50. 50.
    Le-Niculescu, H., Bonfoco, E., Kasuya, Y., Claret, F. X., Green, D. R., Karin, M. 1999Withdrawal of survival factors results in activation of the JNK pathway in neuronal cells leading to Fas ligand induction and cell deathMol. Cell. Biol.19751763PubMedGoogle Scholar
  51. 51.
    Kondo, T., Matsuda, T., Kitano, T., Takahashi, A., Tashima, M., Ishikura, H., Umehara, H., Domae, N., Uchiyama, T., Okazaki, T. 2000Role of c-jun expression increased by heat shock- and ceramide-activated caspase-3 in HL-60 cell apoptosis. Possible involvement of ceramide in heat shock-induced apoptosisJ. Biol. Chem.27576687676PubMedGoogle Scholar
  52. 52.
    Kasibhatla, S., Brunner, T., Genestier, L., Echeverri, F., Mahboubi, A., Green, D. R. 1998DNA damaging agents induce expression of Fas ligand and subsequent apoptosis in T lymphocytes via the activation of NF-kappa B and AP-1Mol. Cell1543551CrossRefPubMedGoogle Scholar
  53. 53.
    Manna, S. K., Sah, N. K., Aggarwal, B. B. 2000Protein tyrosine kinase p56lck is required for ceramide-induced but not tumor necrosis factor-induced activation of NF-kappa B, AP-1, JNK, and apoptosisJ. Biol. Chem.2751329713306PubMedGoogle Scholar
  54. 54.
    Leppa, S., Eriksson, M., Saffrich, R., Ansorge, W., Bohmann, D. 2001Complex functions of AP-1 transcription factors in differentiation and survival of PC12 cellsMol. Cell. Biol.2143694378CrossRefPubMedGoogle Scholar
  55. 55.
    Berry, A., Goodwin, M., Moran, C. L., Chambers, T. C. 2001AP-1 activation and altered AP-1 composition in association with increased phosphorylation and expression of specific Jun and Fos family proteins induced by vinblastine in KB-3 cellsBiochem. Pharmacol.62581591CrossRefPubMedGoogle Scholar
  56. 56.
    Fan, M., Goodwin, M. E., Birrer, M. J., Chambers, T. C. 2001The c-Jun NH(2)-terminal protein kinase/AP-1 pathway is required for efficient apoptosis induced by vinblastineCancer Res.6144504458PubMedGoogle Scholar
  57. 57.
    Bessho, R., Matsubara, K., Kubota, M., Kuwakado, K., Hirota, H., Wakazono, Y., Lin, Y. W., Okuda, A., Kawai, M., Nishikomori, R.,  et al. 1994Pyrrolidine dithiocarbamate, a potent inhibitor of nuclear factor kappa B (NF-kappa B) activation, prevents apoptosis in human promyelocytic leukemia HL-60 cells and thymocytesBiochem. Pharmacol.4818831889CrossRefPubMedGoogle Scholar
  58. 58.
    Garcia-Bermejo, L., Perez, C., Vilaboa, N. E., Blas, E., Aller, P. 1998cAMP increasing agents attenuate the generation of apoptosis by etoposide in promonocytic leukemia cellsJ. Cell. Sci.111Pt637644Google Scholar
  59. 59.
    Beg, A. A., Baltimore, D. 1996An essential role for NF-kappaB in preventing TNF-alpha-induced cell deathScience274782784CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2006

Authors and Affiliations

  • Sergey N. Fedorov
    • 1
    • 2
  • Oleg S. Radchenko
    • 1
  • Larisa K. Shubina
    • 1
  • Nadezhda N. Balaneva
    • 1
  • Ann M. Bode
    • 2
  • Valentin A. Stonik
    • 1
  • Zigang Dong
    • 2
  1. 1.Hormel InstituteUniversity of MinnesotaAustinUSA
  2. 2.Pacific Institute of Bioorganic ChemistryVladivostokRussia

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