Cytotoxicity and antiviral activity of palladium(II) and platinum(II) complexes with 2-(diphenylphosphino)benzaldehyde 1-adamantoylhydrazone

Cytotoxicity and antiviral activity of palladium(II) and platinum(II) complexes with 2-(diphenylphosphino)benzaldehyde 1-adamantoylhydrazone

Metal coordination compounds have an important role in the development of novel drugs. Using the resazurin microtitration assay we assessed the cytotoxicity and antiviral activity of the ligand 2-(diphenylphosphino)benzaldehyde 1-adamantoylhydrazone and its Pd(II) and Pt(II) complexes. Cytotoxicity was tested in A549 human lung adenocarcinoma epithelial cells. We observed that the ligand displayed a more pronounced cytotoxic activity than the platinum-based drug, carboplatin. Morphological evaluation of A549 cells treated with the ligand by acridine orange and ethidium bromide double staining revealed the presence of signs of apoptosis. Antiviral activity against poliovirus type 1 was assessed by examination of the cytopathic effect (CPE) in Hep-2 cells. Cells that were exposed to the 19 μM ligand before infection displayed a maximal significant reduction (by 24.42 ± 1.49%) of the CPE. This was likely due to the inhibition of virus receptors and prevention of viral adsorption. Treatment with 17 μM Pt(II) complex after viral infection caused a maximal significant reduction (by 30.52 ± 3.12%) of the CPE, presumably through an effect on viral replication. The results indicate that the ligand should be viewed as a potential anticancer agent. The ligand and the Pt(II) complex show promising results for further investigation of antiviral activity.

___

  • ReferencesAbu-Surrah AS, Al-Sa’doni H, Abdalla M (2008). Palladium based chemotherapeutic agents. Routes towards complexes with good antitumor activity. Cancer Ther 6: 1–10.Adams J (2001). Proteasome inhibition in cancer: development of PS-341. Semin Oncol 28: 613–619.Baskić D, Popović S, Ristić P, Arsenijević NN (2006). Analysis of cycloheximide-induced apoptosis in human leukocytes: Fluorescence microscopy using annexin V/propidium iodide versus acridin orange/ethidium bromide. Cell Biol Int 30: 924–932.Cantell K, Strander H (1966). Production of interferon by human leukocytes in vitro. Ann Med Exp Biol Fenn 44: 256–273.Cetintas VB, Kucukaslan AS, Kosova B, Tetik A, Selvi N, Cok G, Gunduz C, Eroglu Z (2012). Cisplatin resistance induced by decreased apoptotic activity in non-small-cell lung cancer cell lines. Cell Biol Int 36: 261–265.Council of Europe (2013). European Pharmacopoeia. 8th ed. Strasbourg, France: European Directorate for the Quality of Medicines and Health Care, Council of Europe.De Palma A, Holy A, Hrebabecky H, Neyts J, Sala M (2008). Antiviral compounds of the adamantane type. Patent Number WO 2008131502 A2.Đorđević MM, Jeremić DA, Rodić MV, Simić VS, Brčeski ID, Leovac VM (2014). Synthesis, structure and biological activities of Pd(II) and Pt(II) complexes with 2-(diphenylphosphino)benzaldehyde 1-adamantoylhydrazone. Polyhedron 68: 234–240.EDQM (2009). CombiStats Version 4.0. Strasbourg, France: European Directorate for the Quality of Medicines and Health Care, Council of Europe.Enan G, Abdallah FM, Bobhy H (2012). Effect of acyclovir on bovine herpesvirus type 1 in in vitro cultured cells. Int J Virol 8: 307–312.Freshney RI (2005). Culture of Animal Cells, A Manual of Basic Technique. 5th ed. Hoboken, NJ, USA: John Wiley and Sons, pp. 359–370.Frezza M, Hindo S, Chen D, Davenport A, Schmitt S, Tomco D, Doun QP (2010). Novel metals and metal complexes as platforms for cancer therapy. Curr Pharm Design 16: 1813–1825.FDA (2006). Guidance for Industry, Antiviral Product Development-Conducting and Submitting Virology Studies to the Agency. Silver Spring, MD, USA: Food and Drug Administration Center for Drug Evaluation and Research.Galassi R, Burini A, Ricci S, Pellei M, Rigobello M, Citta A, Dolmella A, Gandinc V, Marzano C (2012). Synthesis and characterization of azolate gold(I) phosphane complexes as thioredoxin reductase inhibiting antitumor agents. Dalton T 41: 5307–5318.Gao E, Wang L, Zhu M, Liu L, Zhang W (2010). Synthesis, characterization, interaction with DNA and cytotoxicity in vitro of the complexes [M(dmphen)(CO3)](H2O [M = Pt(II), Pd(II)]. Eur J Med Chem 45: 311–316.Johnston S, Siegel C (1990). Presumptive identification of enteroviruses with RD, HEp-2, and RMK cell lines. J Clin Microbiol 28: 1049–1050.Liu J, Obando D, Liao V, Lifa T, Codd R (2011). The many faces of the adamantyl group in drug design. Eur J Med Chem 46: 1949–1963.Malešević N, Srdić T, Radulović S, Sladić D, Radulović V, Brčeski I, Anđelković K (2006). Synthesis and characterization of a novel Pd(II) complex with the condensation product of 2-(diphenylphosphino) benzaldehyde and ethyl hydrazinoacetate. Cytotoxic activity of the synthesized complex and related Pd(II) and Pt(II) complexes. J Inorg Biochem 100: 1811–1818. Milenković M, Bacchi A, Cantoni G, Radulović S, Gligorijević N, Aranđelović S, Sladić D, Vujčić M, Mitić D, Anđelković K (2013). Synthesis, characterisation and biological activity of Co(III) complex with the condensation product of 2-(diphenylphosphino)benzaldehyde and ethyl carbazate. Inorg Chim Acta 395: 33–43.Milenković M, Bacchi A, Cantoni G, Vilipić J, Sladić D, Vujčić M, Gligorijević N, Jovanović K, Radulović S, Anđelković K (2013). Synthesis, characterization and biological activity of three square-planar complexes of Ni(II) with ethyl (2E)-2-[2-(diphenylphosphino)benzylidene]hydrazinecarboxylate and monodentate pseudohalides. Eur J Med Chem 68: 111–120.Monto AS (2003). The role of antivirals in the control of influenza vaccine. Vaccine 21: 1796–1800.Rabik CA, Dolan ME (2007). Molecular mechanisms of resistance and toxicity associated with platinating agents. Cancer Treat Rev 33: 9–23.Šmidling D, Mitić-Ćulafić D, Vuković-Gačić B, Simić D, Knežević-Vukčević J (2008). Evaluation of antiviral activity of fractionated extracts of sage Salvia officinalis L. (Lamiaceae). Arch Biol Sci 60: 421–429.Squier MK, Cohen JJ (2001). Standard quantitative assays for apoptosis. Mol Biotechnol 19: 305–312.Starosta R, Bykowska A, Barys M, Wieliczko AK, Staroniewicz Z, Jezowska-Bojczuk M (2011). Novel complexes of tris(aminomethyl)phosphanes with platinum(II): structural, spectroscopic, DFT and biological activity studies. Polyhedron 30: 2914–2921.Ulukaya E, Ari F, Dimas K, Sarimahmut M, Guney E (2011). Cell death-inducing effect of novel palladium(II) and platinum(II) complexes on non-small cell lung cancer cells in vitro. J Cancer Res Clin 137: 1425–1434.Vega-Avila E, Pugsley M (2011). An overview of colorimetric assay methods used to assess survival or proliferation of mammalian cells. P W Pharmacol Soc 54: 10–14.Vejselova D, Kutlu HM (2015). Inhibitory effects of salicylic acid on A549 human lung adenocarcinoma cell viability. Turk J Biol 39: 1–5.WHO (1997). Manual of Laboratory Methods for Testing Vaccines Used in the WHO Expanded Programme on Immunization. WHO/VSQ/97.04. Geneva, Switzerland: World Health Organization.