Abstract
Three ruthenium(II) phosphine/diimine/picolinate complexes were selected aimed at investigating anticancer activity against several cancer cell lines and the capacity of inhibiting the supercoiled DNA relaxation mediated by human topoisomerase IB (Top 1). The structure–lipophilicity relationship in membrane permeability using the Caco-2 cells have also been evaluated in this study. SCAR 5 was found to present 45 times more cytotoxicity against breast cancer cell when compared to cisplatin. SCAR 4 and 5 were both found to be capable of inhibiting the supercoiled DNA relaxation mediated by Top 1. Interaction studies showed that SCAR 4 and 5 can bind to DNA through electrostatic interactions while SCAR 6 is able to bind covalently to DNA. The complexes SCAR were found to interact differently with bovine serum albumin (BSA) suggesting hydrophobic interactions with albumin. The permeability of all complexes was seen to be dependent on their lipophilicity. SCAR 4 and 5 exhibited high membrane permeability (P app > 10 × 10−6 cm·s−1) in the presence of BSA. The complexes may pass through Caco-2 monolayer via passive diffusion mechanism and our results suggest that lipophilicity and interaction with BSA may influence the complexes permeation. In conclusion, we demonstrated that complexes have powerful pharmacological activity, with different results for each complex depending on the combination of their ligands.
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References
Allardyce CS, Dyson PJ (2001) Ruthenium in medicine: current clinical uses and future prospects. Platin Met Rev 45:62–69
Allardyce CS, Dyson PJ (2016) Metal-based drugs that break the rules. Dalton Trans 45:3201–3209. doi:10.1039/C5DT03919C
Anbu S, Ravishankaran R, Karande AA, Kandaswamy M (2012) DNA targeting polyaza macrobicyclic dizinc(II) complexes promoting high in vitro caspase dependent anti-proliferative activity against human carcinoma cancer cells. Dalton Trans 41:12970. doi:10.1039/c2dt31094e
Artursson P, Karlsson J (1991) Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells. Biochem Biophys Res Commun 175:880–885. doi:10.1016/0006-291X(91)91647-U
Artursson P, Palm K, Luthmanb K (2001) Caco-2 monolayers in experimental and theoretical drug transport predictions of drug transport. Adv Drug Deliv Rev 46:27–43
Baka E, Comer JEA, Takács-Novák K (2008) Study of equilibrium solubility measurement by saturation shake-flask method using hydrochlorothiazide as model compound. J Pharm Biomed Anal 46:335–341. doi:10.1016/j.jpba.2007.10.030
Barros FWA, Bezerra DP, Ferreira PMP et al (2013) Inhibition of DNA topoisomerase I activity and induction of apoptosis by thiazacridine derivatives. Toxicol Appl Pharmacol 268:37–46. doi:10.1016/j.taap.2013.01.010
Barton JK, Olmon ED, Sontz PA (2011) Metal complexes for DNA-mediated charge transport. Coord Chem Rev 255:619–634
Camargo MS, da Silva MM, Correa RS et al (2016) Inhibition of human DNA topoisomerase IB by nonmutagenic ruthenium(II)-based compounds with antitumoral activity. Metallomics 8:179–192. doi:10.1039/c5mt00227c
Carter MT, Rodriguez M, Bard AJ (1989) Voltammetric studies of the interaction of metal chelates with DNA. 2. Tris-chelated complexes of cobalt(III) and iron(II) with 1,10-phenanthroline and 2,2-bipyridine. J Am Chem Soc 111:8901–8911. doi:10.1021/ja00206a020
Chang M, Li X, Sun Y et al (2013) A potential mechanism of a cationic cyclopeptide for enhancing insulin delivery across Caco-2 cell monolayers. Biol Pharm Bull 36:1602–1607. doi:10.1248/bpb.b13-00487
Chillemi G, Fiorani P, Castelli S et al (2005) Effect on DNA relaxation of the single Thr718Ala mutation in human topoisomerase I: a functional and molecular dynamics study. Nucleic Acids Res 33:3339–3350. doi:10.1093/nar/gki642
Cohen G, Eisenberg H (1969) Viscosity and sedimentation study of sonicated DNA-proflavine complexes. Biopolymers 8:45–55. doi:10.1002/bip.1969.360080105
Colina-Vegas L, Villarreal W, Navarro M et al (2015) Cytotoxicity of Ru(II) piano-stool complexes with chloroquine and chelating ligands against breast and lung tumor cells: interactions with DNA and BSA. J Inorg Biochem 153:150–161. doi:10.1016/j.jinorgbio.2015.07.016
Corrêa RS, da Silva MM, Graminha AE et al (2016) Ruthenium(II) complexes of 1,3-thiazolidine-2-thione: cytotoxicity against tumor cells and anti-Trypanosoma cruzi activity enhanced upon combination with benznidazole. J Inorg Biochem 156:153–163. doi:10.1016/j.jinorgbio.2015.12.024
Da Silva LL, Donnici CL, Lopes JCD et al (2012) Investigação eletroquímica e calorimétrica da interação de novos agentes antitumorais biscatiônicos com DNA. Quim Nova 35:1318–1324
De Grandis RA, Resende FA, Da Silva MM et al (2016) In vitro evaluation of cyto-genotoxic potential of ruthenium(II) SCAR complexes: a promising class of antituberculosis agents. Mutat Res Genet Toxicol Environ Mutagen 798–799:11–18. doi:10.1016/j.mrgentox.2016.01.007
Doak BC, Over B, Giordanetto F, Kihlberg J (2014) Oral druggable space beyond the rule of 5: insights from drugs and clinical candidates. Chem Biol 21:1115–1142. doi:10.1016/j.chembiol.2014.08.013
Elsadek B, Kratz F (2012) Impact of albumin on drug delivery—new applications on the horizon. J Control Release 157:4–28. doi:10.1016/j.jconrel.2011.09.069
Fossati L, Dechaume R, Hardillier E et al (2008) Use of simulated intestinal fluid for Caco-2 permeability assay of lipophilic drugs. Int J Pharm 360:148–155. doi:10.1016/j.ijpharm.2008.04.034
Gonçalves JE, Ballerini Fernandes M, Chiann C et al (2012) Effect of pH, mucin and bovine serum on rifampicin permeability through Caco-2 cells. Biopharm Drug Dispos 33:316–323
Gou Y, Zhang Y, Qi J et al (2015) Enhancing the copper(II) complexes cytotoxicity to cancer cells through bound to human serum albumin. J Inorg Biochem 144:47–55. doi:10.1016/j.jinorgbio.2014.12.012
Gratton E, Silva N, Mei G et al (1992) Fluorescence lifetime distribution of folded and unfolded proteins. Int J Quantum Chem 42:1479–1489. doi:10.1002/qua.560420522
Grès M, Julian J, Bourriè M et al (1998) Correlation between oral drug absorption in humans, and apparent drug permeability in TC-7 cells, a human epithelial intestinal cell line: comparison with the parental Caco-2 cell line. Pharm Res 15:726–733
He X, Jin L, Tan L (2014) DNA-binding, topoisomerases I and II inhibition and in vitro cytotoxicity of ruthenium(II) polypyridyl complexes: [Ru(dppz)2L](2+) (L = dppz-11-CO2Me and dppz). Spectrochim Acta A 135C:101–109. doi:10.1016/j.saa.2014.06.147
Hernández R, Méndez J, Lamboy J et al (2010) Titanium(IV) complexes: cytotoxicity and cellular uptake of titanium(IV) complexes on caco-2 cell line. Toxicol In Vitro 24:178–183. doi:10.1016/j.tiv.2009.09.010
Hong G, Kreuzer KN (2000) An antitumor drug-induced topoisomerase cleavage complex blocks a bacteriophage T4 replication fork in vivo. Mol Cell Biol 20:594–603. doi:10.1128/MCB.20.2.594-603.2000.Updated
Hu YJ, Liu Y, Zhao RM, Qu SS (2005) Interaction of colchicine with human serum albumin investigated by spectroscopic methods. Int J Biol Macromol 37:122–126. doi:10.1016/j.ijbiomac.2005.09.007
Hubatsch I, Ragnarsson EGE, Artursson P (2007) Determination of drug permeability and prediction of drug absorption in Caco-2 monolayers. Nat Protoc 2:2111–2119. doi:10.1038/nprot.2007.303
Kathiresan S, Dhivya R, Vigneshwar M et al (2015) Biological evaluation of redox stable cisplatin/Cu(II)–DNA adducts as potential anticancer agents. J Coord Chem 8972:1–15. doi:10.1080/00958972.2015.1105366
Kelland L (2007) The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer 7:573–584. doi:10.1038/nrc2167
Kelly JM, Tossi AB, MacConnell DJ, OhUigin C (1885) A study of the interactions of some polypyridylruthenium(II) complexes with DNA using fluorescence spectroscopy, topoisomerisation and thermal denaturation. Nucleic Acids Res 13:6017–6034. doi:10.1093/nar/gkq840
Krishna G, Chen KJ, Lin CC, Nomeir AA (2001) Permeability of lipophilic compounds in drug discovery using in vitro human absorption model, Caco-2. Int J Pharm 222:77–89. doi:10.1016/S0378-5173(01)00698-6
Lakowicz JR (1999) Principles of fluorescence spectroscopy. Kluwer Academic/Plenum Publishers, New York, pp 1–24
Li L-Y, Jia H-N, Yu H-J et al (2012) Synthesis, characterization, and DNA-binding studies of ruthenium complexes [Ru(tpy)(ptn)]2+ and Ru(dmtpy)(ptn)]2+. J Inorg Biochem 113:31–39. doi:10.1016/j.jinorgbio.2012.03.008
Lima CJ, Rodríguez L (2011) Phosphine–gold(I) compounds as anticancer agents: general description and mechanisms of action. Anticancer Agents Med Chem 11:921–928
Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and developmental settings. Adv Drug Deliv Rev 23:3–25. doi:10.1016/S0169-409X(96)00423-1
Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (2001) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 64:4–17. doi:10.1016/j.addr.2012.09.019
Liu J, Zhang T, Lu T et al (2002) DNA-binding and cleavage studies of macrocyclic copper(II) complexes. J Inorg Biochem 91:269–276
Liu JJ, Galettis P, Farr A et al (2008) In vitro antitumour and hepatotoxicity profiles of Au(I) and Ag(I) bidentate pyridyl phosphine complexes and relationships to cellular uptake. J Inorg Biochem 102:303–310. doi:10.1016/j.jinorgbio.2007.09.003
Lu Y, Mahato RI (2009) Pharmaceutical perspectives of cancer therapeutics. Springer, Dordrecht
McKeage MJ, Berners-Price SJ, Galettis P et al (2000) Role of lipophilicity in determining cellular uptake and antitumour activity of gold phosphine complexes. Cancer Chemother Pharmacol 46:343–350. doi:10.1007/s002800000166
Messori L, Camarri M, Ferraro T et al (2013) Promising in vitro anti-Alzheimer properties for a ruthenium(III) complex. ACS Med Chem Lett 4:329–332. doi:10.1021/ml3003567
Motswainyana WM, Ajibade PA (2015) Anticancer activities of mononuclear ruthenium(II) coordination complexes. Adv Chem 2015:1–21. doi:10.1155/2015/859730
Nišavić M, Masnikosa R, Butorac A et al (2016) Elucidation of the binding sites of two novel Ru(II) complexes on bovine serum albumin. J Inorg Biochem 159:89–95. doi:10.1016/j.jinorgbio.2016.02.034
Page S (2012) Ruthenium compounds as anticancer agents. Education in Chemistry. http://www.rsc.org/images/Anticancer%20Drugs_EiC_January2012_tcm18-212416.pdf. Accessed 27 Sept 2016
Pavan FR, Von Poelhsitz G, do Nascimento FB et al (2010) Ruthenium(II) phosphine/picolinate complexes as antimycobacterial agents. Eur J Med Chem 45:598–601. doi:10.1016/j.ejmech.2009.10.049
Pavan FR, Poelhsitz GV, Barbosa MIF et al (2011) Ruthenium(II) phosphine/diimine/picolinate complexes: inorganic compounds as agents against tuberculosis. Eur J Med Chem 46:5099–5107. doi:10.1016/j.ejmech.2011.08.023
Pavan FR, Poelhsitz GV, da Cunha LVP et al (2013) In vitro and in vivo activities of ruthenium(II) phosphine/diimine/picolinate complexes (SCAR) against Mycobacterium tuberculosis. PLoS ONE 8:1–10. doi:10.1371/journal.pone.0064242
Queiroz SL, Batista AA, Oliva G et al (1998) The reactivity of five-coordinate Ru(II) (1,4-bis(diphenylphosphino)butane) complexes with the N-donor ligands: ammonia, pyridine, 4-substituted pyridines, 2,2′-bipyridine, bis(o-pyridyl)amine, 1,10-phenanthroline, 4,7-diphenylphenanthroline and ethylened. Inorg Chim Acta 267:209–221. doi:10.1016/S0020-1693(97)05615-6
Roca J (1995) The mechanisms of DNA topoisomerases. Trends Biochem Sci 20:156–160. doi:10.1016/S0968-0004(00)88993-8
Selvi PT, Palaniandavar M (2002) Spectral, viscometric and electrochemical studies on mixed ligand cobalt(III) complexes of certain diimine ligands bound to calf thymus DNA. Inorg Chim Acta 337:420–428. doi:10.1016/S0020-1693(02)01112-X
Sirajuddin M, Ali S, Badshah A (2013) Drug–DNA interactions and their study by UV–visible, fluorescence spectroscopies and cyclic voltammetry. J Photochem Photobiol B 124:1–19. doi:10.1016/j.jphotobiol.2013.03.013
Stenberg P, Norinder U, Luthman K, Artursson P (2001) Experimental and computational screening models for the prediction of intestinal drug absorption. J Med Chem 44:1927–1937. doi:10.1021/jm001101a
Veber DF, Johnson SR, Cheng H et al (2002) Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem 45:2615–2623. doi:10.1021/jm020017n
Yamashita S, Tanaka Y, Endoh Y et al (1997) Analysis of drug permeation across Caco-2 monolayers—implications for predicting in vivo drug absorption. Pharm Res 14:486–491
Yee S (1997) In vitro permeability across Caco-2 cells (colonic) can predict in vivo (small intestinal) absorption in man—fact or myth. Pharm Res 14:763–766
Živec P, Perdih F, Turel I et al (2012) Different types of copper complexes with the quinolone antimicrobial drugs ofloxacin and norfloxacin: structure, DNA- and albumin-binding. J Inorg Biochem 117:35–47. doi:10.1016/j.jinorgbio.2012.08.008
Acknowledgements
The authors would like to express their deepest gratitude and indebtedness to the São Paulo Research Foundation (FAPESP Grants 2012/22364-1 and 2013/20078-4) and Coordinating Committee for Advancement of Higher Education Staff in Brazil (CAPES) for the financial support granted during the course of this work. Our thanks also go to Michel L. de Campos for his support with the UPLC analysis.
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De Grandis, R.A., de Camargo, M.S., da Silva, M.M. et al. Human topoisomerase inhibition and DNA/BSA binding of Ru(II)–SCAR complexes as potential anticancer candidates for oral application. Biometals 30, 321–334 (2017). https://doi.org/10.1007/s10534-017-0008-z
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DOI: https://doi.org/10.1007/s10534-017-0008-z