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Evaluation of the in vitro anticancer activity of cyclometalated half-sandwich rhodium and iridium complexes coordinated to naphthaldimine-based poly(propyleneimine) dendritic scaffolds
JournalofOrganometallicChemistry774(2014)79e85
ContentslistsavailableatScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Evaluation of the in vitro anticancer activity of cyclometalated
half-sandwich rhodium and iridium complexes coordinated to
naphthaldimine-based poly(propyleneimine) dendritic scaffolds
Lara C. Sudding a, Richard Payne a, Preshendren Govendera, Fabio Edafe b,
Catherine M. Clavel b, Paul J. Dyson b, Bruno Therrienc, Gregory S. Smith a,*
aDepartmentofChemistry,UniversityofCapeTown,PrivateBag,Rondebosch7701,SouthAfrica
bInstitutdesSciencesetIng(cid:1)enierieChimiques,EcolePolytechniqueF(cid:1)ed(cid:1)eraledeLausanne(EPFL),CH1015Lausanne,Switzerland
cInstituteofChemistry,UniversityofNeuchatel,51AvedeBellevaux,CH-2000Neuchatel,Switzerland
a r t i c l e i n f o a b s t r a c t
Articlehistory: Thedevelopmentofcyclometalatedrhodiumandiridiumcomplexesfromfirst-andsecond-generation
Received8August2014 naphthaldimine-basedpoly(propyleneimine)dendrimerscaffoldsofthetype,DAB-(NH2)n(wheren¼4
Receivedinrevisedform or 8, DAB ¼ diaminobutane) has been accomplished. Four metallodendrimers were synthesised, viz.
2 A A 3 v cc a S e il e p a p t b e t l e d e m o 1 b n O e li r c n t 2 e o 0 b 1 1 e 2 4 r O 2 c 0 t 1 o 4 ber2014 S (C c p h * if M f- C b l a ) s 4 e Gn de (1 n e d 4 ri ) m ,b e y rs fir w st it r h ea th ct e in d g im DA er B s -( [ N C H p* 2 M )n C w l2 i ] t 2 h ( n w ap h t e h r t e h M ald ¼ eh R y h de o a r n I d r) s . u R b e s l e a q te u d en m tl o y n m on e u ta c l l l e a a ti r n c g o t m he -
plexes [Cp*MCl(L)] (L ¼ naphthaldimine) (5e6) were obtained in a similar manner. The molecular
structuresof5and6havebeendeterminedbysingle-crystalX-raydiffractionanalysisandtheinvitro
Keywords:
anticanceractivitiesof1e6wereevaluatedagainsttheA2780andA2780cisRhumanovariancarcinoma
Bioorganometallicchemistry
Cyclometalated celllines.
Rhodium
©2014ElsevierB.V.Allrightsreserved.
Iridium
Metallodendrimers
Anticancerdrugs
Introduction Pt(II)metal-baseddrugs.Theredoxchemistryofrutheniumisrich
and compatible with biological media. The overall toxicity of
The discovery of cisplatin as an anticancer transition metal- rutheniumislowerthanplatinum,thusallowinghigherdosesfor
based drug pioneered research into metal-based drug discovery treatment.
inthefieldofmedicinalinorganicchemistry,andmetalcomplexes Metal-based drugs containing rhodium and iridium are
arecurrentlyanimportantresourceforthegenerationofchemical explored to a lesser extent and recent work suggests that these
diversityinthesearchfornoveldiagnosticandtherapeuticagents compounds lend themselves to development as novel anticancer
[1e11]. Despite being used in about 50% of all cancer treatment drugs [19e29]. More recently, researchers have turned their
regimens, cisplatin and other platinum-based drugs found in the attention to cyclometalated complexes in which a chelating ring
clinic are poorly selective and produce several undesirable side- containsastrongM(cid:2)Csigmabond.Thebiologicalpropertiesofthe
effects [12,13].It is theseside-effects thatlimit the dose thatcan cyclometalatedcomplexescanbetweakedbymodificationofthe
be administered to a patient, thus allowing certain tumours to anioniccyclometalatedligandorthroughancillaryligandsaround
developacquiredresistancemechanisms.Researchnowfocusesits themetalcentre.Improvedcytotoxicityandpharmacokineticshave
attentions on the development of new metal-based drugs with been observed for many complexes ascribed to their greater sta-
fewerside-effectsandwithdifferentmechanismsofaction.Among bilityaffordedbythisclassofligand[30,31].
thetransitionmetals,rutheniumappearstobethemostpromising The conceptof multinuclearity is an innovative strategyoften
candidate[14e18].Itpossessesanoctahedralcoordinationgeom- resulting in improved biological activity with respect to mono-
etry,thushavingtwoadditionalbindingsitesincomparisonwith nuclearcompounds[32e35],whichcouldbeattributedtofavour-
ablemodulationofthestability,solubilityand/orlipophilicityofthe
organometallic scaffolds. Sincethe developmentof the trinuclear
* Correspondingauthor.Tel.:þ27216505279;fax:þ27216505195. platinum-based anticancer drug, BBR3464 [trans, trans, trans-
E-mailaddress:gregory.smith@uct.ac.za(G.S.Smith).
http://dx.doi.org/10.1016/j.jorganchem.2014.10.003
0022-328X/©2014ElsevierB.V.Allrightsreserved.
80 L.C.Suddingetal./JournalofOrganometallicChemistry774(2014)79e85
(NH3)2 ePt(Cl) nitrogen, appearing around 3.6 ppm for G1 and G2.13C{1H} NMR
NH2(CH2)6NH2Pt(NH3)2NH2(CH2)6NH2Pte(NH3)2(Cl)][NO3]4 [36], spectra indicate the presence of the characteristic imine carbon
theconceptofmultinuclearityhasnotbeenextensivelyexploredin peakataround161ppmforG1andG2.Tofurtherconfirmthatthe
thedevelopmentofnewanticanceragents.Anattractivestrategy Schiff-base reaction occurred, IR spectroscopy shows imine ab-
usedtoexploitthisconceptmakesuseofmacromoleculessuchas sorption bands at 1639 cm (cid:2)1 for both the first- and second-
dendrimers. generationnaphthaldiminedendrimersG1andG2.
Metallodendrimers, i.e. metal-containing dendritic macromol-
ecules, have recently found potential as diagnostic agents and as
chemotherapeutics[37].Inlinewiththisstrategy,themultivalent/
Synthesisandcharacterisationofrhodiumandiridium
multinuclear nature of metallodendrimers can enhance in- metallodendrimers1e4
teractions between a dendrimer-drug conjugate and a target
bearing multiple receptors. In this respect, we have recently re-
The dinuclear pentamethylcyclopentadienyl (Cp*) rhodium or
portedthesynthesisofaseriesofmetallodendrimers,containing iridiumdimers[Cp*MCl2]2(M¼RhorIr)werereactedwithG1and
ruthenium-areneandosmium-arenefunctionalitieslocatedonthe G2atroomtemperatureinthepresenceofsodiumacetatetoyield
periphery of the dendritic scaffold [32,33,38,39]. A cationic 32- theneutraltetranuclear(1e2)andoctanuclear(3e4)rhodiumand
armed ruthenium-p-cymene-PTA functionalised metal- iridiummetallodendrimers (Scheme 1). Theyelloweorangecom-
lodendrimer was shown to have antiproliferative activity in the pounds(1e4)wereisolatedasair-stablesolidsinmoderateyields.
nanomolar range (A2780, human ovarian cancer cell line) [39].
The complexes are soluble in organic solvents such as dichloro-
Recently, we have reported half-sandwich rhodium and iridium
methane,chloroform,ethanol,dimethylsulfoxideandacetone.
metallodendrimers which displayed moderate to good activity The 1H NMR spectra of the three metallodendrimers reveal
in vitro [40]. Indeed, the biological properties of numerous poly- upfieldshiftsoftheimineresonancefrom~8.4ppminthemetal-
metalliccompoundshavebeenreportedintheliterature[41e47].
freedendrimersG1andG2to~8.0ppmfor1and2,and~8.3ppm
Asanextensionoftheabovework,wehavenowsynthesiseda for3and4.Thisconfirmsthattheiminebondisstillintactandthat
series of polynuclear half-sandwich cyclometalated rhodium and
there is coordination of the metal centre to the imine nitrogen.
iridium complexes, based on a naphthaldimine poly(- ThereissignificantbroadeningofallthepeaksintheNMRspectra,
propyleneimine) (PPI) dendritic scaffold. The cytotoxicities of the
especially observed for the peripheral end-groups, due to the
rhodium and iridium metallodendrimers have been established
multivalentnatureofthedendrimerandonthegivenNMRtime-
usingovarianA2780(cisplatin-sensitive)andA2780cisR(cisplatin-
scale, this averages out to a broadened signal over the same
resistant)cancercelllinesandanon-cancerousHEK(humanem- chemical shift. In all the complexes 1e4, there is a characteristic
bryonickidney)cellline. broadmultipletbetween3.96and4.12ppminthe1HNMRspectra
thatcorrespondstotheprotonsonthecarbonadjacenttotheimine
Resultsanddiscussion nitrogen.FortheRh(III)complex1,thissignalappearsastwobroad
peakswhichisexpectedasthesetwoprotonsareindifferenten-
Synthesisandcharacterisationofnaphthaldimine-functionalised vironments due to diastereotopicity, being adjacent to the chiral
(G1 ,G2
)dendrimers metal centre, whereas for the Ir(III) complexes 2 and 4, the two
signalscoalesceandappearasonebroadpeak.
The naphthaldimine-functionalised first- and second- In the 13C{1H} NMR spectrum there is a carbon peak furthest
generationdendrimers(G1eG2)weresynthesisedbythereaction downfield in each complex, at 133.37 and 136.60 ppm for com-
ofnaphthaldehydewithDAB-(NH2)n(wheren¼4or8forG1andG2 plexes 1 and 2, respectively, which corresponds to the imine
respectively)(Fig.1).Thedendrimerswereisolatedaswhitesolids carbon.
in moderate yields and are readily soluble in dichloromethane, IR spectroscopy was used to confirmwhether there had been
chloroformandacetone. coordinationofthedendrimertothemetalcentre.TheIRspectraof
Inthe1HNMRspectraofbothdendrimersG1andG2thereisa metallodendrimers 1e4 reveal imine absorption peaks at lower
characteristiciminepeakataround8.4ppm.Akeyfeatureinthe1H frequenciesaround1600cm (cid:2)1(for2and4)andaround1610cm (cid:2)1
NMR spectrum is the downfield position of the triplet corre- (for 1 and3), compared tothatof the metal-free dendrimers (G1
spondingtotheprotonsonthecarbonatomadjacenttotheimine andG2)ataround1639cm (cid:2)1.
N
N N
N N
N N
N N N
N N
N N
N
N N
N N N
G1 G2
Fig.1. First-andsecond-generationofnaphthaldimine(G1,G2)dendrimers.
L.C.Suddingetal./JournalofOrganometallicChemistry774(2014)79e85 81
Scheme1. Tetra-andoctanuclearrhodiumandiridiummetallodendrimers1e4.
High resolution-ESI mass spectrometry was used for metal- X-raydiffractionstudiesofcomplexes5and6
lodendrimers (1e4), to confirm that the desired products were
obtained.TheresultsfortheRh(III)complex1showtheappearance X-rayqualitysinglecrystalsfor5wereobtainedfromatoluene/
ofbasepeaksat1959.4369and1923.4751m/zwhichcorrespondto hexanemixture,whilefor6,crystalswereobtainedfromameth-
thepseudomolecularionpeakaswellasapeakcorrespondingto anol/hexanemixture.Themolecularstructuresof5and6confirm
thelossofachlorideligand(1959.52g/mol).InthecaseoftheIr(III) thecharacteristicpseudo-tetrahedral“piano-stool”geometrywith
complex2,thereisabasepeakat1159.3489m/zcorrespondingto ah5-coordinationoftheCp*tothemetalcentre.Thiscoordination
the[Mþ2H]2þ ionaswellasapeakat1122.3962m/zcorresponding formsthe‘seat’ofthepiano-stoolandtheremainingbondsofthe
tothe[M(cid:2)2Cl]2þ ion(2316.78g/mol). C,N chelate and the chloride form the ‘legs’ of the “piano-stool”
(Fig. 2). As emphasized in Fig.2, the complexes are chiral, which
supportsthediastereotopicnatureofthe1HNMRsignals.
Synthesisandcharacterisationofmononuclearrhodiumand
Complex5crystallizeswithamoleculeoftolueneinthemono-
iridiumcomplexes(5,6)
clinicspacegroupP21/n,whilecomplex6crystallizesintheortho-
Analogousmononuclearrhodiumandiridiumcomplexes(5e6)
rhombic space group P 212121. The distances between the metal
centresandthearomaticcarbonatomsrangebetween2.159(3)and
were prepared for comparison as models of the more complex
2.275(3) Å for the rhodium derivative and between 2.140(6) and
macromolecularstructures.Theseweresynthesisedbyreactingthe
2.263(6) for the iridium analogue. The bond length between the
naphthaldimine ligand (L1) with the dinuclear Cp* rhodium or
metal centre and the chloride ligand is2.3984(8) Å forthe Rh(III)
iridium dimers [Cp*MCl2]2 (M ¼ Rh or Ir) in dichloromethane at
complex,and2.391(2)ÅfortheIr(III)complex.Inbothcomplexes,
roomtemperature(Scheme2).
themetalnitrogen-iminebondlengthsarecomparableat2.097(3)
The mononuclear metal complexes 5e6 were isolated as yel-
and 2.088(5) Å, respectively. However, the RheC1 bond length is
loweorangesolidsinmoderateyields.Theyareair-stableandsol-
shorter[2.030(3)Å] thantheIreC1bondlength[2.046(7)Å].The
uble in methanol, ethanol, acetone, dichloromethane and
crystallographicdetailsforbothstructuresaregiveninTable1.
chloroform. The 1H NMR spectra of each metal complex 5 and 6
indicatecoordinationofthemetalcentretotheligandinabiden-
tate fashionwith an upfield shift of theimine peak in the Rh(III) Anticanceractivityofcomplexes1e6
complex5from8.43ppm(forL1)to8.23ppm,whilstthereisno
observableshiftoftheiminepeakintheIr(III)complex6.13C{1H} A preliminary investigation of the biological activity of the
NMR spectroscopy show characteristic carbon peaks at about aforementionedmetallodendrimersandmononuclearcompounds
145ppmforbothcomplexes,correspondingtotheiminecarbon, wasundertakenandtheantiproliferativeactivityof1e6waseval-
furtherupfieldincomparisonwiththeiminecarbonresonancein uatedinvitrointheA2780andA2780cisRovariancancercelllines
themetal-freeligandL1atabout160ppm.TheIRspectraforthe usingtheMTTassaywhichmeasuresmitochondrialdehydrogenase
complexes5and6indicateashiftoftheimineabsorptionbandtoa activityasanindicationofcellviability.TheIC50values(inhibitionof
lower frequency of 1610 cm
(cid:2)1
for the Rh(III) complex 5 and cancercellgrowthatthe50%level)arelistedinTable2andwere
1603cm
(cid:2)1fortheIr(III)complex6.TheESI-massspectrumofthe
calculatedasanaverageovertwoindependentexperiments.
each complex show base peaks corresponding to the pseudomo- Thepolynuclearcompoundsgenerallydisplaymoderatetohigh
lecularionwiththelossofthechlorideion,[M(cid:2)Cl] þ . antiproliferative activity in the A2780 (cisplatin-sensitive) and
Scheme2. Synthesisofthemononuclearrhodiumandiridiumcomplexes5e6.
82 L.C.Suddingetal./JournalofOrganometallicChemistry774(2014)79e85
Fig.2. Molecularstructuresofthemononuclearcomplexes5and6.Thesolvatemoleculein5hasbeenomittedforclarity,thermalellipsoidsaredrawnatthe50%probabilitylevel.
Table1 sensitive and resistant cell lines, suggesting a different mode of
Crystallographicparametersforcomplexes5$tolueneand6.
action to cisplatin. Furthermore, the second generation Ir-
5$toluene 6 metallodendrimer 4 is the most active in the cisplatin-resistant
Chemicalformula C31H29ClNRh C24H29ClIrN
cells (IC50 ¼ 3.0 mM, A2780cisR). Notably, the activity of these
Formulaweight 553.91 559.13 metallodendrimers are comparable with the arene-ruthenium(II)
Crystalsystem Monoclinic Orthorhombic complexesattachedtosimilardendriticscaffolds[33,39].Thecor-
Spacegroup P21/n(no.14) P212121(no.19) relation between the size dependency of the metallodendrimers
Crystalcolourandshape Redblock Redrod andthecytotoxicity,whichwepreviouslyreportedforanalogous
Crystalsize 0.19(cid:3)0.12(cid:3)0.12 0.18(cid:3)0.16(cid:3)0.14
a(Å) 8.4123(4) 11.2492(10) mononuclearandhighergenerationpolynuclearrutheniumcom-
b(Å) 12.7708(5) 12.4866(9) plexes[33]andothersobservedtooforrelateddinuclearcomplexes
c(Å) 26.8982(12) 15.6083(13) [41,42,48,49],isevidentforcomplexes1e6.
b((cid:4)) 94.9730(10) 90
V(Å3) 2878.8(2) 2192.4(3)
Z 4 4 Conclusions
T(K) 173(2) 173(2)
Dc(gcm(cid:2)3) 1.278 1.694 Aseriesofneutral,chelating,cyclometalatedfirst-andsecond-
m(mm(cid:2)1) 0.703 6.220
Scanrange((cid:4)) 2.20<q<28.32 2.09<q<26.18 generation Rh(III) and Ir(III) complexes based on poly(-
Uniquereflections 7169 4326 propyleneimine) dendrimer scaffolds has been prepared and
Observedrefls[I>2s(I)] 5977 3811 characterised. These compounds are air-stable and consequently
Rint 0.0445 0.0553 their anticancer activity was evaluated in vitro. In general, the
FinalRindices[I>2s(I)]a 0.0439,wR20.1273 0.0297,wR20.0631
octanuclear chelating rhodium and iridium metallodendrimers
Rindices(alldata) 0.0541,wR20.1360 0.0381,wR20.0672
Goodness-of-fit 1.052 1.004 showsuperioractivitythananalogousmononuclearrhodiumand
Max,MinDr/e(Å(cid:2)3) 1.443,(cid:2)0.738 1.138,(cid:2)1.574 iridium complexes and comparable activity to ruthenium metal-
a StruPctures were refined on F
0
2:wR2 ¼½ P ½wðF
0
2(cid:2)F
c
2Þ2(cid:5)= P wðF
0
2Þ2(cid:5)1=2, where lodendrimers reported previously. The generalisation, as noted
w(cid:2)1¼½ ðF2ÞþðaPÞ2þbP(cid:5)andP¼½maxðF2;0Þþ2F2(cid:5)=3. beforeforrutheniumdendrimersthatshowsacorrelationbetween
0 0 c
thesizedependencyofthemetallodendrimeranditscytotoxicity,is
notalwaystruefortheserhodiumandiridiumcomplexesandone
A2780cisR (cisplatin-resistant) cell lines. The mononuclear com- needstogotothesecond-generationtogetaslightimprovement.
plexes5and6showmoderateactivity,withthesecomplexesdis- Nonetheless, the most active compounds based on rhodium and
playingbetteractivitythanthefirst-generationderivatives1and2.
iridium have comparable activities to the most active related
However, the octanuclear complexes are the most active of the rutheniumsystems.
series, with the second generation Rh-metallodendrimer 3 being
themostactiveinthe cisplatin-sensitive cell line(IC50 ¼ 8.0mM,
Experimental
A2780). All complexes display similar cytotoxicity in both the
Generalremarks
Table2
IC50valuesof1e6onA2780andA2780cisRhumanovariancancercells,andHEK All synthetic procedures were performed under ambient con-
cells. ditionsunlessotherwisestated.Allreagentswerepurchasedfrom
Compound M na A2780(IC50,mM) A2780cisR(IC50,mM) HEKb(IC50,mM) SigmaeAldrich and used as received. Solvents were dried over
Fluka Molecular Sieve dehydratewith indicator. Rh(III) and Ir(III)
1 Rh 4 >100 >100 >100
2 Ir 4 29.7±0.1 28.1±2.0 n.d. trichloride trihydrate was obtained from Johnson Matthey/Anglo
3 Rh 8 8.0±0.5 3.1±0.3 4.5±0.5 American Platinum Limited. L1 [50], [Cp*RhCl2]2 [51] and
4 Ir 8 13.7±0.1 3.0±0.2 5.0±1.2 [Cp*IrCl2]2 [51] were synthesised following literature methods.
5 Rh 1 13.4±2.4 19.0±1.2 52.9±67.9 Nuclear magnetic resonance (NMR) spectra were recorded on a
6 Ir 1 20.1±13.6 19.0±8.5 72.4±91.1 Varian Unity XR400 spectrometer (1H: 399.95 MHz; 13C{1H}:
Cisplatin Pt 1 1.5 25
100.58 MHz; 31P{1H}: 161.90 MHz) or Varian Mercury XR300
n.d.¼Notdetermined. spectrometer (1H: 300.08 MHz; 13C{1H}: 75.46 MHz; 31P{1H}:
a n¼Numberofmetalswithinthecompound.
ca b nc I e C r 5 o 0 u v s a c lu el e l s li d n e e t . erminedforthemostactivecomplexesagainstanormal,non- 4 12 0 1 0 . . 4 2 7 2 M M H H z z ; ) 1 o 3C r {1H Br } u : k 1 e 0 r 0.6 B 5 ios M pi H n z; G 3 m 1P b { H 1H} s : pe 1 c 6 t 2 r . o 0 m 0 et M er Hz) (1H at :
L.C.Suddingetal./JournalofOrganometallicChemistry774(2014)79e85 83
ambienttemperatureusingtetramethylsilane(TMS)astheinternal reactionmixturewasfilteredthroughCeliteandwashedwithDCM
standard. Infrared (IR) absorptions were measured on a Per- or methanol. The solvent was removed on a rotaryevaporator to
kineElmer Spectrum One FT-IR spectrometer as KBr pellets. obtain the crude product. The solid was dissolved in a minimum
Elementalanalysis(C,H,N)wascarriedoutusingaThermoFlash amountofDCM,suspendedindiethyletherandplacedinthefridge
1112SeriesCHNSeOAnalyser.Forcertainmetallodendrimers,the overnight. The following day a solid was observed, this was
analyses are outside acceptable limits, and are ascribed to the filtered under vacuum yielding the desired product as a light
encapsulationofsolventmoleculesandotherinorganicsaltsbythe yelloweorangeorredeorangesolid.
dendritic compounds. Electrospray Ionisation (ESI) mass spec-
trometry was carried out on a Waters API Quattro Micro triple- [(Cp*RhCl)4 G1 ](1)
quadrupolemass spectrometer inthe positive-ionmode.Melting Yelloweorange solid. Yield ¼ 0.0605 g (52%). IR (KBr pellet)
pointsweredeterminedusingaBüchimelting-pointB-540appa- n(C]N)1609cm (cid:2)1.1HNMR(400MHz,CDCl3)d(ppm)¼1.57(m,
ratusandarecorrected. 4H, NCH2CH2 core); 1.61 (s, 60H, Cp*); 1.70 (m, 8H,
NCH2CH2CH2Nbranch);2.20(brt,8H,NCH2CH2CH2Nbranch);2.92(m,
Generalsynthesisofthenaphthaldiminedendrimers 4H,NCH2CH2core);3.96(splittingofbrm,8H,NCH2CH2CH2Nbranch);
7.30(m,8H,CHAr);7.43(m,8H,CHAr);7.74(m,8H,CHAr);8.03(s,
The DAB-PPI-(NH2)4 (0.120 g, 0.373 mmol) or DAB-PPI-(NH2)8 4H,CHimine).13C{1H}NMR(100MHz,CDCl3)d(ppm)¼9.35;23.56;
(0.526g,0.680mmol)dendriticscaffoldwasdissolvedinethanol 24.64;26.25;51.57;59.72;123.68;123.74;126.50;126.93;128.30;
(G1: 10.0 mL; G2: 50.0 mL) followed by the addition of naph- 128.77; 130.48; 133.37; 135.60; 135.64; 145.66. Melting point:
thaldehyde(G1:0.237g,1.52mmol;G2:0.853g,5.46mmol).The 220e224 (cid:4)C. Elemental Analysis (%): Calc. For C100H120Cl4N6Rh4
reactionmixturewasallowedtostirfor72e96hafterwhichthe (1959.54):C,61.29;H,6.17;N,4.29;Found:C,61.17;H,6.02;N,4.93.
solventwasremovedonarotaryevaporatorandtheresiduewas MS(HR-ESI,m/z):1923.4751[M(cid:2)Cl] þ ;1959.4369[M] þ .
dissolvedinDCM(30.0mL)andwashedwithbrine(15(cid:3)30.0mL).
Theorganiclayerwascollected,driedoveranhydrousMgSO4and [(Cp*IrCl)4 G1 ](2)
then filtered by gravity. The solvent was removed on a rotary Yelloweorangesolid.Yield¼0.0230g(42%).IR(KBrpellet)n(C]
evaporatortoyieldthedesiredproductsaswhitesolids. N)1602cm
(cid:2)1.1HNMR(400MHz,CDCl3)d(ppm)¼1.50(m,8H,
NCH2CH2CH2Nbranch);1.75(m,8H,NCH2CH2core);1.65(s,60H,Cp*);
(G1
) 2.11(m, 4H,NCH2CH2 core);2.49 (brm,8H,NCH2CH2CH2Nbranch);
White solid. Yield ¼ 0.216 g (67%). IR (KBr pellet) n(C]N) 4.12(m,8H,NCH2CH2CH2Nbranch);7.26(brt,8H,CHAr);7.39(brt,8H,
1639 cm (cid:2)1. 1H NMR (400 MHz, CDCl3) d (ppm) ¼ 1.49 (m, 4H, CHAr); 7.73 (br t, 8H, CHAr); 8.02 (br t, 8H, CHAr); 8.29 (br s, 4H,
NCH2CH2 core); 1.89 (m, 8H, NCH2CH2CH2Nbranch); 2.46 (br t, 4H, CHimine). 13C{1H} NMR (100 MHz, CDCl3) d (ppm) ¼ 9.15; 25.64;
NCH2CH2core);2.57(brt,8H,NCH2CH2CH2Nbranch);3.68(brt,8H, 26.35;28.16;51.60;60.96;122.87;123.40;126.47;126.98;128.88;
NCH2CH2CH2Nbranch);7.47(m,8H,CHAr);7.81(brt,12H,CHAr);7.95 130.09; 131.87; 136.60; 141.18; 141.37; 146.27. Melting point:
(m,8H,CHAr);8.40(brd,4H,CHimine).Meltingpoint:104e108(cid:4)C. 226e232 (cid:4)C. Elemental Analysis (%): Calc. for C100H120Cl4Ir4N6
13C{1H} NMR (100 MHz, CDCl3) d (ppm) ¼ 25.25; 28.40; 51.74; (2316.78):C,51.84;H,5.22;N,3.63;Found:C,51.10;H,5.31;N,3.16.
54.11; 59.74; 123.88; 126.36; 126.97; 127.83; 128.41; 128.57;
MS(HR-ESI,m/z):1122.3962[M(cid:2)2Cl]2þ ,1159.3489[Mþ2H]2þ
.
129.66;133.14;134.05;134.64;161.06.ElementalAnalysis(%):Calc.
ForC60H64N6(869.21):C,82.91;H,7.42;N,9.67;Found:C,81.44;H, [(Cp*RhCl)8 G2 ](3)
7.78;N,9.43.MS(LR-ESI,m/z):322.20[Mþ3H þþ3MeOH]3þ . Redeorangesolid.Yield¼0.240g(80%).IR(KBrpellet)n(C]N)
1610 cm (cid:2)1. 1H NMR (400 MHz, CDCl3) d (ppm) ¼ 0.8 (m, 4H,
(G2
) NCH2CH2core);1.18(m,8H,NCH2CH2CH2N1stbranch);1.56(s,120H,
White solid. Yield ¼ 0.842 g (66%). IR (KBr pellet) n(C]N) Cp*); 1.89 (br m,16H, NCH2CH2CH2N2nd branch); 2.20 (br m, 36H,
1639 cm (cid:2)1. 1H NMR (400 MHz, CDCl3) d (ppm) ¼ 1.33 (m, 4H, NCH2CH2 core, NCH2CH2CH2N1st branch, NCH2CH2CH2N1st branch,
NCH2CH2core);1.53(m,8H,NCH2CH2CH2N1stbranch);1.80(m,16H, NCH2CH2CH2N2nd branch): 3.97 (splitting, 16H, NCH2CH2CH2N2nd
NCH2CH2CH2N2ndbranch);2.37(overlappingm,20H,NCH2CH2core, branch);7.20(m,16H,CHAr);7.34(m,8H,CHAr);7.65(m,16H,CHAr);
NCH2CH2CH2N1st branch, NCH2CH2CH2N1st branch); 2.47 (br t, 16H, 7.88(m,8H,CHAr);7.93(brs,8H,CHimine).13C{1H}NMR(100MHz,
NCH2CH2CH2N2ndbranch);3.58(brt,16H,NCH2CH2CH2N2ndbranch); CDCl3) d (ppm) ¼ 9.41; 10.70; 12.80; 26.00; 45.88; 51.83; 52.97;
7.37(m,16H,CHAr);7.70(m,24H,CHAr);7.86(m,16H,CHAr);8.36 54.16;59.90;93.20;95.70;123.73;125.0;126.43;126.91;128.22;
(d,8H,CHimine).13C{1H}NMR(100MHz,CDCl3)d(ppm)¼24.75; 128.83; 130.48; 135.52; 143.36. Melting point: 178e180 (cid:4)C.
25.20; 28.48; 51.77; 52.37; 53.40; 54.26; 59.79; 123.88; 126.34; Elemental Analysis (%): Calc. for C208H256Cl8N14Rh8 (4059.27 g/
126.95; 127.82; 128.39; 128.56; 129.67; 133.13; 134.05; 134.62; mol):C,61.54;H,6.36;N,4.83;Found:C,60.76;H,6.46;N,4.45.MS
160.99.Meltingpoint:64e67(cid:4)C.ElementalAnalysis(%):Calc.For (HR-ESI,m/z):640.9327[M(cid:2)6Cl]6þ
.
C128H144N14(1878.64):C,81.84;H,7.73;N,10.44;Found:C,80.54;
H,7.54;N,10.37.MS(LR-ESI,m/z):408.20[Mþ5H þþMeOH]5þ . [(Cp*IrCl)8 G2 ](4)
Redeorangesolid.Yield¼0.243g(79%).IR(KBrpellet)n(C]N)
Generalsynthesisofthemetallodendrimers 1600 cm (cid:2)1. 1H NMR (400 MHz, CDCl3) d (ppm) ¼ 1.40 (m, 4H,
NCH2CH2core);1.48(m,8H,NCH2CH2CH2N1stbranch);1.60(s,120H,
ThenaphthaldiminedendrimerG1(1:0.0492g,0.0566mmol; Cp*); 1.86 (br m,16H, NCH2CH2CH2N2nd branch); 1.94 (br m, 36H,
2: 0.0205 g, 0.0236 mmol) or dendrimer G2 (3: 0.109 g, NCH2CH2core,NCH2CH2CH2N1stbranch,NCH2CH2CH2N1stbranch);2.50
0.0579 mmol; 4: 0.121 g, 0.0645 mmol), sodium acetate (br m, 16H, NCH2CH2CH2N2nd branch); 4.00 (br m, 16H,
(1:0.0186g,0.227mmol;2:0.0081g,0.0987mmol;3:0.0386g, NCH2CH2CH2N2nd branch);7.32 (m,16H,CHAr);7.65 (m,8H,CHAr);
0.470 mmol; 4: 0.0432 g, 0.527 mmol) and the [Cp*RhCl2]2 7.93(m,16H,CHAr);8.45(brs,8H,CHimine).13C{1H}NMR(100MHz,
(1: 0.0700 g, 0.113 mmol; 3: 0.144 g, 0.232 mmol) or [Cp*IrCl2]2 CDCl3) d (ppm) ¼ 9.17; 20.97; 24.33; 29.15; 51.11e53.19; 60.86;
(2: 0.0376 g, 0.0472 mmol; 4: 0.205 g, 0.258 mmol) dimer were 126.43; 127.08; 127.65; 128.99; 130.04; 131.9; 134.86; 136.55;
stirredtogetherinDCMormethanol(20.0mL)for24h(for1and2) 146.98.Meltingpoint:180e182(cid:4)C.ElementalAnalysis(%):Calc.for
or for 48 h (for 3 and 4) at room temperature, after which the C208H256Cl8Ir8N14(4773.79g/mol):C,52.33;H,5.40;N,4.11;Found:
84 L.C.Suddingetal./JournalofOrganometallicChemistry774(2014)79e85
C,51.460;H,5.27;N,4.54.MS(HR-ESI,m/z):761.7429[M(cid:2)6Cl]6þ ; were refined with isotropic temperature factors and the phenol
1152.3954[M(cid:2)4Cl]4þ . ringwasfittedtoaregularpentagon.Thehydrogenatomsofthe
solventmoleculewereexcludedinthestructuremodel.Crystallo-
Synthesisofthemononuclearcomplexes graphicdetailsaresummarisedinTable1.
Crystal of complex 6 was mounted on a Stoe Image Plate
The naphthaldimine ligand L1 (5: 0.0409 g, 0.207 mmol; 6: Diffraction system equipped with a f circle goniometer, using
0.0408g,0.207mmol),sodiumacetate(5:0.0339g,0.413mmol;6: MoKagraphitemonochromatedradiation(l¼0.71073Å)withf
0.0343g,0.418mmol)andthe[Cp*RhCl2]2(0.0634g,0.102mmol) range0e200(cid:4). The structurewas solved bydirect methodsusing
or[Cp*IrCl2]2(0.0810g,0.102mmol)dimerwerestirredtogetherin theprogramSHELXS-97,whiletherefinementandallfurthercal-
DCMormethanol(20.0mL)for2hatroomtemperature.There- culationswerecarriedoutusingSHELXL-97[14].TheH-atomswere
actionmixturewasfilteredthroughCelite,washingwithDCMor includedincalculatedpositionsandtreatedasridingatomsusing
methanol.Thesolventwasremovedtoobtainthecrudeproduct. the SHELXL default parameters. The non-H atoms were refined
This was then washed with diethyl ether to obtain the desired anisotropically, using weighted full-matrix least-square on F2.
product as an orangeered (5) or orangeebrown (6) solid. The Crystallographic details are summarized in Table 1. Fig. 2 was
Rh(III) complex 5 was recrystallised from toluene and hexane by drawnwithORTEP[56].
slowevaporationandtheIr(III)complex6wasrecrystallisedfrom
methanolandhexane. Cytotoxicitystudy
[Cp*RhClL1](5) ThehumanA2780andA2780cisRovariancarcinomacelllines
Orangeeredsolid.Yield¼0.0480g(50%).IR(KBrpellet)n(C]N)
wereobtainedfromtheEuropeanCollectionofCellCultures(Sal-
1610cm
(cid:2)1.1HNMR(400MHz,CDCl3)d(ppm)¼1.01(t,3J¼7.4Hz,
isbury,UK).CellsweregrownroutinelyinRPMI-1640mediumwith
3H,NCH2CH2CH3); 1.69 (s,15H,Cp*);1.93 (m,1H,NCH2CH2CH3); 10% foetal calf serum (FCS) and antibiotics at 37 (cid:4)C and 5% CO2.
2.11(m,1H,NCH2CH2CH3);3.72(m,1H,NCH2CH2CH3);4.12(m,1H, Cytotoxicity was determined using the MTT assay (MTT ¼ 3(4,5
NCH2CH2CH3);7.29(t,3J¼6.9Hz,1H,CHAr);7.44(t,3J¼6.8Hz,1H, dimethyl2-thiazolyl)-2,5-diphenyl-2H-tetrazoliumbromide).Cells
CHAr);7.74(m,2H,CHAr);7.90(s,1H,CHAr);8.06(s,1H,CHAr);8.23 were seeded in 96-well plates as monolayers with 100 mL of cell
(s,1H, CHimine).13C{1H} NMR (100 MHz, CDCl3) d (ppm) ¼ 11.75; solution(approximately20,000cells)perwellandpre-incubated
63.98; 95.70; 123.84; 126.60; 127.06; 128.70; 129.16; 129.57; for 24 h in medium supplemented with 10% FCS. Compounds
130.50; 134.63; 135.68; 145.21; 171.69; 192.35. Melting point: were prepared as DMSO solution then dissolved in the culture
168e170 (cid:4)C. Elemental Analysis (%): Calc. For C24H29ClNRh mediumandimmediatelyseriallydilutedtotheappropriatecon-
(469.86):C,61.35;H,6.22;N,2.98;Found:C,61.81;H,6.16;N,2.58. centration, to give a final DMSO concentration of 0.5%. A 100 mL
MS(LR-ESI,m/z):434.23[M(cid:2)Cl] þ . portionofdrugsolutionwasaddedtoeachwellandtheplateswere
incubatedforanother72h.Subsequently,MTT(5mg/mLsolution)
[Cp*IrClL1](6) wasaddedtothecellsandtheplateswereincubatedforafurther
Orangeebrown solid. Yield ¼ 0.0800 g (71%). IR (KBr pellet) 2h.Theculturemediumwasaspirated,andthepurpleformazan
n(C]N)1603 cm (cid:2)1.1HNMR(400MHz,CDCl3)d(ppm)¼1.03(t, crystals formed by the mitochondrial dehydrogenase activity of
3J ¼ 7.2 Hz, 3H, NCH2CH2CH3); 1.80 (s, 15H, Cp*); 1.98 (m, 1H, vital cells were dissolved in DMSO. The optical density, directly
NCH2CH2CH3); 2.12 (m, 1H, NCH2CH2CH3); 3.93 (m, 1H, proportional to the number of surviving cells, was quantified at
NCH2CH2CH3);4.11(m,1H,NCH2CH2CH3);7.27(t,3J¼6.8Hz,1H, 590nmusingamultiwellplatereaderandthefractionofsurviving
CHAr);7.42(t,3J¼6.7Hz,1H,CHAr);7.74(m,2H,CHAr);8.01(s,1H, cellswascalculatedfromtheabsorbanceofuntreatedcontrolcells.
CHAr); 8.06 (s, 1H, CHAr); 8.44 (s, 1H, CHimine). 13C{1H} NMR Evaluationisbasedonmeansfromtwoindependentexperiments,
(100MHz,CDCl3)d(ppm)¼22.77;65.23;88.51;123.50;126.57;
eachcomprisingthreemicroculturesperconcentrationlevel.
127.07; 128.37; 128.83; 130.10; 132.06; 136.60; 145.21; 171.69;
192.35. Melting point: 206e208 (cid:4)C. Elemental Analysis (%): Calc. Acknowledgements
ForC24H29ClIrN(559.17):C,51.55;H,5.23;N,2.50;Found:C,51.83;
H,5.35;N,2.63.MS(LR-ESI,m/z):524.40[M(cid:2)Cl] þ . Financial support from the University of Cape Town, the Na-
tionalResearchFoundation(NRF)ofSouthAfrica(UID:66054),and
Single-crystalX-raystructureanalyses agenerousloanofrhodiumandiridiumtrichloridefromJohnson
Matthey/AngloAmericanPlatinumLimitedCorporationaregrate-
Single-crystal X-ray diffraction data for complex 5 were fully acknowledged. The Swiss-South African Joint Research Pro-
collected on a Bruker KAPPA APEX II DUO diffractometer using grammeisalsothankedforashort-termexchangegrantbetween
graphite-monochromated MoKa radiation (c ¼ 0.71073 Å). Data thethreelaboratories.
collectionwascarriedoutat173(2)K.Temperaturewascontrolled
by an Oxford Cryostream cooling system (Oxford Cryostat). Cell AppendixA. Supplementarymaterial
refinementanddatareductionwereperformedusingtheprogram
SAINT [52]. The data were scaled and absorption correction per- CCDC 1018362 5$toluene and 1025190 6 contain the supple-
formedusingSADABS2.Thestructurewassolvedbydirectmethods
mentary crystallographic data for this paper. These data can be
usingSHELXS-972andrefinedbyfull-matrixleast-squaresmethods
obtainedfreeofchargefromTheCambridgeCrystallographicData
basedonF2usingSHELXL-97[53]andusingthegraphicsinterface
Centreviawww.ccdc.cam.ac.uk/data_request/cif.
programX-Seed[54,55].Allnon-hydrogenatoms,exceptthoseof
the solvent molecule, were refined anisotropically. All hydrogen References
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