Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry


ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

Half-Lantern Cyclometalated Platinum(II) Complexes as Anticancer Agents: Molecular Docking, Apoptosis, Cell Cycle Analysis, and Cytotoxic Activity Evaluations

Author(s): Fatemeh Hajipour, Masoud Mahdavinia and Masood Fereidoonnezhad*

Volume 22, Issue 6, 2022

Published on: 13 July, 2021

Page: [1149 - 1158] Pages: 10

DOI: 10.2174/1871520621666210713112105

Price: $65


Background and Objective: In the design of modern metal-based anticancer drugs, platinum-based complexes have gained growing interest. In this study, the anticancer activity of half-lantern cyclometalated Pt(II)‒Pt(II) complexes was evaluated using MTT, apoptosis, cell cycle analysis, and DNA binding studies.

Materials and Methods: The cytotoxicity of Pt(II)‒Pt(II) complexes were evaluated against different cancer cell lines, such as human lung (A549), breast (MCF-7, and MDA-MB-231), ovarian (SKOV-3), and colon (HT-29) as well as normal breast (MCF-10A), and human lung fibroblast (MRC-5) cells using MTT assay. BioLegend's PE Annexin, V Apoptosis Detection Kit with 7AAD, was applied to assess the apoptotic effects of 1A and 1B compound against MCF-7 and A549 cell lines. Cell cycle analysis was determined using the flow cytometry method. The interaction of compounds with four different DNA structures with PDB codes (1BNA, 1LU5, 3CO3, and 198D) has been investigated by molecular docking. To achieve binding to DNA experimentally, the electrophoresis mobility shift assay and comet assay were applied.

Results: In the evaluation of cytotoxic effects, 1A showed the highest cytotoxicity among the studied compounds, and it showed higher potency with more selectivity against normal cell lines than cisplatin. This compound had IC50 of 7.24, 2.21, 1.18, 2.71, 10.65, 18.32, and 49.21 μM against A549, SKOV3, HT29, MCF-7, MDA-MB-231, MRC-5, and MCF-10A, respectively, whereas cisplatin had IC50 of 9.75, 19.02, 107.23, 15.20, 18.09, 14.36, and 24.21 μm, respectively, on the same cell lines. In order to check the DNA binding activity of 1A, and 1B, electrophoretic mobility was also conducted, which indicated that the binding of these compounds led to a slight change in electrophoretic mobility to DNA. The migration of chromosomal DNA from the nucleus in the form of a tail or comet was executed in the comet assay of 1A on MCF-7. Examination of apoptosis of 1A and 1B on the MCF-7 cancer cell line showed that it could increase induction of apoptosis in this cancerous cell in a concentration-dependent manner. Investigating the effect of 1A using cell cycle analysis on MCF-7 cancer cell line showed that this complex affects stage G1 and S of the cell cycle.

Conclusion: 1A has the potential to play a significant role in future biopharmaceutical studies.

Keywords: Half-lantern cyclometalated Pt(II)‒Pt(II) complexes, molecular docking, apoptosis, cytotoxic activity, cell cycle analysis, MTT.

Graphical Abstract
Marques, M. Platinum and palladium polyamine complexes as anticancer agents: The structural factor. ISRN Spectroscopy 2013, 2013
Kostova, I. Platinum complexes as anticancer agents. Recent Patents Anticancer Drug Discov., 2006, 1(1), 1-22.
[] [PMID: 18221023]
Baruah, H.; Barry, C.G.; Bierbach, U. Platinum-intercalator conjugates: From DNA-targeted cisplatin derivatives to adenine binding complexes as potential modulators of gene regulation. Curr. Top. Med. Chem., 2004, 4(15), 1537-1549.
[] [PMID: 15579095]
Fong, C.W. Platinum anti-cancer drugs: Free radical mechanism of Pt-DNA adduct formation and anti-neoplastic effect. Free Radic. Biol. Med., 2016, 95, 216-229.
[] [PMID: 27012421]
Hartmann, J.T.; Lipp, H.P. Toxicity of platinum compounds. Expert Opin. Pharmacother., 2003, 4(6), 889-901.
[] [PMID: 12783586]
Kulkarni, B.; Gondaliya, P.; Kirave, P.; Rawal, R.; Jain, A.; Garg, R.; Kalia, K. Exosome-mediated delivery of miR-30a sensitize cisplatin-resistant variant of oral squamous carcinoma cells via modulating Beclin1 and Bcl2. Oncotarget, 2020, 11(20), 1832-1845.
[] [PMID: 32499869]
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.
[] [PMID: 26865551]
Wang, D.; Lippard, S.J. Cellular processing of platinum anticancer drugs. Nat. Rev. Drug Discov., 2005, 4(4), 307-320.
[] [PMID: 15789122]
Oun, R.; Moussa, Y.E.; Wheate, N.J. The side effects of platinum-based chemotherapy drugs: A review for chemists. Dalton Trans., 2018, 47(19), 6645-6653.
[] [PMID: 29632935]
Jansen, B.A.J.; van der Zwan, J.; den Dulk, H.; Brouwer, J.; Reedijk, J. Dinuclear alkyldiamine platinum antitumor compounds: A structure-activity relationship study. J. Med. Chem., 2001, 44(2), 245-249.
[] [PMID: 11170634]
Romero-Canelón, I.; Sadler, P.J. Next-generation metal anticancer complexes: Multitargeting via redox modulation. Inorg. Chem., 2013, 52(21), 12276-12291.
[] [PMID: 23879584]
Kato, M. Luminescent platinum complexes having sensing functionalities. Bull. Chem. Soc. Jpn., 2007, 80(2), 287-294.
Kato, M.; Omura, A.; Toshikawa, A.; Kishi, S.; Sugimoto, Y. Vapor-induced luminescence switching in crystals of the syn isomer of a dinuclear (bipyridine)platinum(II) complex bridged with pyridine-2-thiolate ions. Angew. Chem. Int. Ed. Engl., 2002, 41(17), 3183-3185.
[<3183:AIDANIE3183>3.0.CO;2-A] [PMID: 12207383]
Yoshida, M.; Kato, M. Regulation of metal–metal interactions and chromic phenomena of multi-decker platinum complexes having π-systems. Coord. Chem. Rev., 2018, 355, 101-115.
Shahsavari, H.R. Babadi, Aghakhanpour R.; Biglari, A.; Niazi, M.; Mastrorilli, P.; Todisco, S.; Gallo, V.; Lalinde, E.; Moreno, M.T.; Giménez, N.; Halvagar, M.R. C(sp2)–c(sp2) reductive elimination from a diarylplatinum(ii) complex induced by a s–s bond oxidative addition at room temperature. Organometallics, 2020, 39(3), 417-424.
Sakamaki, Y.; Ahmadi Mirsadeghi, H.; Fereidoonnezhad, M.; Mirzaei, F.; Moghimi Dehkordi, Z.; Chamyani, S.; Alshami, M.; Abedanzadeh, S.; Shahsavari, H.R.; Beyzavi, M.H. trans-platinum(ii) thionate complexes: Synthesis, structural characterization, and in vitro biological assessment as potent anticancer agents. ChemPlusChem, 2019, 84(10), 1525-1535.
[] [PMID: 31943935]
Fereidoonnezhad, M.; Mirsadeghi, H.A.; Abedanzadeh, S.; Yazdani, A.; Alamdarlou, A.; Babaghasabha, M.; Almansaf, Z.; Faghih, Z.; McConnell, Z.; Shahsavari, H.R.; Beyzavi, M.H. Synthesis and biological evaluation of thiolate gold(I) complexes as thioredoxin reductase (TrxR) and glutathione reductase (GR) inhibitors. New J. Chem., 2019, 43(33), 13173-13182.
Fereidoonnezhad, M.; Shahsavari, H.R.; Lotfi, E.; Babaghasabha, M.; Fakhri, M.; Faghih, Z.; Faghih, Z.; Beyzavi, M.H. (Benzyl isocyanide)gold(I) pyrimidine-2-thiolate complex: Synthesis and biological activity. Appl. Organomet. Chem., 2018, 32(3), e4200.
Fereidoonnezhad, M.; Ramezani, Z.; Nikravesh, M.; Zangeneh, J.; Haghighi, M.G.; Faghih, Z.; Notash, B.; Shahsavari, H.R. Cycloplatinated(II) complexes bearing an O,S-heterocyclic ligand: Search for anticancer drugs. New J. Chem., 2018, 42(9), 7177-7187.
Jamshidi, M.; Babaghasabha, M.; Shahsavari, H.R.; Nabavizadeh, S.M. The influence of thiolate ligands on the luminescence properties of cycloplatinated(ii) complexes. Dalton Trans., 2017, 46(45), 15919-15927.
[] [PMID: 29119183]
Sicilia, V.; Borja, P.; Baya, M.; Casas, J.M. Selective turn-off phosphorescent and colorimetric detection of mercury(II) in water by half-lantern platinum(II) complexes. Dalton Trans., 2015, 44(15), 6936-6943.
[] [PMID: 25781389]
Sicilia, V.; Forniés, J.; Casas, J.M.; Martín, A.; López, J.A.; Larraz, C.; Borja, P.; Ovejero, C.; Tordera, D.; Bolink, H. Highly luminescent half-lantern cyclometalated platinum(II) complex: Synthesis, structure, luminescence studies, and reactivity. Inorg. Chem., 2012, 51(6), 3427-3435.
[] [PMID: 22360773]
Sicilia, V.; Borja, P.; Casas, J.M.; Fuertes, S.; Martín, A. Selective synthesis of new half-lantern benzoquinolate platinum complexes. DFT and photophysical studies on the platinum(II,II) derivative. J. Organomet. Chem., 2013, 731, 10-17.
Alexander, C.; Prajith, N.U.; Priyanka, P.V.; Nithyakumar, A.; Arockia Samy, N. 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.
[] [PMID: 30945024]
Konovalov, B.; Živković, M.D.; Milovanović, J.Z.; Djordjević, D.B.; Arsenijević, A.N.; Vasić, I.R.; Janjić, G.V.; Franich, A.; Manojlović, D.; Skrivanj, S.; Milovanović, M.Z.; Djuran, M.I.; Rajković, S. Synthesis, cytotoxic activity and DNA interaction studies of new dinuclear platinum(ii) complexes with an aromatic 1,5-naphthyridine bridging ligand: DNA binding mode of polynuclear platinum(ii) complexes in relation to the complex structure. Dalton Trans., 2018, 47(42), 15091-15102.
[] [PMID: 30303498]
Wu, X.; Chen, D.G.; Liu, D.; Liu, S.H.; Shen, S.W.; Wu, C.I.; Xie, G.; Zhou, J.; Huang, Z.X.; Huang, C.Y.; Su, S.J.; Zhu, W.; Chou, P.T. Highly emissive dinuclear platinum (III) complexes. J. Am. Chem. Soc., 2020, 142(16), 7469-7479.
[] [PMID: 32223139]
Lo, W.K.; Huff, G.S.; Preston, D.; McMorran, D.A.; Giles, G.I.; Gordon, K.C.; Crowley, J.D. A dinuclear platinum(ii) n4py complex: An unexpected coordination mode for n4py. Inorg. Chem., 2015, 54(14), 6671-6673.
[] [PMID: 26126121]
Vaquero, M.; Busto, N.; Fernández-Pampín, N.; Espino, G.; García, B. Appended aromatic moieties determine the cytotoxicity of neutral cyclometalated platinum(ii) complexes derived from 2-(2-pyridyl)benzimidazole. Inorg. Chem., 2020, 59(7), 4961-4971.
[] [PMID: 32182052]
Neshat, A.; Shahsavari, H.R.; Mastrorilli, P.; Todisco, S.; Haghighi, M.G.; Notash, B. A borane platinum complex undergoing reversible hydride migration in solution. Inorg. Chem., 2018, 57(3), 1398-1407.
[] [PMID: 29336561]
Niazi, M.; Shahsavari, H.R.; Golbon Haghighi, M.; Halvagar, M.R.; Hatami, S.; Notash, B. Reactivity of a half-lantern Pt2(II,II) complex with triphenylphosphine: Selectivity in a protonation reaction. RSC. Adv., 2016, 6(80), 76463-76472.
Niazi, M.; Shahsavari, H.R.; Golbon Haghighi, M.; Halvagar, M.R.; Hatami, S.; Notash, B. Carbon–sulfur bond reductive coupling from a platinum(II) thiolate complex. RSC. Adv., 2016, 6(97), 95073-95084.
Shahsavari, H.R.; Lalinde, E.; Moreno, M.T.; Niazi, M.; Kazemi, S.H.; Abedanzadeh, S.; Barazandeh, M.; Halvagar, M.R. Half-lantern cyclometalated Pt(II) and Pt(III) complexes with bridging heterocyclic thiolate ligands: Synthesis, structural characterization, and electrochemical and photophysical properties. New J. Chem., 2019, 43(20), 7716-7724.
Aoki, R.; Kobayashi, A.; Chang, H-C.; Kato, M. Structures and luminescence properties of cyclometalated dinuclear platinum(ii) complexes bridged by pyridinethiolate ions. Bull. Chem. Soc. Jpn., 2011, 84(2), 218-225.
Koshiyama, T.; Omura, A.; Kato, M. Redox-controlled luminescence of a cyclometalated dinuclear platinum complex bridged with pyridine-2-thiolate ions. Chem. Lett., 2004, 33(10), 1386-1387.
Zembruski, N.C.; Stache, V.; Haefeli, W.E.; Weiss, J. 7-Aminoactinomycin D for apoptosis staining in flow cytometry. Anal. Biochem., 2012, 429(1), 79-81.
[] [PMID: 22796502]
Li, C.J. Flow cytometry analysis of cell cycle and specific cell synchronization with butyrate. Methods Mol. Biol., 2017, 1524, 149-159.
[] [PMID: 27815901]
Imai, R.; Komeda, S.; Shimura, M.; Tamura, S.; Matsuyama, S.; Nishimura, K.; Rogge, R.; Matsunaga, A.; Hiratani, I.; Takata, H.; Uemura, M.; Iida, Y.; Yoshikawa, Y.; Hansen, J.C.; Yamauchi, K.; Kanemaki, M.T.; Maeshima, K. Chromatin folding and DNA replication inhibition mediated by a highly antitumor-active tetrazolato-bridged dinuclear platinum(II) complex. Sci. Rep., 2016, 6, 24712.
[] [PMID: 27094881]
Dasari, S.; Tchounwou, P.B. Cisplatin in cancer therapy: Molecular mechanisms of action. Eur. J. Pharmacol., 2014, 740, 364-378.
[] [PMID: 25058905]
Fereidoonnezhad, M.; Shahsavari, H.R.; Abedanzadeh, S.; Nezafati, A.; Khazali, A.; Mastrorilli, P.; Babaghasabha, M.; Webb, J.; Faghih, Z.; Faghih, Z.; Bahemmat, S. Synthesis, structural characterization, biological evaluation and molecular docking studies of new platinum(II) complexes containing isocyanides. New J. Chem., 2018, 42(11), 8681-8692.
Fereidoonnezhad, M.; Shahsavari, H.R.; Abedanzadeh, S.; Behchenari, B.; Hossein-Abadi, M.; Faghih, Z.; Beyzavi, M.H. Cycloplatinated(II) complexes bearing 1,1′-bis (diphenylphosphino) ferrocene ligand: Biological evaluation and molecular docking studies. New J. Chem., 2018, 42(4), 2385-2392.

Rights & Permissions Print Export Cite as
© 2023 Bentham Science Publishers | Privacy Policy