Three Pt-Pt Complexes with Donor-acceptor Feature: Anticancer Activity, DNA Binding Studies and Molecular Docking Simulation

Author(s): Pezhman Ashoo, Reza Yousefi*, Syed M. Nabavizadeh, Marzieh D. Aseman, Sareh Paziresh, Atiyeh Ghasemi, Ali A. Saboury.

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 19 , Issue 14 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Due to their unique properties and potential applications in variety of areas, recently, a special attention is given to the binuclear platinum (II) complexes. They reveal a highly tunable features upon the modification of their cyclometallating and bridging ligands.

Objective: The aim of this study was to evaluate the anticancer activity and DNA binding affinity of three binuclear platinum (II) complexes, including ht-[(p-FC6H4)Pt(µ-PN)(µ-NP)PtMe2](CF3CO2)(1), ht-[(p- MeC6H4)Pt(µ-PN)(μ-NP)Pt(p MeC6H4) Me] (CF3CO2)(2) and ht-[Pt2Me3(µ-PN)2](CF3CO2) (3).

Methods: MTT assay was performed to study the cell viability of Jurkat and MCF-7 lines against synthesized complexes, followed by apoptosis detection experiments. Several spectroscopic methods with molecular docking simulation were also used to investigate the detail of interaction of these platinum complexes with DNA.

Results: Cell viability assay demonstrated a notable level of cytotoxicity for the synthetic platinum complexes. Further studies proved that a pathway of cell signaling initiating the apoptosis might be activated by these complexes, particularly in the case of complexes 1 and 2. The results of both UV-visible and CD measurements showed the significant ability of these complexes to interact with DNA. While fluorescence data revealed that these complexes cannot enter DNA structure by intercalation, molecular docking assessment proved their DNA groove binding ability.

Conclusion: The remarkable apoptosis inducing activity of the binuclear platinum complexes 1 and 2 and their considerable interaction with DNA suggest them as the potential antitumor medicines.

Keywords: Binuclear platinum (II) complexes, apoptosis, spectroscopic study, flow cytometry, electrophoresis, molecular docking.

[1]
Johnstone, T.C.; Suntharalingam, K.; Lippard, S.J. The next generation of platinum drugs: Targeted Pt (II) agents, nanoparticle delivery, and Pt (IV) prodrugs. Chem. Rev., 2016, 116(5), 3436-3486.
[2]
Jung, Y.; Lippard, S.J. Direct cellular responses to platinum-induced DNA damage. Chem. Rev., 2007, 107(5), 1387-1407.
[3]
Momekov, G.; Bakalova, A.; Karaivanova, M. Novel approaches towards development of non-classical platinum-based antineoplastic agents: Design of platinum complexes characterized by an alternative DNA-binding pattern and/or tumor-targeted cytotoxicity. Curr. Med. Chem., 2005, 12(19), 2177-2191.
[4]
Wang, K.; Gao, E. Recent advances in multinuclear complexes as potential anticancer and DNA binding agents. Anticancer. Agents Med. Chem., 2014, 14(1), 147-169.
[5]
Martinho, N.; Santos, T.C.B.; Florindo, H.F.; Silva, L.C. Cisplatin-membrane interactions and their influence on platinum complexes activity and toxicity. Front. Physiol., 2019, 9, 1898.
[6]
Tsang, R.Y.; Al-Fayea, T.; Au, H-J. Cisplatin overdose: Toxicities and management. Drug Saf., 2009, 32(12), 1109-1122.
[7]
Kostova, I. Platinum complexes as anticancer agents. Recent Patents Anticancer Drug Discov., 2006, 1(1), 1-22.
[8]
Kelland, L. The resurgence of platinum-based cancer chemotherapy. Nat. Rev. Cancer, 2007, 7(8), 573-584.
[9]
Ali, I.; Wani, W.A.; Saleem, K.; Haque, A. Platinum compounds: A hope for future cancer chemotherapy. Anticancer. Agents Med. Chem., 2013, 13(2), 296-306.
[10]
Wheate, N.J.; Walker, S.; Craig, G.E.; Oun, R. The status of platinum anticancer drugs in the clinic and in clinical trials. Dalton Trans., 2010, 39(35), 8113-8127.
[11]
Wang, X. Fresh platinum complexes with promising antitumor activity. Anticancer. Agents Med. Chem., 2010, 10(5), 396-411.
[12]
Bai, L.; Gao, C.; Liu, Q.; Yu, C.; Zhang, Z.; Cai, L.; Yang, B.; Qian, Y.; Yang, J.; Liao, X. Research progress in modern structure of platinum complexes. Eur. J. Med. Chem., 2017, 140, 349-382.
[13]
Farrell, N.P. Multi-platinum anti-cancer agents. Substitution-inert compounds for tumor selectivity and new targets. Chem. Soc. Rev., 2015, 44(24), 8773-8785.
[14]
Czarnomysy, R.; Surażyński, A.; Muszynska, A.; Gornowicz, A.; Bielawska, A.; Bielawski, K. A novel series of pyrazole-platinum(II) complexes as potential anti-cancer agents that induce cell cycle arrest and apoptosis in breast cancer cells. J. Enzyme Inhib. Med. Chem., 2018, 33(1), 1006-1023.
[15]
Alexander, C.; Prajith, N.; Priyanka, P.; Nithyakumar, A.; Samy, N.A. Dinuclear platinum (II) complexes of imidazophenanthroline-based bridging ligands as potential anticancer agents: synthesis, characterization, and in vitro cytotoxicity studies. J. Biol. Inorg. Chem., 2019, 24(3), 405-418.
[16]
Czarnomysy, R.; Bielawski, K.; Muszynska, A.; Bielawska, A.; Gornowicz, A. Biological evaluation of dimethylpyridine–platinum complexes with potent antiproliferative activity. J. Enzyme Inhib. Med. Chem., 2016, 31(suppl. 3), 150-165.
[17]
Shahsavani, M.B.; Ahmadi, S.; Aseman, M.D.; Nabavizadeh, S.M.; Rashidi, M.; Asadi, Z.; Erfani, N.; Ghasemi, A.; Saboury, A.A.; Niazi, A.; Bahaoddini, A.; Yousefi, R. Anticancer activity assessment of two novel binuclear platinum (II) complexes. J. Photochem. Photobiol. B, 2016, 161, 345-354.
[18]
Kumar, C.; Asuncion, E.H. DNA binding studies and site selective fluorescence sensitization of an anthryl probe. J. Am. Chem. Soc., 1993, 115(19), 8547-8553.
[19]
Kennedy, S.D.; Bryant, R.G. Manganese-deoxyribonucleic acid binding modes. Nuclear magnetic relaxation dispersion results. Biophys. J., 1986, 50(4), 669-676.
[20]
Kashanian, S.; Gholivand, M.B.; Ahmadi, F.; Taravati, A.; Colagar, A.H. DNA interaction with Al-N,N′-bis(salicylidene)2,2′-phenylendiamine complex. Spectrochim. Acta A Mol. Biomol. Spectrosc., 2007, 67(2), 472-478.
[21]
Rashidi, M.; Jennings, M.C.; Puddephatt, R.J. Easy making and breaking of metal− metal donor− acceptor bonds in the chemistry of Binuclear Methylplatinum (II) complexes. Organometallics, 2003, 22(13), 2612-2618.
[22]
Shafaatian, B.; Akbari, A.; Nabavizadeh, S.M.; Heinemann, F.W.; Rashidi, M. Aryl, methyl-diplatinum complexes each with a metal-metal donor-acceptor bond and bridging 2-diphenylphosphinopyridine (PN) ligands: general synthetic approach and mechanism of isomerization. Dalton Trans., 2007, 41, 4715-4725.
[23]
Alley, M.C.; Scudiero, D.A.; Monks, A.; Hursey, M.L.; Czerwinski, M.J.; Fine, D.L.; Abbott, B.J.; Mayo, J.G.; Shoemaker, R.H.; Boyd, M.R. Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. Cancer Res., 1988, 48(3), 589-601.
[24]
Gao, E.; Zhu, M.; Yin, H.; Liu, L.; Wu, Q.; Sun, Y. Synthesis, characterization, interaction with DNA and cytotoxicity in vitro of dinuclear Pd(II) and Pt(II) complexes dibridged by 2,2′-azanediyldibenzoic acid. J. Inorg. Biochem., 2008, 102(10), 1958-1964.
[25]
Jamshidi, M.; Yousefi, R.; Nabavizadeh, S.M.; Rashidi, M.; Haghighi, M.G.; Niazi, A.; Moosavi-Movahedi, A-A. Anticancer activity and DNA-binding properties of novel cationic Pt(II) complexes. Int. J. Biol. Macromol., 2014, 66, 86-96.
[26]
Weber, B.; Serafin, A.; Michie, J.; Van Rensburg, C.; Swarts, J.C.; Bohm, L. Cytotoxicity and cell death pathways invoked by two new rhodium-ferrocene complexes in benign and malignant prostatic cell lines. Anticancer Res., 2004, 24(2B), 763-770.
[27]
Herrmann, M.; Lorenz, H.M.; Voll, R.; Grünke, M.; Woith, W.; Kalden, J.R. A rapid and simple method for the isolation of apoptotic DNA fragments. Nucleic Acids Res., 1994, 22(24), 5506-5507.
[28]
Mandal, S.S.; Varshney, U.; Bhattacharya, S. Role of the central metal ion and ligand charge in the DNA binding and modification by metallosalen complexes. Bioconjug. Chem., 1997, 8(6), 798-812.
[29]
Dehkordi, M.N.; Bordbar, A-K.; Lincoln, P.; Mirkhani, V. Spectroscopic study on the interaction of ct-DNA with manganese Salen complex containing triphenyl phosphonium groups. Spectrochim. Acta A Mol. Biomol. Spectrosc., 2012, 90, 50-54.
[30]
Divsalar, A.; Saboury, A.A.; Yousefi, R.; Moosavi-Movahedi, A.A.; Mansoori-Torshizi, H. Spectroscopic and cytotoxic studies of the novel designed palladium(II) complexes: β-lactoglobulin and K562 as the targets. Int. J. Biol. Macromol., 2007, 40(4), 381-386.
[31]
Tabassum, S.; Khan, R.A.; Arjmand, F.; Juvekar, A.S.; Zingde, S.M. Synthesis of carbohydrate-conjugate heterobimetallic Cu(II)-Sn(2)(IV) and Zn(II)-Sn(2)(IV) complexes; their interactions with CT DNA and nucleotides; DNA cleavage, in-vitro cytotoxicity. Eur. J. Med. Chem., 2010, 45(11), 4797-4806.
[32]
Mathew, A. Docking Studies on Anticancer Drugs for Breast Cancer, 2009, International Association of Computer Science and Information Technology-Spring Conference, IEEE, 2009, pp. 567- 570.
[33]
Boneau, C.A. The effects of violations of assumptions underlying the test. Psychol. Bull., 1960, 57(1), 49-64.
[34]
Desoize, B.; Madoulet, C. Particular aspects of platinum compounds used at present in cancer treatment. Crit. Rev. Oncol. Hematol., 2002, 42(3), 317-325.
[35]
Cepeda, V.; Fuertes, M.A.; Castilla, J.; Alonso, C.; Quevedo, C.; Pérez, J.M. Biochemical mechanisms of cisplatin cytotoxicity. Anticancer. Agents Med. Chem., 2007, 7(1), 3-18.
[36]
Yousefi, R.; Aghevlian, S.; Mokhtari, F.; Samouei, H.; Rashidi, M.; Nabavizadeh, S.M.; Tavaf, Z.; Pouryasin, Z.; Niazi, A.; Faghihi, R.; Papari, M.M. The anticancer activity and HSA binding properties of the structurally related platinum (II) complexes. Appl. Biochem. Biotechnol., 2012, 167(4), 861-872.
[37]
Searle, M.S.; Wakelin, L.P. Conformation and dynamics of the deoxyribose rings of a (nogalamycin)2-d (5′-GCATGC)2 complex studied in solution by 1H-n.m.r. spectroscopy. Biochem. J., 1990, 269(2), 341-346.
[38]
Zhang, Z-Z.; Cheng, H. Chemistry of 2-(diphenylphosphino) pyridine. Coord. Chem. Rev., 1996, 147, 1-39.
[39]
Gimeno, M.C.; Laguna, A. Chalcogenide centred gold complexes. Chem. Soc. Rev., 2008, 37(9), 1952-1966.
[40]
Jamali, S.; Mazloomi, Z.; Nabavizadeh, S.M.; Milić, D.; Kia, R.; Rashidi, M. Cyclometalated cluster complex with a butterfly-shaped Pt2Ag2 core. Inorg. Chem., 2010, 49(6), 2721-2726.
[41]
Calhorda, M.J.; Ceamanos, C.; Crespo, O.; Gimeno, M.C.; Laguna, A.; Larraz, C.; Vaz, P.D.; Villacampa, M.D. Heteropolynuclear gold complexes with metallophilic interactions: Modulation of the luminescent properties. Inorg. Chem., 2010, 49(18), 8255-8269.
[42]
Jamali, S.; Ghazfar, R.; Lalinde, E.; Jamshidi, Z.; Samouei, H.; Shahsavari, H.R.; Moreno, M.T.; Escudero-Adán, E.; Benet-Buchholz, J.; Milic, D. Cyclometalated heteronuclear Pt/Ag and Pt/Tl complexes: a structural and photophysical study. Dalton Trans., 2014, 43(3), 1105-1116.
[43]
Espinet, P.; Soulantica, K. Phosphine-pyridyl and related ligands in synthesis and catalysis. Coord. Chem. Rev., 1999, 193, 499-556.
[44]
Khin, C.; Hashmi, A.S.K.; Rominger, F. Gold (I) complexes of P, N ligands and their catalytic activity. Eur. J. Inorg. Chem., 2010, 2010(7), 1063-1069.
[45]
Zou, T.; Lum, C.T.; Lok, C-N.; Zhang, J-J.; Che, C-M. Chemical biology of anticancer gold(III) and gold(I) complexes. Chem. Soc. Rev., 2015, 44(24), 8786-8801.
[46]
Gutiérrez, A.; Cativiela, C.; Laguna, A.; Gimeno, M.C. Bioactive gold(i) complexes with 4-mercaptoproline derivatives. Dalton Trans., 2016, 45(34), 13483-13490.
[47]
Poliseno, L.; Mariani, L.; Collecchi, P.; Piras, A.; Zaccaro, L.; Rainaldi, G. Bcl2-negative MCF7 cells overexpress p53: Implications for the cell cycle and sensitivity to cytotoxic drugs. Cancer Chemother. Pharmacol., 2002, 50(2), 127-130.
[48]
Zamble, D.B.; Lippard, S.J. Cisplatin and DNA repair in cancer chemotherapy. Trends Biochem. Sci., 1995, 20(10), 435-439.
[49]
Enoiu, M.; Jiricny, J.; Schärer, O.D. Repair of cisplatin-induced DNA interstrand crosslinks by a replication-independent pathway involving transcription-coupled repair and translesion synthesis. Nucleic Acids Res., 2012, 40(18), 8953-8964.
[50]
Williams, G.T.; Smith, C.A. Molecular regulation of apoptosis: genetic controls on cell death. Cell, 1993, 74(5), 777-779.
[51]
Nagata, S. Apoptotic DNA fragmentation. Exp. Cell Res., 2000, 256(1), 12-18.
[52]
Enari, M.; Sakahira, H.; Yokoyama, H.; Okawa, K.; Iwamatsu, A.; Nagata, S. A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature, 1998, 391(6662), 43-50.
[53]
Zhang, G.; Gurtu, V.; Kain, S.R.; Yan, G. Early detection of apoptosis using a fluorescent conjugate of annexin V. Biotechniques, 1997, 23(3), 525-531.
[54]
Endresen, P.C.; Prytz, P.S.; Aarbakke, J. A new flow cytometric method for discrimination of apoptotic cells and detection of their cell cycle specificity through staining of F-actin and DNA. Cytometry, 1995, 20(2), 162-171.
[55]
Kishikawa, H.; Jiang, Y.P.; Goodisman, J.; Dabrowiak, J.C. Coupled kinetic analysis of cleavage of DNA by esperamicin and calicheamicin. J. Am. Chem. Soc., 1991, 113(14), 5434-5440.
[56]
Sirajuddin, M.; Ali, S.; Badshah, A. Drug-DNA interactions and their study by UV-Visible, fluorescence spectroscopies and cyclic voltametry. J. Photochem. Photobiol. B, 2013, 124, 1-19.
[57]
Takahara, P.M.; Rosenzweig, A.C.; Frederick, C.A.; Lippard, S.J. Crystal structure of double-stranded DNA containing the major adduct of the anticancer drug cisplatin. Nature, 1995, 377(6550), 649-652.
[58]
Fichtinger-Schepman, A.M.J.; van der Veer, J.L.; den Hartog, J.H.; Lohman, P.H.; Reedijk, J. Adducts of the antitumor drug cis-diamminedichloroplatinum(II) with DNA: Formation, identification, and quantitation. Biochemistry, 1985, 24(3), 707-713.
[59]
Zheng, L.; Baumann, U.; Reymond, J-L. An efficient one-step site-directed and site-saturation mutagenesis protocol. Nucleic Acids Res., 2004, 32(14), e115-e115.
[60]
Zhou, C-Y.; Zhao, J.; Wu, Y-B.; Yin, C-X.; Pin, Y. Synthesis, characterization and studies on DNA-binding of a new Cu(II) complex with N1,N8-bis(l-methyl-4-nitropyrrole-2-carbonyl) triethylenetetramine. J. Inorg. Biochem., 2007, 101(1), 10-18.
[61]
Zhang, L-W.; Wang, K.; Zhang, X-X. Study of the interactions between fluoroquinolones and human serum albumin by affinity capillary electrophoresis and fluorescence method. Anal. Chim. Acta, 2007, 603(1), 101-110.
[62]
Uma Maheswari, P.; Palaniandavar, M. DNA binding and cleavage properties of certain tetrammine ruthenium(II) complexes of modified 1,10-phenanthrolines--effect of hydrogen-bonding on DNA-binding affinity. J. Inorg. Biochem., 2004, 98(2), 219-230.
[63]
Roy, S.; Maheswari, P.U.; Lutz, M.; Spek, A.L.; den Dulk, H.; Barends, S.; van Wezel, G.P.; Hartl, F.; Reedijk, J. DNA cleavage and antitumour activity of platinum(II) and copper(II) compounds derived from 4-methyl-2-N-(2-pyridylmethyl)aminophenol: spectroscopic, electrochemical and biological investigation. Dalton Trans., 2009, 48, 10846-10860.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 19
ISSUE: 14
Year: 2019
Page: [1762 - 1774]
Pages: 13
DOI: 10.2174/1871520619666190702114211
Price: $58

Article Metrics

PDF: 16
HTML: 2
EPUB: 1
PRC: 1

Special-new-year-discount