Abstract
The dinuclear anticancer agents 1,n-bis{chlorido[3-(oxo-κO)-2-methyl-4-(1H)-pyridinonato-κO4](η6-p-cymene)-ruthenium(II)}alkane (PyRu n2 ) exhibit high antiproliferative activity in human cancer cell. Reactivity studies with DNA and protein revealed uncommon protein–DNA and DNA–DNA crosslinking ability. We report here studies on the reactions of the diruthenium organometallics PyRu 62 and PyRu 82 in comparison with a mononuclear analogue PyRu3 with amino acids using mass spectrometry and NMR spectroscopy. The compounds behave very similarly, independent of the spacer length between the metal center and of the nuclearity of the complexes. Incubation with l-cysteine (Cys) results in fast release of the pyridone ligand, with the Ru complexes able to form Cys adducts. In contrast, l-methionine forms, initially, adducts with the metal centers, but over time, the adducts decompose. Similar behavior was observed for the reaction with l-histidine with [Ru(η6-p-cymene)(l-histidine)] species detected.
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Yan YK, Melchart M, Habtemariam A, Sadler PJ (2005) Chem Commun 4764–4776
Jaouen G (ed) (2006) Bioorganometallics: biomolecules, labeling, medicine. Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Hartinger CG, Dyson PJ (2009) Chem Soc Rev 38:391–401
Nazarov AA, Hartinger CG, Dyson PJ (2014) J Organomet Chem 751:251–260
Jaouen G, Vessieres A, Top S (2015) Chem Soc Rev 44:8802–8817
Allardyce CS, Dyson PJ (2016) Dalton Trans 45:3201–3209
Zeng L, Gupta P, Chen Y, Wang E, Ji L, Chao H, Chen Z-S (2017) Chem Soc Rev 46:5771–5804
Köpf-Maier P (1999) Anticancer Res 19:493–504
Jaouen G, Top S, McGlinchey MJ (2015) In: Jaouen G, Salmain M (eds) Bioorganometallic chemistry. Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, pp 43–83
Hillard E, Vessieres A, Thouin L, Jaouen G, Amatore C (2006) Angew Chem Int Ed Engl 45:285–290
Clarke MJ, Zhu F, Frasca DR (1999) Chem Rev 99:2511–2533
Rademaker-Lakhai JM, Van Den Bongard D, Pluim D, Beijnen JH, Schellens JHM (2004) Clin Cancer Res 10:3717–3727
Hartinger CG, Zorbas-Seifried S, Jakupec MA, Kynast B, Zorbas H, Keppler BK (2006) J Inorg Biochem 100:891–904
Hartinger CG, Jakupec MA, Zorbas-Seifried S, Groessl M, Egger A, Berger W, Zorbas H, Dyson PJ, Keppler BK (2008) Chem Biodivers 5:2140–2155
Murray BS, Babak MV, Hartinger CG, Dyson PJ (2016) Coord Chem Rev 306:86–114
Ang WH, Dyson PJ (2006) Eur J Inorg Chem 2006(20):4003–4018
Nazarov AA, Gardini D, Baquie M, Juillerat-Jeanneret L, Serkova TP, Shevtsova EP, Scopelliti R, Dyson PJ (2013) Dalton Trans 42:2347–2350
Nosova YN, Karlov DS, Pisarev SA, Shutkov IA, Palyulin VA, Baquié M, Milaeva ER, Dyson PJ, Nazarov AA (2017) J Organomet Chem 839:91–97
Arshad J, Hanif M, Movassaghi S, Kubanik M, Waseem A, Söhnel T, Jamieson SMF, Hartinger CG (2017) J Inorg Biochem 177:395–401
Ashraf A, Hanif M, Kubanik M, Söhnel T, Jamieson SMF, Bhattacharyya A, Hartinger CG (2017) J Organomet Chem 839:31–37
Pascu GI, Hotze ACG, Sanchez-Cano C, Kariuki BM, Hannon MJ (2007) Angew Chem Int Ed Engl 46:4374–4378
Mendoza-Ferri MG, Hartinger CG, Eichinger RE, Stolyarova N, Jakupec MA, Nazarov AA, Severin K, Keppler BK (2008) Organometallics 27:2405–2407
Mendoza-Ferri MG, Hartinger CG, Nazarov AA, Kandioller W, Severin K, Keppler BK (2008) Appl Organomet Chem 22:326–332
McDonnell U, Kerchoffs JM, Castineiras RP, Hicks MR, Hotze AC, Hannon MJ, Rodger A (2008) Dalton Trans 5:667–675
Mendoza-Ferri MG, Hartinger CG, Mendoza MA, Groessl M, Egger AE, Eichinger RE, Mangrum JB, Farrell NP, Maruszak M, Bednarski PJ, Klein F, Jakupec MA, Nazarov AA, Severin K, Keppler BK (2009) J Med Chem 52:916–925
Mendoza-Ferri MG, Hartinger CG, Nazarov AA, Eichinger RE, Jakupec MA, Severin K, Keppler BK (2009) Organometallics 28:6260–6265
Hartinger CG, Phillips AD, Nazarov AA (2011) Curr Top Med Chem 11:2688–2702
Nováková O, Nazarov AA, Hartinger CG, Keppler BK, Brabec V (2009) Biochem Pharmacol 77:364–374
Wu B, Ong MS, Groessl M, Adhireksan Z, Hartinger CG, Dyson PJ, Davey CA (2011) Chem Eur J 17:3562–3566
Adhireksan Z, Davey GE, Campomanes P, Groessl M, Clavel CM, Yu H, Nazarov AA, Yeo CHF, Ang WH, Dröge P, Rothlisberger U, Dyson PJ, Davey CA (2014) Nat Commun 5:3462
Nazarov AA, Meier SM, Zava O, Nosova YN, Milaeva ER, Hartinger CG, Dyson PJ (2015) Dalton Trans 44:3614–3623
Debreczeni JÉ, Bullock AN, Atilla GE, Williams DS, Bregman H, Knapp S, Meggers E (2006) Angew Chem Int Ed Engl 45:1580–1585
Schmid WF, John RO, Mühlgassner G, Heffeter P, Jakupec MA, Galanski M, Berger W, Arion VB, Keppler BK (2007) J Med Chem 50:6343–6355
Scolaro C, Chaplin AB, Hartinger CG, Bergamo A, Cocchietto M, Keppler BK, Sava G, Dyson PJ (2007) Dalton Trans 5065–5072
Timerbaev AR, Hartinger CG, Aleksenko SS, Keppler BK (2006) Chem Rev 106:2224–2248
Tsang C-N, Bianga J, Sun H, Szpunar J, Lobinski R (2012) Metallomics 4:277–283
Hartinger CG, Groessl M, Meier SM, Casini A, Dyson PJ (2013) Chem Soc Rev 42:6186–6199
Kandioller W, Hartinger CG, Nazarov AA, Kuznetsov ML, John RO, Bartel C, Jakupec MA, Arion VB, Keppler BK (2009) Organometallics 28:4249–4251
Kandioller W, Balsano E, Meier SM, Jungwirth U, Goschl S, Roller A, Jakupec MA, Berger W, Keppler BK, Hartinger CG (2013) Chem Commun 49:3348–3350
Rilak A, Petrović B, Grgurić-Šipka S, Tešić Ž, Bugarčić ŽD (2011) Polyhedron 30:2339–2344
Mijatović AM, Jelić RM, Bogojeski J, Bugarčić ZD, Petrović B (2013) Monatsh Chem 144:1489–1498
Lazić D, Arsenijević A, Puchta R, Bugarčić ŽD, Rilak A (2016) Dalton Trans 45:4633–4646
Acknowledgements
We thank the organizations and foundations that have supported our research efforts in this area, especially the Universities of Auckland and Vienna, EPFL, and A.A.N. is grateful to the RFBR (16-03-00743).
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Nazarov, A.A., Mendoza-Ferri, MG., Hanif, M. et al. Understanding the interactions of diruthenium anticancer agents with amino acids. J Biol Inorg Chem 23, 1159–1164 (2018). https://doi.org/10.1007/s00775-018-1597-x
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DOI: https://doi.org/10.1007/s00775-018-1597-x