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Australian Journal of Chemistry Australian Journal of Chemistry Society
An international journal for chemical science
RESEARCH ARTICLE

Antitumour and Antimetastatic Effects and Safety Profile of a New Magnesium(ii)-Chrysin Complex

Juan J. Martínez Medina A , Javier Rodríguez A , Julia Mermot B and Luciana G. Naso B C
+ Author Affiliations
- Author Affiliations

A Universidad Nacional del Chaco Austral - Comandante Fernández 755, CP: 3700 Presidencia Roque Sáenz Peña, Chaco, Argentina.

B CEQUINOR-CONICET-CICPBA-UNLP, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, Bv. 120 N° 1465, 1900 La Plata, Argentina.

C Corresponding author. Email: naso@quimica.unlp.edu.ar

Australian Journal of Chemistry 73(7) 614-626 https://doi.org/10.1071/CH19333
Submitted: 18 July 2019  Accepted: 9 December 2019   Published: 12 February 2020

Abstract

Chrysin is a flavone found in many plant extracts including blue passion flower, propolis and honey. The magnesium(ii) cation is an essential metal for life and it is involved in a variety of metabolic and physiological functions. Biological activities of flavonoids can be improved by complexation with metals. For this reason, Mgchrys was synthesised. The complex was characterised by spectroscopic techniques (ultraviolet–visible absorption spectroscopy (UV-Vis), Fourier-transform infrared spectroscopy (FTIR), 1H and 13C-NMR) and elemental and thermogravimetric analysis. The results indicated that chrysin reacts with magnesium(ii) through a 4-carbonyl-5-hydroxy chelation site. The computational study suggests the coexistence of at least twelve conformers of Mgchrys at room temperature. There are six most stable conformers that show square-pyramidal and distorted square-pyramidal geometries. In addition, anticancer and antimetastatic activities of Mgchrys on the A549 cell line were evaluated and compared with the metal and the free ligand. The complex did not show cytotoxicity against normal lung fibroblasts but it behaved as a cytotoxic drug against the cancer cell line with oxidative stress being its probable mechanism of action. However, Mgchrys inhibited the different steps involved in the metastatic cascade: adhesion to fibronectin, migration and invasion. The compounds displayed no acute toxicity (Artemia salina test) and no mutagenic effect (Ames test).


References

[1]  E. Middleton, Adv. Exp. Med. Biol. 1998, 439, 175.
         | Crossref | GoogleScholarGoogle Scholar | 9781303PubMed |

[2]  B. Khoo, S. Chua, P. Balaram, Int. J. Mol. Sci. 2010, 11, 2188.
         | Crossref | GoogleScholarGoogle Scholar | 20559509PubMed |

[3]  R. Mani, V. Natesan, Phytochemistry 2018, 145, 187.
         | Crossref | GoogleScholarGoogle Scholar | 29161583PubMed |

[4]  M. Witkowski, J. Hubert, A. Mazur, Magnes. Res. 2011, 24, 163.
         | Crossref | GoogleScholarGoogle Scholar | 22064327PubMed |

[5]  S. Volpe, J. Mao, M. Guerrera, Am. Fam. Physician 2009, 80, 157.
         | 19621856PubMed |

[6]  W. Al-Delaimy, E. Rimm, W. Willett, M. Stampfer, F. Hu, J. Am. Coll. Nutr. 2004, 23, 63.
         | Crossref | GoogleScholarGoogle Scholar | 14963055PubMed |

[7]  J. Li, K. Yu, J. Bai, H. Zhang, J. Chao, Oxid. Antioxid. Med. Sci. 2014, 3, 231.
         | Crossref | GoogleScholarGoogle Scholar |

[8]  R. Maitra, R. Roy, S. Ghosh, S. Mallick, UJPSR 2016, 2, 21.

[9]  N. Ghosh, T. Chakraborty, S. Mallick, S. Mana, D. Singha, B. Ghosh, S. Roy, Spectrochim. Acta Part A 2015, 151, 807.
         | Crossref | GoogleScholarGoogle Scholar |

[10]  R. M. M. Oliveira, J. F. de Souza Daniel, I. de Aguiar, M. F. das Graças Fernandes Silva, J. Batista Fernandes, R. M. Carlos, J. Inorg. Biochem. 2013, 129, 35.
         | Crossref | GoogleScholarGoogle Scholar |

[11]  Q. Panhwar, S. Memon, J. Coord. Chem. 2011, 64, 2117.
         | Crossref | GoogleScholarGoogle Scholar |

[12]  C. Spoerlein, K. Mahal, H. Schmidt, R. Schobert, J. Inorg. Biochem. 2013, 127, 107.
         | Crossref | GoogleScholarGoogle Scholar | 23973682PubMed |

[13]  F. Yang, H. Jin, J. Pi, J. Jiang, L. Liu, H. Bai, P. Yang, J. Cai, Bioorg. Med. Chem. Lett. 2013, 23, 5544.
         | Crossref | GoogleScholarGoogle Scholar | 24007917PubMed |

[14]  Y. Zeng, N. Yang, W. Liu, N. Tang, J. Inorg. Biochem. 2003, 97, 258.
         | Crossref | GoogleScholarGoogle Scholar | 14511888PubMed |

[15]  L. Naso, E. Ferrer, L. Lezama, T. Rojo, S. Etcheverry, P. Williams, J. Biol. Inorg. Chem. 2010, 15, 889.
         | Crossref | GoogleScholarGoogle Scholar | 20364393PubMed |

[16]  B. S. Nunes, F. D. Carvalho, L. M. Guilhermino, G. Van Stappen, Environ. Pollut. 2006, 144, 453.
         | Crossref | GoogleScholarGoogle Scholar | 16677747PubMed |

[17]  S. A. Mansour, M. F. Gad, Food Chem. Toxicol. 2010, 48, 377.
         | Crossref | GoogleScholarGoogle Scholar | 19853633PubMed |

[18]  P. McCarren, C. Springer, L. Whitehead, J. Cheminform. 2011, 3, 51.
         | Crossref | GoogleScholarGoogle Scholar | 22107807PubMed |

[19]  G. Micera, E. Garribba, Int. J. Quantum Chem. 2012, 112, 2486.
         | Crossref | GoogleScholarGoogle Scholar |

[20]  J. Pusz, S. Wolowiec, J. Therm. Anal. Calorim. 2012, 110, 813.
         | Crossref | GoogleScholarGoogle Scholar |

[21]  J. Pusz, B. Nitka, Microchem. J. 1997, 56, 373.
         | Crossref | GoogleScholarGoogle Scholar |

[22]  J. Pusz, B. Nitka, A. Zielinska, I. Wawer, Microchem. J. 2000, 65, 245.
         | Crossref | GoogleScholarGoogle Scholar |

[23]  L. Naso, E. G. Ferrer, L. Lezama, T. Rojo, S. B. Etcheverry, P. Williams, J. Biol. Inorg. Chem. 2010, 15, 889.
         | Crossref | GoogleScholarGoogle Scholar | 20364393PubMed |

[24]  V. Uivarosi, S. Barbuceanu, V. Aldea, C. Arama, M. Badea, R. Olar, D. Marinescu, Molecules 2010, 15, 1578.
         | Crossref | GoogleScholarGoogle Scholar | 20336002PubMed |

[25]  J. Pusz, B. Nitka, S. Kopacz, Y. I. Korenman, Russ. J. Gen. Chem 2003, 73, 634.
         | Crossref | GoogleScholarGoogle Scholar |

[26]  M. Badea, R. Olar, V. Uivarosi, D. Marinescu, V. Aldea, S. F. Barbuceanu, G. M. Nitulescu, J. Therm. Anal. Calorim. 2011, 105, 559.
         | Crossref | GoogleScholarGoogle Scholar |

[27]  V. Uivarosi, E. M. Pahontu, A. Munteanu, Rev. Chim. (Bucharest) 2014, 65, 33.

[28]  F. Yang, H. Jin, J. Pi, J. Jiang, L. Liu, H. Bai, P. Yang, J. Cai, Bioorg. Med. Chem. Lett. 2013, 23, 5544.
         | Crossref | GoogleScholarGoogle Scholar | 24007917PubMed |

[29]  N. F. L. Machado, L. A. E. Batista de Carvalho, J. C. Otero, M. P. M. Marques, Spectrochim. Acta, Part A 2013, 109, 116.
         | Crossref | GoogleScholarGoogle Scholar |

[30]  N. Sundaraganesan, G. Mariappan, S. Manoharan, Spectrochim. Acta, Part A 2012, 87, 67.
         | Crossref | GoogleScholarGoogle Scholar |

[31]  S. B. Bukhari, S. Memon, M. Mahroof-Tahir, M. I. Bhanger, Spectrochim. Acta, Part A 2009, 71, 1901.
         | Crossref | GoogleScholarGoogle Scholar |

[32]  N. Wang, C. Cai, X. He, S. Pang, Y. Zhang, Spectrochim. Acta, Part A 2018, 192, 420.
         | Crossref | GoogleScholarGoogle Scholar |

[33]  G. B. Deacon, R. J. Phillips, Coord. Chem. Rev. 1980, 33, 227.
         | Crossref | GoogleScholarGoogle Scholar |

[34]  K. Nakamoto, Infrared Spectra of Inorganic and Coordination Compounds 1986 (John Wiley and Sons, Inc.: New York, NY).

[35]  Y.-M. Lee, S. K. Kang, G. Chung, Y.-K. Kim, S.-Y. Won, S.-N. Choi, J. Coord. Chem. 2003, 56, 635.
         | Crossref | GoogleScholarGoogle Scholar |

[36]  H. Liu, Y. Mou, J. Zhao, J. Wang, L. Zhou, M. Wang, D. Wang, J. Han, Z. Yu, F. Yang, Molecules 2010, 15, 7933.
         | Crossref | GoogleScholarGoogle Scholar | 21060300PubMed |

[37]  A. A. Ansari, Main Group Chem. 2008, 7, 43.
         | Crossref | GoogleScholarGoogle Scholar |

[38]  V. Uivarosi, M. Badea, R. Olar, C. Drǎghici, Ş. F. Bǎrbuceanu, Molecules 2013, 18, 7631.
         | Crossref | GoogleScholarGoogle Scholar | 23884117PubMed |

[39]  C. B. Black, H.-W. Huang, J. A. Cowan, Coord. Chem. Rev. 1994, 135, 165.
         | Crossref | GoogleScholarGoogle Scholar |

[40]  T. A. Evans, J. J. Katz, Biochim. Biophys. Acta 1975, 396, 414.
         | Crossref | GoogleScholarGoogle Scholar | 1174519PubMed |

[41]  R. K. Clayton, in The Chlorophylls (Eds L. P. Vernon, G. R. Seely) 1966, pp. 609–641 (Academic Press: New York, NY).

[42]  J. Janczak, Polyhedron 2011, 30, 2933.
         | Crossref | GoogleScholarGoogle Scholar |

[43]  V. Kinzhybalo, J. Janczak, J. Mol. Struct. 2009, 921, 1.
         | Crossref | GoogleScholarGoogle Scholar |

[44]  J. Janczak, Polyhedron 2014, 70, 164.
         | Crossref | GoogleScholarGoogle Scholar |

[45]  A. Patra, M. Bera, Carbohydr. Res. 2014, 384, 87.
         | Crossref | GoogleScholarGoogle Scholar | 24370943PubMed |

[46]  H. Xuan, Y. Wang, A. Li, C. Fu, Y. Wang, W. Peng, Evid. Based Complement. Alternat. Med. 2016, 2016, 9641965.
         | Crossref | GoogleScholarGoogle Scholar | 27123037PubMed |

[47]  S. Samarghandian, M. A. Nezhad, G. Mohammadi, Anticancer. Agents Med. Chem. 2014, 14, 901.
         | Crossref | GoogleScholarGoogle Scholar | 24521149PubMed |

[48]  G. Farruggia, S. Castiglioni, A. Sargenti, C. Marraccini, A. Cazzaniga, L. Merolle, S. Iotti, C. Cappadone, J. A. Maier, Magnes. Res. 2014, 27, 25.
         | Crossref | GoogleScholarGoogle Scholar | 24776097PubMed |

[49]  S. A. Mirmalek, E. Jangholi, M. Jafari, S. Yadollah-Damavandi, M. A. Javidi, Y. Parsa, T. Parsa, S. A. Salimi-Tabatabaee, H. G. Kolagar, S. K. Jalil, R. Alizadeh-Navaei, Asian Pac. J. Cancer Prev. 2016, 17, 131.
         | Crossref | GoogleScholarGoogle Scholar | 27165250PubMed |

[50]  J. Wang, J. Yi, Cancer Biol. Ther. 2008, 7, 1875.
         | Crossref | GoogleScholarGoogle Scholar | 18981733PubMed |

[51]  P. G. Wells, G. P. McCallum, C. S. Chen, J. T. Henderson, C. J. J. Lee, J. Perstin, T. J. Preston, A. W. Wong, Toxicol. Sci. 2009, 108, 4.
         | Crossref | GoogleScholarGoogle Scholar | 19126598PubMed |

[52]  J.-j. Shao, A.-p. Zhang, W. Qin, L. Zheng, Y.-f. Zhu, X. Chen, Biochem. Biophys. Res. Commun. 2012, 423, 448.
         | Crossref | GoogleScholarGoogle Scholar | 22659738PubMed |

[53]  W. F. Hodnick, S. Ahmad, R. S. Pardini, Adv. Exp. Med. Biol. 1998, 439, 131.
         | Crossref | GoogleScholarGoogle Scholar | 9781300PubMed |

[54]  C. Li, L. Sun, C. Panga, Sci. Rep. 2015, 5, 9819.
         | Crossref | GoogleScholarGoogle Scholar | 25909282PubMed |

[55]  G. Sponchiado, M. L. Adam, C. D. Silva, B. S. Soley, C. de Mello-Sampayo, D. A. Cabrini, C. J. Correr, M. F. Otuki, J. Ethnopharmacol. 2016, 178, 289.
         | Crossref | GoogleScholarGoogle Scholar | 26680588PubMed |

[56]  A. Lagarto Parra, R. Silva Yhebra, I. Guerra Sardiñas, L. Iglesias Buela, Phytomedicine 2001, 8, 395.
         | Crossref | GoogleScholarGoogle Scholar |

[57]  S. Rajabi, A. Ramazani, M. Hamidi, T. Naji, J. Pharm. Sci. 2015, 23, 20.
         | Crossref | GoogleScholarGoogle Scholar |

[58]  A. Bacchi, M. Carcelli, P. Pelagatti, C. Pelizzi, G. Pelizzi, F. Zani, J. Inorg. Biochem. 1999, 75, 123.
         | Crossref | GoogleScholarGoogle Scholar | 10450607PubMed |

[59]  M. Amararathna, M. R. Johnston, H. P. V. Rupasinghe, Int. J. Mol. Sci. 2016, 17, 1352.
         | Crossref | GoogleScholarGoogle Scholar |

[60]  K. Park, H. Park, M. Kim, G. Hong, A. Nagappan, H. Lee, S. Yumnam, W. Lee, C. Won, S. Shin, G. Kim, J. Funct. Foods 2014, 7, 287.
         | Crossref | GoogleScholarGoogle Scholar |

[61]  H. H. Popper, Cancer Metastasis Rev. 2016, 35, 75.
         | Crossref | GoogleScholarGoogle Scholar | 27018053PubMed |

[62]  P. Chanvorachote, S. Chamni, C. Ninsontia, P. Plaimee Phiboonchaiyanan Potential, Anticancer Res. 2016, 36, 5707.
         | Crossref | GoogleScholarGoogle Scholar | 27793892PubMed |

[63]  World Cancer Research Fund/American Institute for Cancer Research, Food, Nutrition and the Prevention of Cancer: A Global Perspective 1997 (American Institute for Cancer Research: Washington, DC).

[64]  L. Le Marchand, S. P. Murphy, J. H. Hankin, L. R. Wilkens, L. N. Kolonel, J. Natl. Cancer Inst. 2000, 92, 154.
         | Crossref | GoogleScholarGoogle Scholar | 10639518PubMed |

[65]  K. Sak, Pharmacogn. Rev. 2014, 8, 122.
         | Crossref | GoogleScholarGoogle Scholar | 25125885PubMed |

[66]  U. Ndagi, N. Mhlongo, M. E. Soliman, Drug Des. Devel. Ther. 2017, 11, 599.
         | Crossref | GoogleScholarGoogle Scholar | 28424538PubMed |

[67]  P. Hohenberg, W. Kohn, Phys. Rev. 1964, 136, B864.
         | Crossref | GoogleScholarGoogle Scholar |

[68]  W. Kohn, L. J. Sham, Phys. Rev. 1965, 140, A1133.
         | Crossref | GoogleScholarGoogle Scholar |

[69]  R. G. Parr, W. Yang, Density Functional Theory of Atoms and Molecules 1989 (Oxford University Press: New York, NY).

[70]  M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery, J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin, K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels, O. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox, Gaussian 09, Revision A.1 2009 (Gaussian Inc.: Wallingford, CT).

[71]  A. D. Becke, J. Chem. Phys. 1993, 98, 5648.
         | Crossref | GoogleScholarGoogle Scholar |

[72]  C. Lee, W. Yang, R. G. Parr, Phys. Rev. B Condens. Matter 1988, 37, 785.
         | Crossref | GoogleScholarGoogle Scholar | 9944570PubMed |

[73]  K. Lirdprapamongkol, H. Sakurai, N. Kawasaki, M. K. Choo, Y. Saitoh, Y. Aozuka, P. Singhirunnusorn, S. Ruchirawat, J. Svasti, I. Saiki, Eur. J. Pharm. Sci. 2005, 25, 57.
         | Crossref | GoogleScholarGoogle Scholar | 15854801PubMed |

[74]  F. Li, C. Li, H. Zhang, Z. Lu, Z. Li, Q. You, N. Lu, Q. Guo, Toxicol. Appl. Pharmacol. 2012, 261, 217.
         | Crossref | GoogleScholarGoogle Scholar | 22538171PubMed |

[75]  L. Wang, J. Ho, C. Glackin, M. Martins-Green, Transl. Oncol. 2012, 5, 344.
         | Crossref | GoogleScholarGoogle Scholar | 23066443PubMed |

[76]  A. A. Musa, J. Appl. Pharm. Sci. 2012, 2, 155.
         | Crossref | GoogleScholarGoogle Scholar |

[77]  D. M. Maron, B. N. Ames, Mutat. Res. 1983, 113, 173.
         | Crossref | GoogleScholarGoogle Scholar | 6341825PubMed |