IMMUNOMODULATORY POTENTIAL OF PALLADIUM(II) COMPLEXES WITH (1E,6E)-1,7-BIS (3,4-DIMETHOXYPHENYL) HEPTA-1,6-DIENE-3,5-DIONE

Eva  FISCHER-FODOR; Roman  MIKLÁŠ; Ludovic Tibor  KRAUSZ; Piroska  VIRAG; Daniela Cristina  MOLDOVAN; Maria  PERDE SCHREPLER; Ioana  BERINDAN-NEAGOE; Ferdinand  DEVÍNSKY; Natalia Lucia  MIKLÁŠOVÁ

Authors

Eva FISCHER-FODOR Department of Chemical Theory of Drugs, Faculty of Pharmacy, Comenius University, Bratislava, Slovakia. Corresponding author: fischer.eva@iocn.ro. https://orcid.org/0000-0002-0898-0547
Roman MIKLÁŠ Research Department, Comprehensive Cancer Center, "Prof. Dr. I. Chiricuta" Institute of Oncology, Cluj-Napoca, Romania. Corresponding author: fischer.eva@iocn.ro. https://orcid.org/0000-0002-7899-3474
Ludovic Tibor KRAUSZ Faculty of Medicine, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj Napoca; Public Health Center, Miercurea Ciuc, Romania. Email: tibor.krausz@umfcluj.ro. https://orcid.org/0000-0002-2545-6640
Piroska VIRAG Department of Chemical Theory of Drugs, Faculty of Pharmacy, Comenius University, Bratislava, Slovakia. Corresponding author: fischer.eva@iocn.ro. https://orcid.org/0000-0002-2545-6640
Daniela Cristina MOLDOVAN Regional Blood Transfusion Center, Cluj-Napoca, Romania. Corresponding author: fischer.eva@iocn.ro.
Maria PERDE SCHREPLER Department of Chemical Theory of Drugs, Faculty of Pharmacy, Comenius University, Bratislava, Slovakia. Corresponding author: fischer.eva@iocn.ro. https://orcid.org/0000-0001-8581-0982
Ioana BERINDAN-NEAGOE Faculty of Medicine, Institute of Molecular Biology, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania. Email: ioana.neagoe@umfcluj.ro. https://orcid.org/0000-0001-5828-1325
Ferdinand DEVÍNSKY Department of Chemical Theory of Drugs, Faculty of Pharmacy, Comenius University, Bratislava, Slovakia. Email: devinsky@fpharm.uniba.sk. https://orcid.org/0000-0002-8059-9994
Natalia Lucia MIKLÁŠOVÁ Department of Chemical Theory of Drugs, Faculty of Pharmacy, Comenius University, Bratislava, Slovakia. Email: miklasova@fpharm.uniba.sk. https://orcid.org/0000-0002-8682-1760

Keywords:

(1E,6E)-1,7-bis(3,4-dimethoxyphenyl)hepta-1,6-diene-3,5-dione, palladium complex, cancer therapy, immune response

Abstract

In chemotherapy, the metal-based cytotoxic drugs are invariable components of therapeutic protocols, despite the biologic drugs expansion. A current tendency is to design metal-based drugs with highest efficacy and limited toxicity on normal human cells implicated in immune response. Therefore we synthesized and characterized two palladium(II) complexes with (1E,6E)-1,7-bis(3,4-dimethoxypenyl)hepta-1,6-diene-3,5-dione, a curcuminoid like ligand; their cytotoxicity towards tumor cells was tested, and their expected impact on T and B lymphocytes was measured in vitro. The lymphocytes treatment with the free ligand, and with the two complexes 1 and 2, increased significantly the proportion of the T helper CD4 positive cell population, concomitant with the decrease of T effector CD8 positive cells. The B cells were not affected by 1, but 2 has a minor inhibitory effect on CD19+ and CD45RA+ cells. The cells function was tested through the compounds modulator effect on membrane markers CD25 and GITR, both being slightly down regulated by 2, compensating of CD4+ overexpression and CD8+ down regulation. Moreover, complex 1 displayed minimal interference with the cellular antitumor immunity, acting as a selective inhibitor of cancer cells growth.

References

S. Dasari, P.B. Tchounwou, European Journal of Pharmacology, 2014, 740, 364.

N. Hashima, B.B. Aggarwal, International Journal of Biochemistry and Molecular Biology, 2012, 3, 328.

S.C. Gupta, S. Prasad, J.H. Kim, S. Patchva, L.J. Webb, I.K. Priyadarsini, B.B. Aggarwal, Natural Products Report, 2011, 28,1937-55.

Z.C. Ding, G. Zhou, Clinical and Developmental Immunology, 2012, 2012, 890178.

A. Valentini, F. Conforti, A. Crispini, A. De Martino, R. Condello, C. Stellitano, G. Rotilio, M. Ghedini, G. Federici, S. Bernardini, D. Pucci, Journal of Medicinal Chemistry, 2009, 52, 484.

L. Baum, A. Ng, Journal of Alzheimer’s Disease, 2004, 6, 367.

N. Miklášová, R. Mikláš, F. Devínsky, Palladium complexes of curcumin and its analogues and methods of preparation of the same, Patent WO 2014/175841 A1, 2014.

N. Miklášová, E. Fischer-Fodor, R. Mikláš, L. Kucková, J. Kožíšek, T. Liptaj, O. Soritau, J. Valentová, F. Devínsky, Inorganic Chemistry Communications, 2014, 46, 229.

G. Karp. Cell and Molecular Biology- Concepts and Experiments, John Wiley & Sons, Hoboken, USA, ISBN-13 978-0-470-48337-4, 6th Ed, 2010, Chapter 17.

V.C. Liu, L.Y. Wong, T. Jang, A.H. Shah, I. Park, X. Yang, Q. Zhang, S. Lonning, B.A. Teicher, C. Lee, Journal of Immunology, 2007, 178, 2883.

P.J. Roughley, D.A. Whiting, Journal of the Chemical. Society Perkin Transactions 1, 1973, 2379.

A. Kessel, T. Haj, R. Peri, A. Snir, D. Melamed, E. Sabo, E. Toubi, Autoimmunity Reviews, 2012, 11, 670.

J.A. Ledbetter, N.K. Tonks, E.H. Fischer, E.A. Clark, Proceedings of the National Academy of Sciences of the USA, 1988, 85, 8628.

G. Nocentini, C. Riccardi, European Journal of Immunology, 2005, 35, 1016.

C. Morimoto, T. Takeuchi, S.F. Schlossman, Clinical and Experimental Rheumatolology, 1989, 7, S3.

T. Ramirez-Montagut, A. Chow, D. Hirschhorn-Cymerman, T.H. Terwey, A.A. Kochman, S. Lu, R.C. Miles, S. Sakaguchi, A.N. Houghton, M.R. van den Brink, Journal of Immunology, 2006, 76, 6434.

A.L. Côté, P. Zhang, J.A. O'Sullivan, V.L. Jacobs, C.R. Clemis, S. Sakaguchi, J.A. Guevara-Patiño, M.J. Turk, Journal of Immunology, 2011, 186, 275.

E. Fischer-Fodor, A.M. Vălean, P. Virag, P. Ilea, C. Tatomir, F. Imre-Lucaci, M. Perde Schrepler, L.T. Krausz, L.B. Tudoran, C.G. Precup, I. Lupan, E. Hey-Hawkins, L. Silaghi-Dumitrescu, Metallomics, 2014, 6, 833.

J. Ceballos-Torres, P. Virag, M. Cenariu, S. Prashar, M. Fajardo, E. Fischer-Fodor, S. Gómez-Ruiz. Chemistry - A European Journal, 2014, 18, 10811.