Synthesis and Biological Activity of a New Pt(II) Complex Involving 4-bromo-2,6-bis-hydroxymethyl-phenol and Nicotinamide

Document Type : Research Article


Trakya University, Department of Chemistry, 22030 Edirne, TURKEY


IIn the present study, a Pt(II) complex including 4-Bromo-2,6-bis-hydroxymethyl-phenol (BBHMP) and nicotinamide (NA) was synthesized and structurally analyzed by using spectral and thermal analysis methods. BBHMP and its Pt(II) complex in the presence of BBHMP and NA were investigated for their antimicrobial, cytotoxicity, gene expression, and antioxidant properties. The antimicrobial activity results showed that the platinum complex displayed a significant effect against Staphylococcus aureus and Candida albicans. The cytotoxicity of BBHMP and platinum complex were determined against human prostate adenocarcinoma (DU145) and breast (MCF7) cancer cell lines by applying the MTT assay. Cytotoxicity results suggested that the Pt(II) complex exhibited moderate cytotoxicity against the growth of these cancer cell lines when compared with the reference drug cisplatin is more effective than free BBHMP and NA. Gene expression results proved that the Pt(II) complex is a special bioactive chemical constituent and potential anticancer agent. The results obtained showed that the complex had highly inhibitory effects on gene expression. In addition, Pt(II) complex also displayed effective antioxidant activity.


Main Subjects

[1] Yonemura M., Arimura K., Inoue K., Usuki N., Ohba M., Ohkawa H., Coordination-Position İsomeric MIICuII and CuIIMII (M = Co, Ni, Zn) Complexes Derived From Macrocyclic Compartmental Ligands,  Inorg. Chem., 41 (3): 582-589 (2002).
[2] Rajendiran T.M., Kannappan R., Mahalakshmy R., Rajeswari J., Venkatesan R., Rao P., New Unsymmetrical L-Phenoxo Bridged Binuclear Copper(II) Complexes, Trans. Metal Chem., 28 (4): 447-454 (2003).
[3] Ambrosi G., Formica M., Fusi V., Giorgi L., Micheloni M., Polynuclear Metal Complexes of Ligands Containing Phenolic Units, Coord. Chem. Rev., 252 (10-11): 1121–1152 (2008).
[4] Zhou Y., Zhang J.F., Yoon J., Fluorescence and Colorimetric Chemosensors for Fluoride-Ion Detection, Chem. Rev., 114 (10): 5511-5571 (2014).
[6] Crisp G.T., Turner P.D., Tiekink E.R.T., Crystal structure of 4-bromo-2,6- bis(hydroxymethyl)phenol, CsH9Br03,  Ζ. Kristallogr., 215 (3): 443-444 (2000).
[7] Chokkanathan U., Geetha K., Synthesis, Characterization and Biological Applications of a Multidentate Ligand and İts Copper(II) Complexes, Int. J. App. Adv. Sci. Res. (IJAASR), 1(2): 146-151 (2016).
[8] Altun Ö., Yoruç Z., Pd(II) complex with 4-bromo-bis-hydroxymethyl phenol and Nicotinamide: Synthesis and Spectral Analysis, World Academy Sci. Eng. Techn. Int. J. Chem. Mat. Eng., 12 (9): 471-474 (2018).
[10] Lim L.Y., Go M.L., Caffeine and Nicotinamide Enhances the Aqueous Solubility of the Antimalarial Agent Halofantrine, Eur. J. Pharm. Sci., 10 (1): 17-28 (2000).
[11] Turan-Zitouni G., Sıvacı M., Kılıç F.S., Erol K., Synthesis of Some Triazolyl-Antipyrine Derivatives And İnvestigation of Analgesic Activity, Eur. J. Med. Chem., 36 (7-8): 685-689 (2001).
[12] Evstigneev M.P., Evstigneev V.P., Hernandez Santiago A.A., Davies D.B., Effect of a Mixture of Caffeine and Nicotinamide on the Solubility of Vitamin (B2) in Aqueous Solution, Eur. J. Pharm. Sci., 28 (1-2): 59-66 (2006).
[13] Lawal A., Obaleye J.A., Adediji J.F., Amolegbe S.A., Bamigboye M.O., Yunus-Issa M.T.L., Synthesis, Characterization and Antimicrobial Activities of Some Nicotinamide–metal Complexes, J. Appl. Sci. Environ. Manage., 18 (2): 205-208 (2014).
[14] Dilip C.S., Thangaraj V., Rai A.P., Synthesis, Spectroscopic Characterisation, Biological and DNA Cleavage Properties of Complexes of Nicotinamide, Arab. J. Chem., 9 (1): S731-S742 (2016).
[15] Tella A.C., Owalude S.O., Sunday G.M., Olatunji J.,  Adetitun D.O., Kolawole M.O., Synthesis, Thermal Properties, and Biological Study of Metal(II) Nicotinamide Complexes Containing Fumarate Dianion and Fumaric Acid: Crystal Structure of [Ni(H2O)4(nia)2](fum)·(H2fum), Inorg. Nano-Metal Chem., 47 (6): 859-864 (2017).
[18] Cakır S., Biçer E., Aoki K., Coşkun E., Structural Features of a new [Fe(nicotinamide)2(H2O)4]. [Fe(H2O)6).SO4.2H2O Complex, Cryst. Res. Tech.., 41 (3): 314-320 (2006).
[19] Cakır S., Biçer E., Voltammetric and Spectroscopic Studies of Vanadium(V)– Nicotinamide Interactions at Physiological pH, Turk. J. Chem. 31(2): 223 - 231 (2007).
[20] Hokelek, T., Yavuz, V., Dal, H., Necefoğlu, H., Crystal structure and Hirshfeld Surface Analysis of aqua-bis-(nicotinamide-κN)bis-(4-sulfamoylbenzoato- κO1)copper(II), Acta Crystallogr. E Crystallogr. Commun., 74 (Pt 1): 45-50 (2018).
[21] Clinical and Laboratory Standards Institute, “Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts: Approved Standard M27-A2”, Wayne (PA), CLSI (2002).
[22] Clinical and Laboratory Standards Institute, "Performance Standards for Antimicrobial Susceptibility Testing", 15th Informational Supplement. CLSI Document M100-S22, PA (2012).
[23] Wiegand I., Hilpert K., Hancock R.E.W., Agar and Broth Dilution Methods to Determine the Minimal İnhibitory Concentration (MIC) of Antimicrobial Substances, Nature Protocols, 3 (2): 163-175 (2008).
[26] Bharath K.S., Naga S.S.P.K.C., Santhoshi A., Pranay K.K., Suryanarayana M.U., Jayathirtha R.V., Efficient Synthesis and Antimicrobial Activity of 2-Pyridyl-4-thiazolidinones from 2-Chloro Nicotinaldehydes, Iran. J. Chem. Chem. Eng. (IJCCE), 38 (3): 97-105 (2019).
[31] Kim R., Emi M., Tanabe K., Role of Mitochondria as the Gardens of Cell Death, Cancer Chemoth Pharm., 57 (5): 545-553 (2006).
[34] Kai Z., Jingxia Q., Jun G., Jun Z., Heping L., Guoyong Z., Synthesis, Characterization, Molecular Docking and Cytotoxicity Studies of Bagasse Xylem Ferulate-Acrylamide/Methyl Methacrylate Composite, Iran. J. Chem. Chem. Eng. (IJCCE), 38(3): 107-116 (2019).
[36] Sathiyaraj S., Butcher R.J., Jayabalakrishnan C., Synthesis, Characterization, DNA Interaction and in Vitro Cytotoxicity Activities of Ruthenium(II) Schiff Base Complexes, J. Mol. Struct., 1030: 95–103 (2012).
[37] Hongmei Z., “Apoptosis and Medicine: Extrinsic and intrinsic apoptosis signal pathway review in biochemistry”, Genetics and Molecular Biology, T.M. Ntuli, ed. (2002).   
[38] Fulda S., Debatin K.M.,  Debatin, Extrinsic Versus Intrinsic Apoptosis Pathways in Anticancer Chemotherapy, Oncogene, 25 (34): 4798-4811 (2006).
[39] Güçlü H.,  Doganlar Z.B., Gürlü V.P., Özal A., Dogan A., Turhan M.A., Doganlar O., Effects of Cisplatin-5-Fluorouracil Combination Therapy on Oxidative Stress, DNA Damage, Mitochondrial Apoptosis, and Death Receptor Signalling in Retinal Pigment Epithelium Cells, Cutaneous and Ocular Toxicology, 37 (3): 291–304 (2018).
[40] Zaim Ö., Doğanlar O., Zreigh M.M., Doğanlar Z.B., Özcan H., Synthesis, Cancer-Selective Antiproliferative and Apoptotic Effects of Some (±)-Naringenin Cycloaminoethyl Derivatives, Chem. Biodivers., 15 (7) e1800016: 1-15 (2018).
[41] Ali Reza Aliabadi A.R., Hojat H.N., Yazdan B., 4-Halo-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)benzamide and Benzothioamide Derivatives: Synthesis and in Vitro Anticancer Assessment, Iran. J. Chem. Chem. Eng. (IJCCE), 39 (5): 35-44 (2020).
[42] Blois M.S., Antioxidant Determinations by the Use of a Stable Free Radical. Nature, 181 (4617): 1199-1200 (1958).
[43] Choudhary A., Sharma R., Nagar M., Mohsin M., Meena H.S., Synthesis, Characterization and Antioxidant Activity of Some Transition Metal Complexes with Terpenoid Derivatives, J. Chil. Chem. Soc., 56 (4): 911-917 (2011).
[45] Muhammad Z., Farooq A., Muhammad N.Z., Muhammad F.N., Abdullah I.H., Ehsan U.M., Effect of Ultrasonic Extraction Regimes on Phenolics and Antioxidant Attributes of Rice (oryza sativa L.) Cultivars, Iran. J. Chem. Chem. Eng. (IJCCE), 37(1): 109-119 (2018).
[46] Mohamed E.S., Samir A.M., Seham Y.H., Mohamed A.M., Galile Y., Synthesis, Reactions and Antioxidant Activity of 5-(3', 4'-dihydroxy-tetrahydrofuran-2'-yl)-2-methyl-3-carbohydrazide, Iran. J. Chem. Chem. Eng. (IJCCE), 38 (6): 229-242 (2019).
[47] Sara S.L., Amir S., Davar S., Hasan H., Evaluation of Antibacterial and Antioxidant Activities of Essential Oil of Lime (Citrus aurantifolia) Pomace Powder, Iran. J. Chem. Chem. Eng. (IJCCE), 40(3): 832-840 (2021).
[48] Hristea E.N., Caproiu M.T., Pencu G., Hillebrand M., Constantinescu T., Balaban A.T., Reaction of 2,2-Diphenyl-1-picrylhydrazyl with HO•, O2 •–, HO–, and HOO– Radicals and AnionsInt. J. Mol. Sci., 7: 130-143 (2006).
[50] Kettle S.F.A., “Coordination Compounds”, Thomas Nelson and Sons, London (1975).
[52] Dyer J.R., “Application of Absorption Spectroscopy of Organic Compounds”, Prentice-Hall, New Jersey (1965).
[53] Siiman O., Fresco J., Electronic Spectra of the Dithioacetylacetone Complexes of Nickel(II), Palladium(II), and Platinum(II), J. Am. Chem. Soc., 92 (9): 2652-2656 (1970).
[54] Lever A.B.P., “Inorganic Electronic Spectroscopy”, 2nd ed., Elsevier, New York (1984).
[56] Socrates G., “Infrared Characterization Group Frequencies”, John Wiley and Sons Inc., New York (1980).
[58] Simpson N., Shaw D.J., Frederix P.W.J.M., Gillies A.H., Adamczyk K., Greetham G.M., Towrie M., Parker A.W., Hoskisson P.A., Hunt N.T., Infrared Spectroscopy of Nicotinamide Adenine Dinucleotides in One and Two Dimensions, J. Phys. Chem., B, 117(51): 16468−16478 (2013).
[59] Nakamato K., Morimoto V., Martell A.E., Infrared Spectra of Aqueous Solutions. I. Metal Chelate Compounds of Amino Acids,  J. Am. Chem. Soc., 83 (22): 4528-4532 (1961).
[60] Nakamato K., “Infrared and Raman Spectra of Inorganic and Coordination Compounds”, John Wiley and Sons Inc., New York (2006).
[61] Lambert J.B., Shurwell H.F., Verbit L., Cooks R.G., Stout G.H., “Organic Structural Analysis, Mac Millan, New York (1976).
[62] Olsen R.A., Liu L., Ghaderi N., Johns A., Hatcher M.E., Mueller L.J., The Amide Rotational Barriers in Picolinamide and Nicotinamide: NMR and ab Initio Studies,  J. Am. Chem. Soc., 125 (33): 10125-10132 (2003).
[63] Czochralski J., A New Method for the Measurement of the Crystallization Rate of Metals, Zeitschrift für Physikalische Chemie, 92 (1): 219–221 (1918).
[64] Jones P.G., Crystal Growing, Chemistry in Britain, 17 (5): 222-225 (1981). (Tips of crystal growing)
[65] Van Der Sluis P., Hezemans A.M.F., Kroon J.,  Crystallization of Low-Molecular-Weight Organic Compounds for X-Ray Crystallography, J. Appl. Crystallogr. 22 (4): 340-344 (1989).
[66] Salem M.A., Bakr E.A., El-Attar H.G., Pt@Ag and Pd@Ag Core/Shell Nanoparticles for Catalytic Degradation of Congo Red in Aqueous Solution, Spectrochim. Acta Part A, 188: 155-163 (2018).
[67] Warren B.E.,  “X-Ray Diffraction”, 2nd ed. Dover, New York (1990).
[68] Velammal S.P., Devi T.A., Amaladhas T.P., Antioxidant, Antimicrobial and Cytotoxic Activities of Silver and Gold Nanoparticles Synthesized Using Plumbago Zeylanica Bark, J. Nanostructure Chem. 6 (3): 247-260 (2016).
[69] Giovagnini L., Ronconi L., Aldinucci D., Lorenzon D., Sitran S., Fregona D., Synthesis, Characterization, and Comparative in Vitro Cytotoxicity Studies of Platinum(II), Palladium(II), and Gold(III) Methylsarcosinedithiocarbamate Complexes, J. Med. Chem., 48 (5): 1588-1595 (2005).
[70] Carotti S., Guerri A., Mazzei T., Messori L., Mini E., Orioli P., Gold(III) Compounds as Potential Antitumor Agents: Cytotoxicity and DNA Binding Properties of Some Selected Polyamine- Gold(III) Complexes, Inorg. Chim. Acta, 281(1): 90-94 (1998).
[71] Abbate F., Orioli P., Bruni B., Marcon G., Messori L., Crystal Structure and Solution Chemistry of the Cytotoxic Complex 1,2-Dichloro(O-Phenanthroline) Gold(III) Chloride, Inorg. Chim. Acta, 311: 1-5 (2000).
[72] Casini A., Diawara M.C., Scopelliti R., Zakeeruddin S.M., Gratzel M., Dyson P.J., Synthesis, Characterisation and Biological Properties of Gold(III) Compounds with Modified Bipyridine and Bipyridylamine Ligands, Dalton Trans., 39: 2239-2245 (2010).
[75] Filipovic N.R., Markovic I., Mitic,D., Polovic N., Milcic M., Dulovic M., Jovanovic M., Savic M., Niksic M., Andelkovic K., Todorovic T.J., A Comparative Study of in Vitro Cytotoxic, Antioxidant, and Antimicrobial Activity of Pt(II), Zn(II), Cu(II), and Co(III) Complexes with N-Heteroaromatic Schiff Base (E)-2-[N'-(1-Pyridin-2-Yl-Ethylidene) Hydrazino]Acetate, Biochem. Mol. Toxicol., 28 (3): 99-110 (2014).
[77] Pahontu E., Paraschivescu C., Ilies D.C., Poirier D., Oprean C., Paunescu V., Gulea A., Rosu T., Bratu O., Synthesis and Characterization of Novel Cu(II), Pd(II) and Pt(II) Complexes with 8-Ethyl-2-hydroxytricyclo (,7)tridecan-13-onethiosemicarbazone: Antimicrobial and in Vitro Antiproliferative Activity, Molecules, 21 (5): 1-18 (2016).
[78] Gomez G.D., Chavez J.D., Blanco A.C., Fierro A.G., Salazar J.E.J., Matsumura P.D., Quiroz L.E.G., Gonzalez A.D., Nicotinamide Sensitizes Human Breast Cancer Cells to the Cytotoxic Effects of Radiation and Cisplatin, Oncology Reports, 33(2): 721-728 (2015).
[79] Blagosklonny M.V., Pardee A.B., Exploiting Cancer Cell Cycling for Selective Protection of Normal Cells, Cancer Res., 61 (11): 4301-4305 (2001). A
[80] Gümüş F., Algül O., Eren G.; Eroğlu H., Diril N., Gür S., Özkul A., Synthesis, Cytotoxic Activity on MCF-7 Cell Line and Mutagenic Activity of Platinum(II) Complexes with 2-Substituted Benzimidazole Ligands, Eur. J. Med. Chem., 38 (5): 473-480 (2003). 
[81] Li L.J., Wang C., Tian C., Yangi X.Y., Hua X.X., Du J.L., Water-Soluble Platinum(II) Complexes of Reduced Amino Acid Schiff Bases: Synthesis, Characterization, and Antitumor Activity, Res. Chem. Intermediat., 39 (2): 733-746 (2013).
[82] Volarevic V., Vujic J.M., Milovanovic M., Kanjevac T., Volerevic A. Trifunovic S.R., Arsenijevic N., Cytotoxic Effects of Palladium(II) and Platinum(II) Complexes with O, O'-dialkyl Esters of (S, S)-ethylenediamine-N,N'-di-2-(4-methyl) Pentanoic Acid on Human Colon Cancer Cell Lines, J. BUON., 18(1): 131-137 (2013).
[83] Mukherjee S., Mitra I., Reddy V.P.B., Fouzder C., Mukherjee S., Ghosh S., Chatterji U., Moi S.C., Effect of Pt(II) Complexes on Cancer and Normal Cells Compared to Clinically Used Anticancer Drugs: Cell Cycle Analysis, Apoptisis and DNA/BSA Binding Study, Journal of Molecular Liquids, 247: 126-140 (2017).
[84] Pranczk J., Jacewicz D., Wyrzykowski D., Chmurzynski L., Platinum(II) and Palladium(II) Complex Compounds as Anti-Cancer Drugs. Methods of Cytotoxicity Determination, Curr. Pharm. Anal., 10(1): 2-9 (2014).
[85] Ito K., Sugita Y., Saito T., Komatsu S., Sato N., Isomur M., Yoshida W., Kubo K., Maeda H., Effects of Nicotinamide on Cytotoxicity-İnduced Morphological Changes in Osteoblastic Cells in Vitro, J. Hard Tissue Biology, 25(4): 357-364 (2016).
[87] Alee M., Khaghani S., Behroozfar K., Hesari Z., Ghorbanhosseini S.S., Nourbakhsh M., Inhibition of Nicotinamide Phosphoribosyltransferase Induces Apoptosis in Ostrogen Receptor-Positive MCF7 Breast Cancer Cells, J. Breast Cancer, 20 (1): 20-26 (2017).
[88] Plutin A.M., Alvarez A., Mocelo R., Ramos R., Sanchez O.C.,  Castellano E.E., Da Silva M.M., Villarreal W., Colina-Vegas L,. Pavan F.R., Batista A.A., Structure/Activity of PtII/N,N-Disubstituted-N'-acylthiourea Complexes: Anti‑Tumor and Anti-Mycobacterium tuberculosis Activities, J. Braz. Chem. Soc., 29 (6): 1256-1267 (2018).
[90] Maji M., Karmakar S., Ruturaj; Gupta A., Mukherjee A., Oxamusplatin: a Cytotoxic Pt(ii) Complex of a Nitrogen Mustard with Resistance to Thiol Based Sequestration Displays Enhanced Selectivity Towards Cancer, Dalton Trans., 49(8): 2547-2558 (2020).
[91] Shimizu Y., Yoshikawa Y., Kenmotsu T., Komeda S., Yoshikawa K., Conformational Transition of DNA by Dinuclear Pt(II) Complexes Causescooperative Inhibition of Gene Expression, Chemical Physics Letters, 678: 123-129 (2017).
[92] Anderson R.M., Bitterman K.J., Wood J.G., Medvedik O., Sinclair D.A., Nicotinamide and PNC1 Govern Lifespan Extension by Calorie Restriction in Saccharomyces Cerevisiae, Nature, 423: 181-185 (2003).
[93] Isbilir S.S., Sagıroglu A., Total Phenolic Content, Antiradical and Antioxidant Activities of Wild and Cultivated Rumex Acetosella L. Extracts,  Biological Agriculture and Horticulture, 29 (4): 219-226 (2013).
[94] Isbilir S.S., Kabala S.I., Yagar H., Assessment of in Vitro Antioxidant and Antidiabetic Capacities of Medlar (Mespilus Germanica). Not. Bot. Horti. Agrobo, 47 (2): 384-389 (2019).
[95] Sanna V., Pala N., Dessi G., Manconi P., Mariani A., Dedol S., Rassu M., Crosio C., Iaccarino C., Sechi M., Single-Step Green Synthesis And Characterization of Gold-Conjugated Polyphenol Nanoparticles with Antioxidant and Biological Activities, Int. J. Nanomed., 9: 4935-4951 (2014).
[97] Simic V., Kolarevic S., Brceski I., Jeremic D., Vukovic-Gacic B., Cytotoxicity and Antiviral Activity of Palladium(II) and Platinum(II) Complexes with 2-(diphenylphosphino) Benzaldehyde 1-Adamantoylhydrazone, Turk. J. Biol., 40: 661-669 (2016).
[98] Saritha V., Anilakumar K.R., Khanum F., Antioxidant and Antibacterial Activity of Aloe Vera Gel Extracts,  Int. J. Pharm. Biol. Arch., 1 (4): 376-384 (2010).