Generic placeholder image

Current Medicinal Chemistry

Author(s): Si-Qi Zhang, Li-Hua Gao, Hua Zhao and Ke-Zhi Wang*

DOI: 10.2174/0929867326666181203143422

DownloadDownload PDF Flyer Cite As
Recent Progress in Polynuclear Ruthenium Complex-Based DNA Binders/Structural Probes and Anticancer Agents

Page: [3735 - 3752] Pages: 18

  • * (Excluding Mailing and Handling)

Abstract

Ruthenium complexes have stood out by several mononuclear complexes which have entered into clinical trials, such as imidazolium [trans-RuCl4(1H-imidazole)(DMSO-S)] (NAMI-A) and ([Ru(II)(4,4'-dimethyl-2,2'-bipyridine)2-(2(2'-,2'':5'',2'''-terthiophene)-imidazo[4,5-f] [1,10]phenanthroline)] 2+) (TLD-1433), opening a new avenue for developing promising ruthenium-based anticancer drugs alternative to Cisplatin. Polynuclear ruthenium complexes were reported to exhibit synergistic and/or complementary effects: the enhanced DNA structural recognition and DNA binding as well as in vitro anticancer activities. This review overviews some representative polynuclear ruthenium complexes acting as DNA structural probes, DNA binders and in vitro anticancer agents, which were developed during last decades. These complexes are reviewed according to two main categories of homo-polynuclear and hetero-polynuclear complexes, each of which is further clarified into the metal centers linked by rigid and flexible bridging ligands. The perspective, challenges and future efforts for investigations into these exciting complexes are pointed out or suggested.

Keywords: Ruthenium, DNA, DNA structural probe, cytotoxicity, binding mode, Cisplatin-based drugs, anticancer drugs.

[1]
Wong, E.; Giandomenico, C.M. Current status of platinum-based antitumor drugs. Chem. Rev., 1999, 99(9), 2451-2466.
[http://dx.doi.org/10.1021/cr980420v] [PMID: 11749486]
[2]
Pizarro, A.M.; Sadler, P.J. Unusual DNA binding modes for metal anticancer complexes. Biochimie, 2009, 91(10), 1198-1211.
[http://dx.doi.org/10.1016/j.biochi.2009.03.017] [PMID: 19344743]
[3]
Komeda, S.; Moulaei, T.; Woods, K.K.; Chikuma, M.; Farrell, N.P.; Williams, L.D. A third mode of DNA binding: Phosphate clamps by a polynuclear platinum complex. J. Am. Chem. Soc., 2006, 128(50), 16092-16103.
[http://dx.doi.org/10.1021/ja062851y] [PMID: 17165762]
[4]
Wheate, N.J.; Collins, J.G. Multinuclear platinum complexes as anticancer drugs. Coord. Chem. Rev., 2003, 241, 133-145.
[http://dx.doi.org/10.1016/S0010-8545(03)00050-X]
[5]
Benjamin, J.; Ang, D.L.; Wright, E.P.; Aldrich-Wright, J.R. Metal complex interactions with DNA. Dalton Trans., 2015, 44(8), 3505-3526.
[http://dx.doi.org/10.1039/C4DT02700K] [PMID: 25427534]
[6]
Li, X.; Gorle, A.K.; Sundaraneedi, Ma. Kinetically-inert polypyridylruthenium(II) complexes as therapeutic agents. Coord. Chem. Rev., 2017, 375, 134-147.
[http://dx.doi.org/10.1016/j.ccr.2017.11.011]
[7]
Zeng, L.; Gupta, P.; Chen, Y.; Wang, E.; Ji, L.; Chao, H.; Chen, Z.S. The development of anticancer ruthenium(ii) complexes: from single molecule compounds to nanomaterials. Chem. Soc. Rev., 2017, 46(19), 5771-5804.
[http://dx.doi.org/10.1039/C7CS00195A] [PMID: 28654103]
[8]
Schatzschneider, Photoactivated biological activity of transition‐metal complexes. Eur. J. Inorg. Chem., 2010, 10, 1451-1467.
[9]
Gill, M.R.; Thomas, J.A. Ruthenium(II) polypyridyl complexes and DNA--from structural probes to cellular imaging and therapeutics. Chem. Soc. Rev., 2012, 41(8), 3179-3192.
[http://dx.doi.org/10.1039/c2cs15299a] [PMID: 22314926]
[10]
Poynton, F.E.; Bright, S.A.; Blasco, S.; Williams, D.C.; Kelly, J.M.; Gunnlaugsson, T. The development of ruthenium(ii) polypyridyl complexes and conjugates for in vitro cellular and in vivo applications. Chem. Soc. Rev., 2017, 46(24), 7706-7756.
[http://dx.doi.org/10.1039/C7CS00680B] [PMID: 29177281]
[11]
Notaro, A.; Gasser, G. Monomeric and dimeric coordinatively saturated and substitutionally inert Ru(ii) polypyridyl complexes as anticancer drug candidates. Chem. Soc. Rev., 2017, 46(23), 7317-7337.
[http://dx.doi.org/10.1039/C7CS00356K] [PMID: 29027562]
[12]
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.
[http://dx.doi.org/10.2174/18715206113139990313] [PMID: 23869783]
[13]
Liu, P.; Jia, J.; Zhao, Y.; Wang, K.Z. Recent advances on dark and light-activated cytotoxity of imidazole-containing ruthenium complexes. Mini Rev. Med. Chem., 2016, 16(4), 272-289.
[http://dx.doi.org/10.2174/1389557516666151120120524] [PMID: 26586123]
[14]
Higgins, S.L.H.; White, T.A.; Winkel, B.S.; Brewer, K.J. Redox, spectroscopic, and photophysical properties of Ru-Pt mixed-metal complexes incorporating 4,7-diphenyl-1,10-phenanthroline as efficient DNA binding and photocleaving agents. Inorg. Chem., 2011, 50(2), 463-470.
[http://dx.doi.org/10.1021/ic100958r] [PMID: 21155537]
[15]
Rademaker-Lakhai, J.M.; van den Bongard, D.; Pluim, D.; Beijnen, J.H.; Schellens, J.H.M. A Phase I and pharmacological study with imidazolium-trans-DMSO-imidazole-tetrachlororuthenate, a novel ruthenium anticancer agent. Clin. Cancer Res., 2004, 10(11), 3717-3727.
[http://dx.doi.org/10.1158/1078-0432.CCR-03-0746] [PMID: 15173078]
[16]
Leijen, S.; Burgers, S.A.; Baas, P.; Pluim, D.; Tibben, M.; van Werkhoven, E.; Alessio, E.; Sava, G.; Beijnen, J.H.; Schellens, J.H. Phase I/II study with ruthenium compound NAMI-A and gemcitabine in patients with non-small cell lung cancer after first line therapy. Invest. New Drugs, 2015, 33(1), 201-214.
[http://dx.doi.org/10.1007/s10637-014-0179-1] [PMID: 25344453]
[17]
Hartinger, C.G.; Jakupec, M.A.; Zorbas-Seifried, S.; Groessl, M.; Egger, A.; Berger, W.; Zorbas, H.; Dyson, P.J.; Keppler, B.K. KP1019, a new redox-active anticancer agent--preclinical development and results of a clinical phase I study in tumor patients. Chem. Biodivers., 2008, 5(10), 2140-2155.
[http://dx.doi.org/10.1002/cbdv.200890195] [PMID: 18972504]
[18]
Trondl, R.; Heffeter, P.; Kowol, C.R.; Jakupec, M.; Berger, W.; Keppler, B.K. NKP-1339, the first ruthenium-based anticancer drug on the edge to clinical application. Chem. Sci. (Camb.), 2014, 5, 2925-2932.
[http://dx.doi.org/10.1039/C3SC53243G]
[19]
Intravesical photodynamic therapy (PDT) in BCG refractory high-risk non-muscle invasive bladder cancer. Available at: https://clinicaltrials.gov/ct2/show/study/NCT03053635 (Accessed date: June 18, 2018)
[20]
Xu, L.; Zhang, D.; Huang, J.; Deng, M.; Zhang, M.; Zhou, X. High fluorescence selectivity and visual detection of G-quadruplex structures by a novel dinuclear ruthenium complex. Chem. Commun. (Camb.), 2010, 46(5), 743-745.
[http://dx.doi.org/10.1039/B918045A] [PMID: 20087506]
[21]
Ju, C.C.; Zhang, A.G.; Yuan, C.L.; Zhao, X.L.; Wang, K.Z. The interesting DNA-binding properties of three novel dinuclear Ru(II) complexes with varied lengths of flexible bridges. J. Inorg. Biochem., 2011, 105(3), 435-443.
[http://dx.doi.org/10.1016/j.jinorgbio.2010.12.004] [PMID: 21421130]
[22]
Liu, P.; Liu, J.; Zhang, Y.Q.; Wu, B.Y.; Wang, K.Z. Synthesis, DNA binding and photocleavage, and cellular uptake of an alkyl chain-linked dinuclear ruthenium(II) complex. J. Photochem. Photobiol. B, 2015, 143, 89-99.
[http://dx.doi.org/10.1016/j.jphotobiol.2015.01.004] [PMID: 25618813]
[23]
Liu, P.; Wu, B.Y.; Liu, J.; Dai, Y.C.; Wang, Y.J.; Wang, K.Z. DNA binding and photocleavage properties, cellular uptake and localization, and in-vitro cytotoxicity of dinuclear ruthenium(II) complexes with varying lengths in bridging alkyl linkers. Inorg. Chem., 2016, 55(4), 1412-1422.
[http://dx.doi.org/10.1021/acs.inorgchem.5b01934] [PMID: 26811966]
[24]
Zhang, Y.; Lai, L.; Cai, P.; Cheng, G.Z.; Xu, X.M.; Liu, Y. Synthesis, characterization and anticancer activity of dinuclear ruthenium(II) complexes linked by an alkyl chain. New J. Chem., 2015, 39, 5805.
[http://dx.doi.org/10.1039/C5NJ00582E]
[25]
Singh, S.B.; Kumbhar, A.S.; Khan, A. Honeycomb-like ordered assembly of DNA induced by flexible binuclear ruthenium(II)-polypyridyl complexes. Chemistry, 2016, 22(44), 15760-15771.
[http://dx.doi.org/10.1002/chem.201602488] [PMID: 27618785]
[26]
Li, G.Y.; Guan, R.L.; Ji, L.N.; Chao, H. DNA condensation induced by metal complexes. Coord. Chem. Rev., 2014, 281, 100-113.
[http://dx.doi.org/10.1016/j.ccr.2014.09.005]
[27]
Li, X.; Heimann, K.; Li, F.; Warner, J.M.; Richard Keene, F.; Grant Collins, J. Dinuclear ruthenium(ii) complexes containing one inert metal centre and one coordinatively-labile metal centre: syntheses and biological activities. Dalton Trans., 2016, 45(9), 4017-4029.
[http://dx.doi.org/10.1039/C5DT04885K] [PMID: 26841356]
[28]
Saeed, H.K.; Saeed, I.Q.; Buurma, N.J.; Thomas, J.A. The structure of linkers affects the DNA binding properties of tethered dinuclear ruthenium(II) metallo-intercalators. Chemistry, 2017, 23(23), 5467-5477.
[http://dx.doi.org/10.1002/chem.201605750] [PMID: 28072487]
[29]
Wang, H.Y.; Qian, Y.; Wang, F.X.; Habtemariam, A.; Mao, Z.W.; Sadler, P.J.; Liu, H.K. Ruthenium(II)-arene metallacycles: crystal structures, interaction with DNA, and cytotoxicity. Eur. J. Inorg. Chem., 2017, 1792-1799.
[http://dx.doi.org/10.1002/ejic.201601226]
[30]
Gonzalez, V.; Wilson, T.; Kurihara, I.; Imai, A.; Thomas, J.A.; Otsuki, J. A dinuclear ruthenium(II) complex that functions as a label-free colorimetric sensor for DNA. Chem. Commun. (Camb.), 2008, (16), 1868-1870.
[http://dx.doi.org/10.1039/b802073f] [PMID: 18401501]
[31]
Andersson, J.; Lincoln, P. Stereoselectivity for DNA threading intercalation of short binuclear ruthenium complexes. J. Phys. Chem. B, 2011, 115(49), 14768-14775.
[http://dx.doi.org/10.1021/jp2062767] [PMID: 22010604]
[32]
Almaqwashi, A.A.; Paramanathan, T.; Lincoln, P.; Rouzina, I.; Westerlund, F.; Williams, M.C. Strong DNA deformation required for extremely slow DNA threading intercalation by a binuclear ruthenium complex. Nucleic Acids Res., 2014, 42(18), 11634-11641.
[http://dx.doi.org/10.1093/nar/gku859] [PMID: 25245944]
[33]
Swavey, S.; DeBeer, M.; Li, K. Photoinduced interactions of supramolecular ruthenium(II) complexes with plasmid DNA: synthesis and spectroscopic, electrochemical, and DNA photocleavage studies. Inorg. Chem., 2015, 54(7), 3139-3147.
[http://dx.doi.org/10.1021/ic502340p] [PMID: 25798576]
[34]
Zhao, X.L.; Li, Z.S.; Zheng, Z.B.; Zhang, A.G.; Wang, K.Z. pH luminescence switch, DNA binding and photocleavage, and cytotoxicity of a dinuclear ruthenium complex. Dalton Trans., 2013, 42(16), 5764-5777.
[http://dx.doi.org/10.1039/c3dt33116d] [PMID: 23450276]
[35]
Li, Z.S.; Yang, H.X.; Zhang, A.G.; Luo, H.; Wang, K.Z. pH effects on optical and DNA binding properties of a thiophene-containing ruthenium(II) complex. Inorg. Chim. Acta, 2011, 370(1), 132.
[http://dx.doi.org/10.1016/j.ica.2011.01.039]
[36]
Meng, T.T.; Wang, H.; Zheng, Z.B.; Wang, K.Z. pH switchable “Off-On-Off” near-infrared luminescence based on a dinuclear Ru(II) complex. Inorg. Chem., 2017, 56(9), 4775-4779.
[http://dx.doi.org/10.1021/acs.inorgchem.7b00223] [PMID: 28387505]
[37]
Mardanya, S.; Karmakar, S.; Mondal, D.; Baitalik, S. Homo- and heterobimetallic ruthenium(II) and osmium(II) complexes based on a pyrene-biimidazolate spacer as efficient DNA-binding probes in the near-infrared domain. Inorg. Chem., 2016, 55(7), 3475-3489.
[http://dx.doi.org/10.1021/acs.inorgchem.5b02912] [PMID: 27011117]
[38]
Holder, A.A.; Taylor, P.; Magnusen, A.R.; Moffett, E.T.; Meyer, K.; Hong, Y.; Ramsdale, S.E.; Gordon, M.; Stubbs, J.; Seymour, L.A.; Acharya, D.; Weber, R.T.; Smith, P.F.; Dismukes, G.C.; Ji, P.; Menocal, L.; Bai, F.; Williams, J.L.; Cropek, D.M.; Jarrett, W.L. Preliminary anti-cancer photodynamic therapeutic in vitro studies with mixed-metal binuclear ruthenium(II)-vanadium(IV) complexes. Dalton Trans., 2013, 42(33), 11881-11899.
[http://dx.doi.org/10.1039/c3dt50547b] [PMID: 23783642]
[39]
Braga, S.S.; Silva, A.M.S. A new age for iron: antitumoral ferrocenes. Organometallics, 2013, 32, 5626-5639.
[http://dx.doi.org/10.1021/om400446y]
[40]
Anderson, C.M.; Jain, S.S.; Silber, L.; Chen, K.; Guha, S.; Zhang, W.; McLaughlin, E.C.; Hu, Y.; Tanski, J.M. Synthesis and characterization of water-soluble, heteronuclear ruthenium(III)/ferrocene complexes and their interactions with biomolecules. J. Inorg. Biochem., 2015, 145, 41-50.
[http://dx.doi.org/10.1016/j.jinorgbio.2014.12.017] [PMID: 25621836]
[41]
Sun, S.; Wang, J.; Mu, D.; Wang, J.; Bao, Y.; Qiao, B.; Peng, X. A heterodinuclear metal complex for direct imaging of rRNA in living cells. Chem. Commun. (Camb.), 2014, 50(65), 9149-9152.
[http://dx.doi.org/10.1039/C4CC04501G] [PMID: 24989073]
[42]
Massai, L.; Fernández-Gallardo, J.; Guerri, A.; Arcangeli, A.; Pillozzi, S.; Contel, M.; Messori, L. Design, synthesis and characterisation of new chimeric ruthenium(II)-gold(I) complexes as improved cytotoxic agents. Dalton Trans., 2015, 44(24), 11067-11076.
[http://dx.doi.org/10.1039/C5DT01614B] [PMID: 25996553]
[43]
Takarada, J.E.; Guedes, A.P.M.; Correa, R.S.; Silveira-Lacerda, E.P.; Castelli, S.; Iacovelli, F.; Deflon, V.M.; Batista, A.A.; Desideri, A. Ru/Fe bimetallic complexes: Synthesis, characterization, cytotoxicity and study of their interactions with DNA/HSA and human topoisomerase IB. Arch. Biochem. Biophys., 2017, 636, 28-41.
[http://dx.doi.org/10.1016/j.abb.2017.10.015] [PMID: 29107586]
[44]
Liang, X.; Zou, X.; Tan, L.; Zhu, W. Study on nucleic acid (CT-DNA and yeast tRNA) binding behaviors and cytotoxic properties of a heterodinuclear Ru(II)-Co(III) polypyridyl complex. J. Inorg. Biochem., 2010, 104(12), 1259-1266.
[http://dx.doi.org/10.1016/j.jinorgbio.2010.08.006] [PMID: 20837360]
[45]
Higgins, S.L.H.; Brewer, K.J. Designing red-light-activated multifunctional agents for the photodynamic therapy. Angew. Chem. Int. Ed. Engl., 2012, 51(46), 11420-11422.
[http://dx.doi.org/10.1002/anie.201204933] [PMID: 23055391]
[46]
Higgins, S.L.H.; Tucker, A.J.; Winkel, B.S.J.; Brewer, K.J. Metal to ligand charge transfer induced DNA photobinding in a Ru(II)-Pt(II) supramolecule using red light in the therapeutic window: a new mechanism for DNA modification. Chem. Commun., 2012, 48, 67-69.
[http://dx.doi.org/10.1039/C1CC15780A] [PMID: 22075568]
[47]
Zhu, J.; Rodríguez-Corrales, J.A.; Prussin, R.; Zhao, Z.; Dominijanni, A.; Hopkins, S.L.; Winkel, B.S.J.; Robertson, J.L.; Brewer, K.J. Exploring the activity of a polyazine bridged Ru(ii)-Pt(ii) supramolecule in F98 rat malignant glioma cells. Chem. Commun. (Camb.), 2016, 53(1), 145-148.
[http://dx.doi.org/10.1039/C6CC07978D] [PMID: 27901157]
[48]
Wang, J.; Zigler, D.F.; Hurst, N.; Othee, H.; Winkel, B.S.J.; Brewer, K.J. A new, bioactive structural motif: Visible light induced DNA photobinding and oxygen independent photocleavage by RuII, RhIII bimetallics. J. Inorg. Biochem., 2012, 116, 135-139.
[http://dx.doi.org/10.1016/j.jinorgbio.2012.06.015] [PMID: 23018276]
[49]
Anderson, C.M.; Taylor, I.R.; Tibbetts, M.F.; Philpott, J.; Hu, Y.; Tanski, J.M. Hetero-multinuclear ruthenium(III)/platinum(II) complexes that potentially exhibit both antimetastatic and antineoplastic properties. Inorg. Chem., 2012, 51(23), 12917-12924.
[http://dx.doi.org/10.1021/ic301981s] [PMID: 23150984]
[50]
Jain, S.S.; Anderson, C.M.; DiRienzo, F.; Taylor, I.R.; Jain, K.; Guha, S.; Hoque, N. RNA binding and inhibition of primer extension by a Ru(III)/Pt(II) metal complex. Chem. Commun. (Camb.), 2013, 49(44), 5031-5033.
[http://dx.doi.org/10.1039/c3cc40699g] [PMID: 23615723]
[51]
Wragg, A.; Gill, M.R.; Turton, D.; Adams, H.; Roseveare, T.M.; Smythe, C.; Su, X.; Thomas, J.A. Tuning the cellular uptake properties of luminescent heterobimetallic iridium(III)-ruthenium(II) DNA imaging probes. Chemistry, 2014, 20(43), 14004-14011.
[http://dx.doi.org/10.1002/chem.201403693] [PMID: 25208528]
[52]
Ramu, V.; Gill, M.R.; Jarman, P.J.; Turton, D.; Thomas, J.A.; Das, A.; Smythe, C. A cytostatic ruthenium(II)-platinum(II) bis(terpyridyl) anticancer complex that blocks entry into S phase by up-regulating p27KIP1. Chemistry, 2015, 21(25), 9185-9197.
[http://dx.doi.org/10.1002/chem.201500561] [PMID: 25950156]
[53]
Mardanya, S.; Mondal, D.; Baitalik, S. Bimetallic Ru(ii) and Os(ii) complexes based on a pyrene-bisimidazole spacer: synthesis, photophysics, electrochemistry and multisignalling DNA binding studies in the near infrared region. Dalton Trans., 2017, 46(48), 17010-17024.
[http://dx.doi.org/10.1039/C7DT03355A] [PMID: 29184930]
[54]
Jain, A.; Wyland, K.R.; Davis, D.H. Redox, spectroscopic, photo-induced ligand exchange, and DNA interaction studies of a new Ru(II)Pt(II) bimetallic complex. J. Coord. Chem., 2018, 71, 231-242.
[http://dx.doi.org/10.1080/00958972.2017.1420788]
[55]
Zheng, Z.B.; Wu, Y.Q.; Wang, K.Z.; Li, F. pH luminescence switching, dihydrogen phosphate sensing, and cellular uptake of a heterobimetallic ruthenium(II)-rhenium(I) complex. Dalton Trans., 2014, 43(8), 3273-3284.
[http://dx.doi.org/10.1039/C3DT52568F] [PMID: 24356444]
[56]
Zeglis, B.M.; Pierre, V.C.; Barton, J.K. Metallo-intercalators and metallo-insertors. Chem. Commun. (Camb.), 2007, (44), 4565-4579.
[http://dx.doi.org/10.1039/b710949k] [PMID: 17989802]