Synthesis of iridium and ruthenium complexes with (N,N), (N,O) and (O,O) coordinating bidentate ligands as potential anti-cancer agents.

Dalton Dynamic Article Links Transactions Cite this: Dalton Trans., 2012, 41, 13800 COMMUNICATION www.rsc.org/dalton Synthesis of iridium and ruthenium complexes with (N,N), (N,O) and (O,O) † coordinating bidentate ligands as potential anti-cancer agents Stephanie J.Lucas,a RianneM.Lord,aRachelL.Wilson,aRogerM.Phillips,bVisuvanatharSridharanaand Patrick C.McGowan*a Received13thAugust2012,Accepted13thSeptember2012 DOI:10.1039/c2dt32104a SeveralRu-areneandIr–Cp*complexeshavebeenprepared incorporating (N,N), (N,O) and (O,O) coordinating bidentate ligandsandhavebeenfoundtobeactiveagainstbothHT-29 and MCF-7 cell lines. By incorporating a biologically active ligand into a metal complex the anti-cancer activity is increased. Inrecentyears,organometalliccomplexeshaveshownpromising activity as anti-cancer agents.1–4 Design concepts for such organometallic drugs, however, are still in their infancy. There Scheme1 Synthesis of the iridium Cp* halide picolinamide com- are few recently reported studies on the anti-cancer activity of plexes1and2. iridium complexes.5,6 Sadler et al. have recently reported the organometallic half-sandwich Ir(III) complexes of general struc- ture [(η5Cp ‡ )Ir(XY)Cl]0/+ where Cp ‡ is either Cp* or a functio- nalised Cp ligand.7 Their potency towards A2780 human ovarian cancer cells increases with phenyl substitution on the cyclopentadienyl ligand. We have previously shown that ruthenium arene picolinamide complexes possess anti-cancer activity.8,9 Iridium Cp* picolinamide complexes have been pre- pared previously, but, to the best of our knowledge have not beentestedasanti-canceragents.10 We aimed to explore the synthesis of Ru(II)/Ir(III) complexes with the general structure [Ru(p-cymene)(XY)Cl]/[IrCp*(XY)- Cl], where XY is a bidentate ligand which binds to the metal through(N,N),(N,O)or(O,O)coordination,andtheirapplication as anti-cancer agents. All complexes were prepared through deprotonation of the bidentate ligand. Complexes 1 and 2 were prepared by refluxing [IrCp*Cl ] with two equivalents of the 2 correspondingpicolinamideandNH PF inethanol(Scheme1). 4 6 The picolinamide ligands bind through the nitrogens, indi- catedbythelossoftheamideprotoninthe1HNMRspectrum. Wehavepreviouslyshownthatpicolinamideligandscanbind as (N,O) donors in charged Ru(p-cymene) complexes however Scheme2 Synthesis of the iridium Cp* and ruthenium p-cymene ketoiminatecomplexes3and4. aSchoolofChemistry,UniversityofLeeds,WoodhouseLane,Leeds,LS2 9JT,UK.E-mail:P.C.McGowan@leeds.ac.uk;Fax:+44(0)113436565; theywereshowntobeinactiveagainstarangeofcelllines.9We Tel:+44(0)1133436404 were interested in preparing similar neutral complexes with bTheInstituteofCancerTherapeutics,UniversityofBradford,West (N,O)coordinatedligands,suchasketoiminates. Yorkshire,BD71DP,UK.E-mail:R.M.Phillips@bradford.ac.uk; Fax:+44(0)1274233234;Tel:+44(0)1274235367 Complexes 3 and 4 were‡ prepared by stirring either †Electronic supplementary information (ESI) available: Experimental [IrCp*Cl ] or [Ru(p-cymene)Cl ] with 3′-fluorophenyl- 2 2 2 2 procedures for compounds, cell line experimental and crystal structure 3(phenylamino)-2-buten-1-one and triethylamine in dichloro- determination details. CCDC 890355, 890356 and 890357. For ESI methane(Scheme2).Redsinglecrystalsof3weregrownfroma and crystallographic data in CIF or other electronic format see DOI: 10.1039/c2dt32104a dichloromethane/hexane solvent system and of 4 from a 13800 | DaltonTrans.,2012,41,13800–13802 Thisjournalis©TheRoyalSocietyofChemistry2012 .10:15:41 3102/50/32 no lliH lepahC ta aniloraC htroN fo ytisrevinU yb dedaolnwoD .2102 rebmetpeS 41 no dehsilbuP View Article Online / Journal Homepage / Table of Contents for this issue Scheme3 SynthesisoftheiridiumCp*2-hydroxy-1,4-napthoquinone complex5. Fig.2 Molecular structure of 5. Hydrogen atoms are omitted for clarity.Displacementellipsoidsareatthe50%probabilitylevel. Table1 IC values for complexes 1–5 along with cisplatin, 50 [IrCp*Cl ] ,[Ru(p-cymene) Cl ] and2-hydroxy-1,4-napthoquinonefor 22 2 22 reference. Cultures 1 and 2 refer to different sets of MCF-7 cells, with differentIC valuesforcisplatin(—meansnottested).Thedrugswere 50 incubatedfor5days MCF-7IC /μM 50 HT-29IC / 50 Compound μM Culture1 Culture2 Cisplatin 2.4±0.1 0.528±0.003 6.1±0.7 [IrCp*Cl ] 92±4 100±2 — 22 [Ru(p-cymene) Cl ] 198±5 184±3 — 2 22 1 34.1±0.7 39±2 — 2 81±1 149±1 — 3 5.1±0.3 — 11.0±0.4 4 3.5±0.3 — 7.1±0.4 5 20±1 13.2±0.2 — 2-Hydroxy-1,4- 81±1 22±1 — napthoquinone oxygens were substituted with S or Se.14 Quinones exhibit bio- logical properties, such as anti-microbacterial and anti- tumour.15,16 The 1,4-naphthoquinone pharmacophore is known to impart anti-cancer activity17 in a number of drugs, for examplestreptonigrin18andmitomycins.19Anotheradvantageis that naphthoquinone will increase the hydrophobicity of the Fig.1 (a),(b)Molecularstructureof3.Solventomittedforclarity,(c) metal complex and possibly allowing easier passive transport (d) Molecular structure of 4. Hydrogen atoms are omitted for clarity. Displacementellipsoidsareatthe50%probabilitylevel. intocells. Complex 5 was prepared in the same manner as 3 and 4 but with an excess of 2-hydroxy-1,4-napthoquinone and triethyl- methanolic solution. The molecular structures are shown in amine(Scheme3). Fig. 1, showing that the ketoiminate binds in an (N,O) fashion. Purplecrystalsof5wereobtained byvapourdiffusionfroma There are similaritiesin that they conform to the 3-legged piano dichloromethane/pentanesolventsystem.‡TheX-raystructureof stoolwithCp*andp-cymeneringsrespectively.Therearediffer- 5 can be seen in Fig. 2. As with 3 and 4 the complex adopts a ences in the ligand arrangement around the metal centre (shown piano stool configuration. The ligand retains its planarity when in Fig. 1(b) and (d)) and we were interested in investigating complexed which may allow intercalation of the quinone with theseeffectsforthecomplexes’cytotoxiccapabilities. DNA. Given the ease of synthesis and large potential for structure The cytotoxic activity of the complexes 1–5 along with activity relationships, we decided to investigate the possible cisplatin, [IrCp*Cl ] , [Ru(p-cymene) Cl ] and 2-hydroxy-1,4- 2 2 2 2 2 cooperative effects of biologically active organic compounds napthoquinone, were tested against HT-29 and MCF-7 cell lines which would bind to metals as (O,O) donors. The naphtho- withtheIC resultsshowninTable1. 50 quinone ligand has been reported to form complexes with Sn,11 Compound1showsmoderateactivityagainstbothHT-29and Co12andPt13buttothebestofourknowledge,notwithiridium MCF-7celllines,withIC valueof34μMand39μMrespect- 50 or ruthenium. IrCp* benzoquinone complexes have been ively.Compound2however,showspooractivitywithanIC of 50 previously reported but were found to be inactive unless the 81 μM for HT-29 cell lines and 149 μM for MCF 7 cell lines. Thisjournalis©TheRoyalSocietyofChemistry2012 DaltonTrans.,2012,41,13800–13802 | 13801 .10:15:41 3102/50/32 no lliH lepahC ta aniloraC htroN fo ytisrevinU yb dedaolnwoD .2102 rebmetpeS 41 no dehsilbuP View Article Online This shows that the position of the fluorides on the aryl ring of 3 C.G.Hartinger,S.Zorbas-Seifried,M.A.Jakupec,B.Kynast,H.Zorbas the picolinamide ligand has a significant effect on cytotoxicity. andB.K.Keppler,J.Inorg.Biochem.,2006,100,891–904. 4 A. L. Noffke, A. Habtemariam, A. M. Pizarro and P. J. Sadler, Chem. Theketoiminatecomplexes3and4havehighactivities,compar- Commun.,2012,48,5219–5246. ablewith cisplatin, with IC 50 values of 5.1 and 3.5 μM(2.4 μM 5 M.Gras,B.Therrien,G.Suss-Fink,A.Casini,F.EdafeandP.J.Dyson, for cisplatin) for HT-29 cells, and 11.0 and 7.1 μM (6.1 μM for J.Organomet.Chem.,2010,695,1119–1125. 6 Z.Liu,A.Habtemariam,A.M.Pizarro,G.J.ClarksonandP.J.Sadler, cisplatin) for MCF-7 cells. The iridium napthoquinone complex Organometallics,2012,30,4702–4710. 5 shows a cooperative effect, having higher activity than both 7 Z.Liu,L.Salassa, A.Habtemariam,A. M.Pizarro,G. J.Clarksonand the napthoquinone ligand and metal source [IrCp*Cl ] , most P.J.Sadler,Inorg.Chem.,2012,50,5777–5783. 2 2 noticeably for the HT-29 cells where complex 5 is four times as 8 S.H.vanRijt,A.J.Hebden,T.Amaresekera,R.J.Deeth,G.J.Clarkson, activeasthefreeligandwithIC 50 valuesof20and81μM. 7 S 7 . 5 P 3 a – rs 7 o 7 n 6 s 4 , . P. C. McGowan and P. J. Sadler, J. Med. Chem., 2009, 52, The anti cancer activity of complexes 1–5 correlates with the 9 K.D.Camm,A.El-Sokkary,A.L.Gott,P.G.Stockley,T.Belyaevaand type of bidentate ligand, where cytotoxicity of (N,O) > (O,O) > P.C.McGowan,DaltonTrans.,2009,10914–10925. (N,N). 10 M.Watanbe,J.HoriandK.Murata,US2010/0234596A1,2010. 11 V. Valla, M. Bakola-Christianopoulou, P. Akrivos, V. Kojic and Insummary,wehavepreparedfouriridiumandoneruthenium G.Bogdanovic,Synth.React.Inorg.Met.-Org.Nano-Met.Chem.,2006, arene complexes with either (N,N), (N,O) or (O,O) coordinating 36,765–775. ligands The piano stool complexes were active against both 12 C. M. Martín-Navarro, A. López-Arencibia, J. Lorenzo-Morales, S.Oramas-Royo,R.Hernández-Molina,A.Estévez-Braun,Á.G.Ravelo, HT-29andMCF7celllineswiththe(N,O)complexesbeingthe B.ValladaresandJ.E.Piñero,Exp.Parasitol.,2010,126,106–108. mostactiveshowingcomparableactivitywithcisplatin.Bycom- 13 A. P. Neves, G. B. da Silva, M. D. Vargas, C. B. Pinheiro, plexing the 2-hydroxy-1,4-napthoquinone to iridium, a coopera- L. d. C. Visentin, J. D. B. M. Filho, A. J. Araujo, L. V. Costa-Lotufo, tive effect can be seen whereby the resulting complex is more C.PessoaandM.O.deMoraes,DaltonTrans.,2010,39,10203–10216. 14 H. Amouri, J. Moussa, A. K. Renfrew, P. J. Dyson, M. N. Rager and activethanboththeligandandstartingdimer. 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Rockwell 2 L.RonconiandP.J.Sadler,Coord.Chem.Rev.,2007,251,1633–1648. andA.C.Sartorelli,CancerCommun,1991,3,351–356. 13802 | DaltonTrans.,2012,41,13800–13802 Thisjournalis©TheRoyalSocietyofChemistry2012 .10:15:41 3102/50/32 no lliH lepahC ta aniloraC htroN fo ytisrevinU yb dedaolnwoD .2102 rebmetpeS 41 no dehsilbuP View Article Online