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Expanding on the Structural Diversity of Flavone- Derived RutheniumII6-arene) Anticancer Agents

Mario Kubanik
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  • School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
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/ Jason K. Y. Tu
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  • School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
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/ Tilo Söhnel
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  • School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
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/ Michaela Hejl
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  • University of Vienna, Faculty of Chemistry, Institute of Inorganic Chemistry, Waehringer Str. 42, 1090 Vienna, Austria
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/ Michael A. Jakupec
  • Corresponding author
  • University of Vienna, Faculty of Chemistry, Institute of Inorganic Chemistry, Waehringer Str. 42, 1090 Vienna, Austria
  • University of Vienna, Research Platform “Translational Cancer Therapy Research”, Waehringer Str. 42, A-1090 Vienna, Austria
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/ Wolfgang Kandioller
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  • University of Vienna, Faculty of Chemistry, Institute of Inorganic Chemistry, Waehringer Str. 42, 1090 Vienna, Austria
  • University of Vienna, Research Platform “Translational Cancer Therapy Research”, Waehringer Str. 42, A-1090 Vienna, Austria
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/ Bernhard K. Keppler
  • Corresponding author
  • University of Vienna, Faculty of Chemistry, Institute of Inorganic Chemistry, Waehringer Str. 42, 1090 Vienna, Austria
  • University of Vienna, Research Platform “Translational Cancer Therapy Research”, Waehringer Str. 42, A-1090 Vienna, Austria
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/ Christian G. Hartinger
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  • School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
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Published Online: 2015-12-07 | DOI: https://doi.org/10.1515/medr-2015-0001

Abstract

3-Hydroxyflavones belong to the naturally occurring class of flavonoids and have been extensively studied with regard to medicinal application. Moreover, it has been demonstrated that these compounds act as bioactive chelates to the ruthenium(II)–arene moiety. Such organometallic complexes have shown promising anticancer activity against tumor cells via a multitargeting mode of action, interacting with DNA and inhibiting topoisomerase IIα. In this paper, we present the synthesis and characterization of an extended series of 3-hydroxyflavone ligands and their corresponding ruthenium-p-cymene complexes to study the impact of substitution pattern as well as of electron-withdrawing and –donating substituents at the flavonol-phenyl group. The ligands and complexes were characterized by elemental analysis, ESI-MS, 1D as well as 2D NMR spectroscopy. The structures of four Ru(η6-p-cymene) complexes were determined in solid state by single-crystal X-ray diffraction, and the impact of the substitution pattern with regard to in vitro anticancer activity in human cancer cell lines is discussed. Structural differences, calculated octanol-water partition coefficients (clogP) of the flavonols and aqueous solubility were used to rationalize the finding that chlorido[3-(oxo-κO)-2-(3,5- dimethoxyphenyl)-chromen-4-onato-κO](η6-p-cymene)ruthenium(II) 2b exhibits the highest cytotoxicity with IC50 values in the low μM range in all tested cell lines.

Keywords: Bioorganometallic chemistry; Cancer chemotherapy; Flavonols; Ruthenium complexes; X-ray diffraction analysis

References

  • [1] Workman, P., Collins, I. Modern Cancer Drug Discovery: Integrating Targets, Technologies, and Treatments for Personalized Medicine. In Cancer Drug Design and Discovery, 2nd ed.; Neidle, S., Ed. Academic Press: San Diego, 2014; pp 3-53. Google Scholar

  • [2] Klein, A.V., Hambley, T.W. Platinum-Based Anticancer Agents. In Ligand Design in Medicinal Inorganic Chemistry, John Wiley & Sons, Ltd: 2014; pp 9-45. Google Scholar

  • [3] Primik, M.F., Filak, L.K., Arion, V.B. Metal-Based Indolobenzazepines and Indoloquinolines: From Moderate CDK Inhibitors to Potential Antitumor Drugs. In Advances in Organometallic Chemistry and Catalysis, John Wiley & Sons, Inc.: 2013; pp 605-617. Google Scholar

  • [4] Oehninger, L., Stefanopoulou, M., Alborzinia, H., Schur, J., Ludewig, S., Namikawa, K., Munoz-Castro, A., Koster, R.W., Baumann, K., Wolfl, S., Sheldrick, W.S., Ott, I., Evaluation of arene ruthenium(II) N-heterocyclic carbene complexes as organometallics interacting with thiol and selenol containing biomolecules, Dalton Trans., 2013; 42, 1657-1666. Web of ScienceGoogle Scholar

  • [5] Kandioller, W., Balsano, E., Meier, S.M., Jungwirth, U., Goschl, S., Roller, A., Jakupec, M.A., Berger, W., Keppler, B.K., Hartinger, C.G., Organometallic anticancer complexes of lapachol: metal centre-dependent formation of reactive oxygen species and correlation with cytotoxicity, Chem. Commun., 2013; 49, 3348-3350. CrossrefWeb of ScienceGoogle Scholar

  • [6] Ang, W.H., De Luca, A., Chapuis-Bernasconi, C., Juillerat- Jeanneret, L., Lo Bello, M., Dyson, P.J., Organometallic Ruthenium Inhibitors of Glutathione-S-Transferase P1-1 as Anticancer Drugs, ChemMedChem, 2007; 2, 1799-1806. Web of ScienceCrossrefGoogle Scholar

  • [7] Ang, W.H., Parker, L.J., De Luca, A., Juillerat-Jeanneret, L., Morton, C.J., Lo Bello, M., Parker, M.W., Dyson, P.J., Rational Design of an Organometallic Glutathione Transferase Inhibitor, Angew. Chem., Int. Ed. Engl., 2009; 48, 3854-3857. Google Scholar

  • [8] Hanif, M., Nazarov, A.A., Legin, A., Groessl, M., Arion, V.B., Jakupec, M.A., Tsybin, Y.O., Dyson, P.J., Keppler, B.K., Hartinger, C.G., Maleimide-functionalised organoruthenium anticancer agents and their binding to thiol-containing biomolecules, Chem. Commun., 2012; 48, 1475-1477. CrossrefWeb of ScienceGoogle Scholar

  • [9] Haquette, P., Salmain, M., Svedlung, K., Martel, A., Rudolf, B., Zakrzewski, J., Cordier, S., Roisnel, T., Fosse, C., Jaouen, G., Cysteine-Specific, Covalent Anchoring of Transition Organometallic Complexes to the Protein Papain from Carica papaya, ChemBioChem, 2007; 8, 224-231. CrossrefWeb of ScienceGoogle Scholar

  • [10] Tan, Y.Q., Dyson, P.J., Ang, W.H., Acetal-functionalized RAPTA complexes for conjugation and labeling, Organometallics, 2011; 30, 5965-5971. CrossrefWeb of ScienceGoogle Scholar

  • [11] Babak, M.V., Plażuk, D., Meier, S.M., Arabshahi, H.J., Reynisson, J., Rychlik, B., Błauż, A., Szulc, K., Hanif, M., Strobl, S., Roller, A., Keppler, B.K., Hartinger, C.G., Half-Sandwich Ruthenium(II) Biotin Conjugates as Biological Vectors to Cancer Cells, Chem. Eur. J., 2015; 21, 5110-5117. CrossrefGoogle Scholar

  • [12] Goldbach, R.E., Rodriguez-Garcia, I., van Lenthe, J.H., Siegler, M.A., Bonnet, S., N-Acetylmethionine and Biotin as Photocleavable Protective Groups for Ruthenium Polypyridyl Complexes, Chem. Eur. J., 2011; 17, 9924-9929. CrossrefWeb of ScienceGoogle Scholar

  • [13] Ang, W.H., Daldini, E., Juillerat-Jeanneret, L., Dyson, P.J., Strategy To Tether Organometallic Ruthenium-Arene Anticancer Compounds to Recombinant Human Serum Albumin, Inorg. Chem., 2007; 46, 9048-9050. Google Scholar

  • [14] Pagano, N., Wong, E.Y., Breiding, T., Liu, H., Wilbuer, A., Bregman, H., Shen, Q., Diamond, S.L., Meggers, E., From Imide to Lactam Metallo-pyridocarbazoles: Distinct Scaffolds for the Design of Selective Protein Kinase Inhibitors, J. Org. Chem., 2009; 74, 8997-9009. CrossrefWeb of ScienceGoogle Scholar

  • [15] Nazarov, A.A., Hartinger, C.G., Dyson, P.J., Opening the lid on piano-stool complexes: An account of ruthenium(II)-arene complexes with medicinal applications, J. Organomet. Chem., 2014; 751, 251-260. Google Scholar

  • [16] Kurzwernhart, A., Kandioller, W., Bachler, S., Bartel, C., Martic, S., Buczkowska, M., Muhlgassner, G., Jakupec, M.A., Kraatz, H.B., Bednarski, P.J., Arion, V.B., Marko, D., Keppler, B.K., Hartinger, C.G., Structure-Activity Relationships of Targeted RuII(η6-p-Cymene) Anticancer Complexes with Flavonol-Derived Ligands, J. Med. Chem., 2012; 55, 10512-10522. CrossrefGoogle Scholar

  • [17] Kurzwernhart, A., Kandioller, W., Bartel, C., Bachler, S., Trondl, R., Muhlgassner, G., Jakupec, M.A., Arion, V.B., Marko, D., Keppler, B.K., Hartinger, C.G., Targeting the DNA-topoisomerase complex in a double-strike approach with a topoisomerase inhibiting moiety and covalent DNA binder, Chem. Commun., 2012; 48, 4839-4841. Web of ScienceCrossrefGoogle Scholar

  • [18] Kurzwernhart, A., Kandioller, W., Enyedy, E.A., Novak, M., Jakupec, M.A., Keppler, B.K., Hartinger, C.G., 3-Hydroxyflavones vs. 3-hydroxyquinolinones: structure-activity relationships and stability studies on RuII(arene) anticancer complexes with biologically active ligands, Dalton Trans., 2013; 42, 6193-6202. Web of ScienceGoogle Scholar

  • [19] Schwarz, M.B., Kurzwernhart, A., Roller, A., Kandioller, W., Keppler, B.K., Hartinger, C.G., Rhodium(Cp*) Compounds with Flavone-derived Ligand Systems: Synthesis and Characterization, Z. Anorg. Allg. Chem., 2013; 639, 1648-1654. Google Scholar

  • [20] Prajapati, R., Dubey, S.K., Gaur, R., Koiri, R.K., Maurya, B.K., Trigun, S.K., Mishra, L., Structural characterization and cytotoxicity studies of ruthenium(II)–dmso–chloro complexes of chalcone and flavone derivatives, Polyhedron, 2010; 29, 1055-1061. CrossrefGoogle Scholar

  • [21] el Amrani, F.B.-A., Perelló, L., Borrás, J., Torres, L., Development of Novel DNA Cleavage Systems Based on Copper Complexes. Synthesis and Characterisation of Cu(II) Complexes of Hydroxyflavones, Met. Based Drugs, 2000; 7, 365-370. Google Scholar

  • [22] Dangleterre, L., Cornard, J.-P., Interaction of lead(II) chloride with hydroxyflavones in methanol: A spectroscopic study, Polyhedron, 2005; 24, 1593-1598. CrossrefGoogle Scholar

  • [23] Sathish, S., Narayan, G., Rao, N., Janardhana, C., A Self-Organized Ensemble of Fluorescent 3-Hydroxyflavone-Al(III) Complex as Sensor for Fluoride and Acetate Ions, J. Fluoresc., 2007; 17, 1-5. Web of ScienceGoogle Scholar

  • [24] Santos, J.P., Zaniquelli, M.E.D., De Giovani, W.F., Galembeck, S.E., Aluminum ion complex formation with 3-hydroxyflavone in Langmuir and Langmuir–Blodgett films, Colloids Surf., A, 2002; 198–200, 569-576. Google Scholar

  • [25] Lapouge, C., Dangleterre, L., Cornard, J.-P., Spectroscopic and Theoretical Studies of the Zn(II) Chelation with Hydroxyflavones, J. Phys. Chem. A, 2006; 110, 12494-12500. CrossrefGoogle Scholar

  • [26] Nichenametla, S.N., Taruscio, T.G., Barney, D.L., Exon, J.H., A Review of the Effects and Mechanisms of Polyphenolics in Cancer, Crit. Rev. Food Sci, Nutr., 2006; 46, 161-183. Google Scholar

  • [27] Fotsis, T., Pepper, M.S., Aktas, E., Breit, S., Rasku, S., Adlercreutz, H., Wähälä, K., Montesano, R., Schweigerer, L., Flavonoids, Dietary-derived Inhibitors of Cell Proliferation and in Vitro Angiogenesis, Cancer Res., 1997; 57, 2916-2921. Google Scholar

  • [28] Harborne, J.B., Williams, C.A., Advances in flavonoid research since 1992, Phytochemistry, 2000; 55, 481-504. Google Scholar

  • [29] Ross, J.A., Kasum, C.M., Dietary Flavonoids: Bioavailability, Metabolic Effects, and Safety, Annu. Rev. Nutr., 2002; 22, 19. Web of ScienceCrossrefGoogle Scholar

  • [30] Cushnie, T.P.T., Lamb, A.J., Antimicrobial activity of flavonoids, Int. J. Antimicrob. Agents, 2005; 26, 343-356. Google Scholar

  • [31] García-Lafuente, A., Guillamón, E., Villares, A., Rostagno, M., Martínez, J., Flavonoids as anti-inflammatory agents: implications in cancer and cardiovascular disease, Inflamm. Res., 2009; 58, 537-552. Google Scholar

  • [32] Chen, Z.-T., Chu, H.-L., Chyau, C.-C., Chu, C.-C., Duh, P.-D., Protective effects of sweet orange (Citrus sinensis) peel and their bioactive compounds on oxidative stress, Food Chem., 2012; 135, 2119-2127. Google Scholar

  • [33] Chaudhuri, S., Banerjee, A., Basu, K., Sengupta, B., Sengupta, P.K., Interaction of flavonoids with red blood cell membrane lipids and proteins: Antioxidant and antihemolytic effects, Int. J. Biol. Macromol., 2007; 41, 42-48. CrossrefWeb of ScienceGoogle Scholar

  • [34] Shen, K.-H., Chen, Z.-T., Duh, P.-D., Cytotoxic Effect of Eucalyptus citriodora Resin on Human Hepatoma HepG2 Cells, Am. J. Chin. Med., 2012; 40, 399-413. CrossrefWeb of ScienceGoogle Scholar

  • [35] Kandioller, W., Hartinger, C.G., Nazarov, A.A., Kuznetsov, M.L., John, R.O., Bartel, C., Jakupec, M.A., Arion, V.B., Keppler, B.K., From Pyrone to Thiopyrone Ligands−Rendering Maltol-Derived Ruthenium(II)−Arene Complexes That Are Anticancer Active in Vitro, Organometallics, 2009; 28, 4249-4251. Web of ScienceCrossrefGoogle Scholar

  • [36] Kandioller, W., Hartinger, C.G., Nazarov, A.A., Bartel, C., Skocic, M., Jakupec, M.A., Arion, V.B., Keppler, B.K., Maltol-derived ruthenium-cymene complexes with tumor inhibiting properties: the impact of ligand-metal bond stability on anticancer activity in vitro, Chem. Eur. J., 2009; 15, 12283-12291. CrossrefGoogle Scholar

  • [37] Kandioller, W., Hartinger, C.G., Nazarov, A.A., Kasser, J., John, R., Jakupec, M.A., Arion, V.B., Dyson, P.J., Keppler, B.K., Tuning the anticancer activity of maltol-derived ruthenium complexes by derivatization of the 3-hydroxy-4-pyrone moiety, J. Organomet. Chem., 2009; 694, 922-929. Google Scholar

  • [38] Bradley, D., Williams, G., Lawton, M., Drying of Organic Solvents: Quantitative Evaluation of the Efficiency of Several Desiccants, J. Org. Chem., 2010; 75, 8351-8354. Web of ScienceGoogle Scholar

  • [39] Bennett, M.A., Smith, A.K., Arene ruthenium(II) complexes formed by dehydrogenation of cyclohexadienes with ruthenium(III) trichloride, J. Chem. Soc., Dalton Trans., 1974, 233. Google Scholar

  • [40] Sheldrick, G.M., A short history of SHELX, Acta Crystallogr., Sect. A: Found. Crystallogr., 2008; A64, 112-122. Web of ScienceGoogle Scholar

  • [41] Korch, C., Spillman, M.A., Jackson, T.A., Jacobsen, B.M., Murphy, S.K., Lessey, B.A., Jordan, V.C., Bradford, A.P., DNA profiling analysis of endometrial and ovarian cell lines reveals misidentification, redundancy and contamination, Gynecol. Oncol., 2012; 127, 241-248. Web of ScienceGoogle Scholar

  • [42] Tetko, I.V., Gasteiger, J., Todeschini, R., Mauri, A., Livingstone, D., Ertl, P., Palyulin, V.A., Radchenko, E.V., Zefirov, N.S., Makarenko, A.S., Tanchuk, V.Y., Prokopenko, V.V., Virtual computational chemistry laboratory--design and description, J. Comput. Aided Mol. Des., 2005; 19, 453-463. CrossrefGoogle Scholar

  • [43] Bennett, M., Burke, A.J., O’Sullivan, W.I., Aspects of the Algar-Flynn-Oyamada (AFO) reaction, Tetrahedron, 1996; 52, 7163-7178. CrossrefGoogle Scholar

About the article

Published Online: 2015-12-07


Citation Information: Metallodrugs, Volume 1, Issue 1, Pages 24–35, ISSN (Online) 2300-3618, DOI: https://doi.org/10.1515/medr-2015-0001.

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© 2015 Mario Kubanik, et al.. This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License. BY-NC-ND 3.0

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