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Neutral and cationic multinuclear half-sandwich rhodium and iridium complexes coordinated to poly(propyleneimine) dendritic scaffolds: Synthesis and cytotoxicity
JournalofOrganometallicChemistry729(2013)20e27
ContentslistsavailableatSciVerseScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Neutral and cationic multinuclear half-sandwich rhodium and iridium
complexes coordinated to poly(propyleneimine) dendritic scaffolds:
Synthesis and cytotoxicity
Richard Paynea, Preshendren Govendera, Bruno Therrienb, Catherine M. Clavelc, Paul J. Dysonc,
Gregory S. Smitha,*
aDepartmentofChemistry,UniversityofCapeTown,PrivateBag,Rondebosch7701,SouthAfrica
bInstitutdeChimie,UniversitédeNeuchâtel,AvenuedeBellevaux51,CH-2000Neuchâtel,Switzerland
cInstitutdesSciencesetIngénierieChimiques,EcolePolytechniqueFédéraledeLausanne(EPFL),CH-1015Lausanne,Switzerland
a r t i c l e i n f o a b s t r a c t
Articlehistory: Thedevelopmentofmultinuclearpentamethylcyclopentadienyl(Cp*)rhodiumandiridiumcomplexes
Received17October2012 from first- and second-generation 2-iminopyridyl and salicylaldimine based poly(propyleneimine)
Receivedinrevisedform dendrimerscaffoldsofthetype,DAB-(NH2)n(n¼4or8,DAB¼diaminobutane)hasbeenaccomplished.
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Eightcompoundsweresynthesised,viz.(Cp*MCl)4Gn(1e8),byfirstreactingDAB-(NH2)nwitheither2-
pyridinecarboxaldehyde or salicylaldehyde and subsequently metallating the Schiff-base dendrimers
with[Cp*MCl2]2(whereM¼Rh,Ir).Relatedmononuclearcomplexes[Cp*MCl(L)](L¼iminopyridylor
Keywords: salicylaldimine)(9e12)wereobtainedinasimilarmanner.Themolecularstructuresof9e12havebeen
Bioorganometallicchemistry
determinedbysingle-crystalX-raydiffractionanalysisandtheinvitroanticanceractivitiesof1e12were
Poly(propyleneimine)
Rhodium evaluatedagainsttheA2780andA2780cisRhumanovariancarcinomacelllines.
Iridium
(cid:1)2013ElsevierB.V.Allrightsreserved.
Dendrimers
Anticancerdrugs
1. Introduction molecules fromthe blood is restricted bythe normal endothelial
layer surrounding the blood vessels. Furthermore, the lack of
Despite the clinical success of cisplatin and later generation a lymphatic drainage system for tumour tissues results in an
platinumdrugs,theirlimitedselectivitytowardtumourtissueand accumulationofthedrugmacromolecules.
high toxicity has lead to interest in compounds based on other Metallodendrimers, i.e. metal-containing macromolecules, can
transition metals as anticancer chemotherapeutic agents [1]. Ex- beusedtoexploitsizeselectiveuptakeofdrugsintotumourcells,
amples of these include complexes based on titanium [2], ruthe- and have, recently found potential as diagnostic agents and as
nium[3],osmium[4],gold[5],rhodium[6],iridium[7]aswellas chemotherapeutics[11].Inlinewiththisstrategy,themultivalent/
others. Metal-based drugs containing rhodium and iridium are multinuclear nature of metallodendrimers can enhance in-
sparse and recent work suggests that these compounds lend teractions between a dendrimer-drug conjugate and a target
themselvestodevelopmentasnovelanticancerdrugs[8]. bearing multiple receptors, which in turn further improves the
Abiomedicalstrategyusedtoselectivelytargettumoursmakes selectivity to cancer cells. Indeed, the biological properties of
useofmacromoleculessuchasdendrimersorproteins[9].These numerouspolymetalliccompoundshavebeenreportedinthelit-
macromolecules target cancer cells selectively through the erature[12].
‘enhanced permeability and retention’ effect, a phenomenon in Recently, we have prepared a series of ruthenium-arene met-
whichmacromoleculescanpermeatethroughtheporoustumour allodendrimers,demonstratingaclearcorrelationbetweenthesize
vasculatureasaresultofanincreaseinbloodvesselpermeability of the metallodendrimerandits cytotoxicity[13].To gainfurther
within diseasedtissues [10].Forhealthy tissues, the migration of insightonthebiologicalactivityasafunctionofthemetal,wehave
now synthesised half-sandwich rhodium and iridium analogues.
Thecytotoxicitiesoftherhodiumandiridiummetallodendrimers
* Correspondingauthor.Tel.:þ27216505279;fax:þ27216505195. havebeenestablishedusinghumanovarianA2780(cisplatinsen-
E-mailaddress:gregory.smith@uct.ac.za(G.S.Smith). sitive)andA2780cisR(cisplatinresistant)cancercelllinesandtheir
0022-328X/$eseefrontmatter(cid:1)2013ElsevierB.V.Allrightsreserved.
http://dx.doi.org/10.1016/j.jorganchem.2013.01.009
R.Payneetal./JournalofOrganometallicChemistry729(2013)20e27 21
antiproliferative activity compared to related ruthenium-arene solvents such as dichloromethane, chloroform, ethanol, dime-
metallodendrimer. thylsulfoxideandacetone.
Uponcomplexationofeitherrhodiumoriridium,the1HNMR
spectra of the tetranuclear complexes display broadened peaks,
2. Resultsanddiscussion
with the aliphatic protons of the dendritic core and side arms
2.1.
Synthesisandcharacterisationofsalicylaldimine-(G1 ,G2
)and
occurring at similar shifts to those of the dendritic precursors. A
iminopyridyl-functionalised(G3 ,G4
)dendrimers
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9.10 ppm suggests coordination of the metal to the aromatic ni-
AseriesofperipherallymodifiedSchiff-basedligandsbasedon
trogenatominthe2-pyridylcomplexes.Thereisalsoadistinctshift
a poly(propyleneimine) scaffold were synthesised following pub-
oftheimineprotonsignalsuggestingcoordinationatthisposition.
lished literature methods [14]. The salicylaldimine-functionalised The 1H NMR spectra for the second-generation complexes show
first- and second-generation dendrimers (G1eG2) were syn-
similarshiftstothefirst-generation.Infraredspectroscopicstudies
8 the fo s r ise G d 1 b a y n t d he G r 2 e , a r c e t s io p n ec o t f iv s e a l l y ic ). yl T a h ld e eh fi y rs d t e - w an it d hD se A c B o - n (N d- H g 2 e ) n n e ( r n at ¼ io 4 n , 1 sh 6 o 15 wa c s m h (cid:2) if 1 tin fo th r e( t C h ] e N s ) a im li i c n y e l p al e d a i k m t i o ne alo c w o e m r p w le a x v e e s nu a m n b d er a a r r o o u u n n d d
t im he i s n i o se p d yri b d y yl t - h fu e n r c e t a io c n ti a o l n ise o d f 2- d p e y n ri d d r i i n m e e c r a s rbo ( x G a 3 l e de G h 4 y ) de w w e i r t e h D s A yn B - - a 16 b 3 so 0 rp c t m io (cid:2) n 1 b f a o n r ds th c e an 2 b -p e y o ri b d s y e l r i v m e i d ne for co t m he p l l i e g x a e n s d . T a h t e ca ( . C 1 ] 55 N 0 )p c y m rid (cid:2) y 1 l
(NH2)n(n¼4,8forG3andG4,respectively)(Fig.1).
andaround1600cm
(cid:2)1forthemetalcomplexesintheIRspectra.
Thesecondgenerationdendriticcomplexesshowsimilartrends.
2.2. Synthesisandcharacterisationofrhodiumandiridium The analogous mononuclear rhodium and iridium complexes
metallodendrimers1e8 (9e12) were prepared for comparison as model analogues. They
weresynthesisedbyreactingsalicylaldimine(L1)or2-pyridylimine
The dinuclear pentamethylcyclopentadienyl (Cp*) rhodium or (L2) with the dinuclear Cp* rhodium or iridium complexes
iridiumcomplexes[Cp*MCl2]2(M¼RhorIr)werereactedwiththe [Cp*MCl2]2(M¼Rh,Ir)indichloromethaneatroomtemperature
dendrimers G1eG4 at room temperature in dichloromethane (Scheme1).
(neutral complexes) or ethanol:dichloromethane (cationic com- The mononuclear metal complexes (9e12) are isolated as
plexes) to yield either neutral or cationic tetranuclear and octa- yelloweorange solids in moderateyields. They are air-stable and
nuclearrhodiumandiridiummetallodendrimers(1e8)(Fig.2).The soluble in dichloromethane (neutral only), chloroform (neutral
yelloweorangecompounds(1e8)areisolatedasair-stablesolidsin only), ethanol, dimethylsulfoxide and acetone. The imineprotons
moderate yields (23e72%). The complexes are soluble in organic displayadistinctshiftrelativetothefreeligand(8.30ppmto8.87e
Fig.1. First-andsecond-generationofsalicylaldimine(G1,G2)andiminopyridyl(G3,G4)dendrimers.
22 R.Payneetal./JournalofOrganometallicChemistry729(2013)20e27
2.3. X-raydiffractionstudiesofcomplexes9e12
X-rayqualitycrystalsfor9e12wereobtainedbyslowdiffusion
ofdiethyletherintoaconcentrateddichloromethanesolutionof9
or10andaconcentratedacetonesolutionof11or12.Themolec-
ularstructuresof9and10showthatthemetalcoordinatestothe
oxygenandtheiminenitrogen,whilethemolecularstructuresof11
and 12 show that the metal coordinates to the pyridyl nitrogen
atomandtheiminenitrogenatom.ORTEPdrawingsof9and10are
showninFig.3and11and12areshowninFig.4withselectedbond
lengths and angles given inTable 1. Foreach complex, the metal
centreisstereogenic,however,allcomplexeshavebeenisolatedas
racemicmixtures.Theyallcrystallizeinthecentrosymmetricspace
group P 21/n with only one molecule per asymmetric unit. The
crystallographicdetailsaregiveninTable3.
Allcomplexesshowthemetalcentretoadopttheso-calledpi-
ano-stoolgeometry,withthemetalbeingcoordinatedtothepen-
tamethylcyclopentadienylligand,onechlorideatom,andtheNXO
(9and10)orNXN(11and12)chelatingligand.In9and10,theMe
NandNeOdistancesaresimilartothosefoundinanalogousNXO
complexesofCp*rhodiumandiridium[15,16],whilein11and12
the MeN distances follow the same trend as those observed in
related NXN complexes [17]. Overall, all geometrical parameters
areasanticipated.
2.4. Anticanceractivityofcomplexes1e12
The antiproliferative activity of 1e12 was evaluated in vitro
againsttheA2780andA2780cisRovariancancercelllinesusingthe
MTTassaywhichmeasuresmitochondrialdehydrogenaseactivity
asanindicationofcellviability.TheIC50values(inhibitionofcancer
Fig.2. Tetra-andoctanuclearCp*rhodiumandiridiumdendriticcompounds1e8. cellgrowthatthe50%level)arelistedinTable2andwerecalcu-
latedasanaverageoverthetwoindependentexperiments.
Thepolynuclearcompoundsgenerallydisplaymoderatetohigh
anti-proliferative activity in the A2780 (cisplatin sensitive) and
9.35ppmfor2-pyridylimine;8.23ppmto7.79e7.84ppmforsali- A2780cisR(cisplatin resistant)cell lines.The correlation between
cylaldimine), suggesting coordination occurring at the imine ni- thesizedependencyofthemetallodendrimersandthecytotoxicity,
trogen,whilethearomaticprotonadjacenttothepyridylnitrogen whichwepreviouslyreportedforanalogousrutheniumcomplexes
atom in the 2-pyridyl complexes appears more downfield than [13] and others observed too for related dinuclear complexes
fortheuncoordinatedligand(8.56ppme9.10ppm).Ashiftinthe [12b,c],isevidentforcomplexes1e8.Themononuclearcomplexes
(C]N)pyridylabsorptionbandintheIRspectrumof11and12isseen show moderate to poor activity, whereas the octanuclear com-
fromaround1568cm
(cid:2)1to1605cm (cid:2)1.The(C]N)imineabsorption
plexesarehighlycytotoxic.Incertaincases,thecationiccomplexes
bandaround1652cm
(cid:2)1shiftstoaround1635cm (cid:2)1andconfirms
are morecytotoxic than their neutral congeners. Notably, the ac-
thatcoordinationoccurredatthissite. tivity of these metallodendrimers is comparable with the arene-
Scheme1. Synthesisofthemononuclearpentamethylcyclopentadienylrhodiumandiridiumcomplexes9e12.
R.Payneetal./JournalofOrganometallicChemistry729(2013)20e27 23
Fig.3. Molecularstructureofthemononuclearcomplexes9(left)and10(right)showingellipsoidsatthe50%probabilitylevel.
ruthenium(II) complexes attached to similar dendritic scaffolds cyclopentadienyl complex found to be the most active. As noted
[13b]. All complexes display poorer biological activity in the cis- before, this study shows a clear correlation between the size de-
platin resistant cell line except 7, 9,10, [11](PF6) and [12](PF6). pendencyofthemetallodendrimeranditscytotoxicity,andinter-
Metallodendrimer8isthemostactivecompound(IC50 ¼0.75mM) estingly,themostactivecompoundsbasedonrhodiumandiridium
amongtheseries,followedby4(IC50 ¼2.6mMinA2780cells)and6 have comparable activities to the most active related ruthenium
(IC50 ¼ 3.3 mM in A2780). However, from these studies it is not andosmiumsystems.
possibletosaythattheiridium-basedcompoundsaremoreactive
than their rhodium counterparts. Importantly, the metal- 4. Experimental
lodendrimers are consistently selective toward cancer cell lines
(A2780/A2780cisR)overtheHEKcells. 4.1. Generalremarks
3. Conclusions All reagentswere purchased fromSigmaeAldrichand used as
received.[Cp*MCl2]2(M¼Rh,Ir)[18],G1eG4[14]andL1eL2[14]
A series of chelating neutral and cationic first- and second- were prepared according to published literature methods. Nu-
generation rhodium(III) and iridium(III) complexes based onpol- clearmagneticresonance(NMR)spectrawererecordedonaVarian
y(propyleneimine) dendrimer scaffolds have been prepared and UnityXR400spectrometer(1H:399.95MHz;13C{1H}:100.58MHz;
characterised. These compounds are air-stable and consequently orVarianMercuryXR300spectrometer(1H:300.08MHz;13C{1H}:
their anticancer activity was evaluated in vitro. In general, the 75.46 MHz; or Bruker Biospin GmbH spectrometer (1H:
chelatingrhodiumandiridiummetallodendrimersshowsuperior 400.22 MHz; 13C{1H}: 100.65 MHz; at ambient temperature.
activity than analogous mononuclear rhodium and iridium com- Infrared(IR)spectraweremeasuredonaPerkineElmerSpectrum
plexes and comparable activity to ruthenium metallodendri- 100 FT-IR spectrometeras KBr pellets or in NaCl solution cells in
mers reported previously, with the octanuclear cationic iridium dichloromethane.Elementalanalysis(C,H,N)wascarriedoutusing
Fig.4. Molecularstructureofthemononuclearcomplexes11(left)and12(right)showingellipsoidsatthe50%probabilitylevelwithPF6 (cid:2)anionbeingomittedforclarity.
24 R.Payneetal./JournalofOrganometallicChemistry729(2013)20e27
Table1 NCH2CH2CH2Nbranch), 2.96 (br m, 12H, NCH2CH2core, NCH2CH2
Selectedbondlengthsandanglesfor9,10,[11](PF6)and[12](PF6). CH2Nbranch),4.05(brm,8H,NCH2CH2CH2Nbranch),6.42(brt,4H,Ar),
9 10 [11](PF6) [12](PF6)
6.88(brd,4H,Ar),7.16(brm,8H,Ar),8.10(brs,4H,HC]N).13C{1H}
Distances(
(cid:2)
A)
NMR(100MHz,CDCl3):d(ppm)¼8.6(Cp*CH3);21.7,25.7,49.9,
MeNpyridyl 2.070(2) 2.071(3) 2.1071(16) 2.095(4) 62.0, 63.8 (CH2); 92.9 (Cp* C); 114.3, 123.3, 134.2, 134.7 (CHAr);
MeNimine 2.1083(17) 2.088(4) 122.0,166.4(CAr);165.2(CHimine).Elementalanalysis(%):calc.for
M
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C84H112N6Rh4Cl4O4 $CH2Cl2 (2166.1): C, 46.58; H, 5.21; N, 3.88;
Mecentroid 1.776 1.768 1.783 1.791 found: C, 46.68; H, 6.44; N, 3.62. MS (HR-ESI-TOF, m/z): 876
Angles((cid:3)) [M(cid:2)2Cl]2þ .Meltingpoint:144(cid:3)Ce148(cid:3)C.
Npyridyl eMeNimine 76.79(7) 76.35(14)
N N p p y y r r i i d d y y l l e e M M e e O Cl 8 8 7 6 . . 4 5 5 9 ( ( 9 8 ) ) 8 8 6 5 . . 7 5 8 7 ( ( 1 1 4 4 ) ) 82.99(5) 81.80(10) 4.2. D 2. ar [ k (C r p e * d Rh s C o l l ) i 8 d G , 2 y ] i ( e 2 ld ) : 72.3%. IR: KBr pellets, n/cm (cid:2)1: 1621 (s,
O
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C
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88.75(6) 85.87(11)
90.22(5) 88.30(10) imine,C]N).1HNMR(400MHz,CDCl3):d(ppm)¼1.42(s,120H,
Cp* CH3), 1.84e3.16 (overlapping m, 64H, NCH2CH2core, NCH2
CH2core, NCH2CH2CH2N1st branch, NCH2CH2CH2N1st branch, NCH2CH2
aThermoFlash1112SeriesCHNS-OAnalyser.Meltingpointswere CH2N1st branch, NCH2CH2CH2N2nd branch, NCH2CH2CH2N2nd branch),
determined using a Büchi Melting Point Machine B-540. Electro- 4.07(brm,16H,NCH2CH2CH2N2ndbranch),6.41(brm,8H,Ar),6.84
spray ionisation mass spectrometry was carried out on a Waters (brd,8H,Ar),7.12(brt,8H,Ar),7.19(brm,8H,Ar),8.14(brm,8H,
SynaptG2massspectrometer.Datawererecordedinpositive-ion
HC]N).13C{1H}NMR(100MHz,CDCl3):d(ppm)¼8.8(Cp*CH3);
mode. 21.6,25.9,31.3,46.0,50.4,52.8,62.1,64.2(CH2);93.1(Cp*C);114.5,
123.7,134.5,135.0 (CHAr); 122.5,165.6 (CAr); 166.6 (CHimine). Ele-
4.2. Generalsynthesisoftheneutralcomplexes1e4
mental analysis (%): calc. for C176H240N14Rh8Cl8O8 $2CH2Cl2
(4389.8):C,48.16;H,5.51;N,4.47;found:C,48.21;H,6.60;N,4.13.
MS (HR-ESI-TOF, m/z): 811[M (cid:2) 4Cp*]4þ . Melting point: 151 (cid:3)Ce
Triethylamine (0.027 mL, 0.197 mmol for 1; 0.032 mL, 154(cid:3)C.
0.232 mmol for 3; 0.037 mL, 0.265 mmol for 2; 0.024 mL,
( 0 0 .1 .0 7 3 5 6 m g m , o 0 l .0 f 4 or 9 4 m ) m wa o s l a fo d r de 1 d ; d 0 r .0 o 4 p 3 wi g s , e 0 to .05 a 8 st m irr m ed ol so fo lu r ti 3 o ) n o o r f G G1 2 4.2. M 3. u [ s ( t C a p rd *I - r y C e l) ll 4 o G w 1 ] s ( o 3 l ) id,yield:22.6%.IR:KBrpellets,n/cm (cid:2)1:1621
(0.053 g, 0.033 mmol for 2; 0.035 g, 0.022 mmol for 4) in (s,imine,C]N).1HNMR(400MHz,CDCl3):d(ppm)¼1.48(s,60H,
dichloromethane(25.0mL).Theyellowsuspensionwasallowedto
Cp*CH3),1.90(brm,12H,NCH2CH2core,NCH2CH2CH2branch),2.44(br
stir at room temperature for 30 min. [Cp*RhCl2]2 (0.062 g,
m, 12H, NCH2CH2core, NCH2CH2CH2Nbranch), 4.12 (br m, 8H,
0.101mmolfor1;0.083g,0.134mmolfor2)or[Cp*IrCl2]2(0.098g,
NCH2CH2CH2Nbranch),6.38(brt,4H,Ar),6.80(brm,4H,Ar),7.21(br
0
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solvent was removed under reduced pressure and the remaining
r s e o s lv id e u n e tr t e a m ke o n ve u d p fr i o n m e t t h h e an fi o lt l r . a T te hi u s n m de i r xt r u e r d e uc w ed as p fi re lt s e s r u e r d e, a y n ie d ld t in h g e m C) in ; e 1 ). 15 E .0 le , m 12 e 2 n . t 4 a , l 1 a 3 n 4 a .1 l , y 1 si 3 s 4. ( 2 %) ( : CH ca A l r c ); . 1 fo 2 r 1.8 C , 8 1 4H 64 11 .8 2N ( 6 C I A r r 4 ) C ; l4 1 O 6 4 2 $ .2 CH (C 2C H l i 2 -
(2578.4):C,42.29;H,4.73;N,3.52;Found:C,42.86;H,6.20;N,3.66.
thedesiredproducts. MS(HR-ESI-TOF,m/z):2181[MþH] þ .Meltingpoint:152(cid:3)Ce157(cid:3)C.
4.2. O 1. ra [ n (C g p e * e R b h r C o l) w 4 G n 1 s ] o ( l 1 id ) ,yield:43.7%.IR:KBrpellets,n/cm (cid:2)1:1620 4.2. M 4. u [ s ( t C a p rd *I - r y C e l) ll 8 o G w 2 ] s ( o 4 l ) id,yield:63.4%.IR:KBrpellets,n/cm (cid:2)1:1619
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CH2core, NCH2CH2CH2N1st branch, NCH2CH2CH2N1st branch, NCH2CH2
Table2 CH2N1st branch, NCH2CH2CH2N2nd branch, NCH2CH2CH2N2nd branch),
IC50valuesofG1eG4and1e12onA2780andA2780cisRhumanovariancancercells, 4.12(brm,16H,NCH2CH2CH2N2ndbranch),6.40(brm,8H,Ar),6.81
andHEKcells. (brm,8H,Ar),7.19(brm,16H,Ar),8.14(brm,8H,HC]N).13C{1H}
Compound na A2780(IC50,mM) A2780cisR(IC50,mM) HEKb(IC50,mM) NMR(100Mhz,CDCl3):d(ppm)¼8.8(Cp*CH3);25.5,29.7,30.1,
G1 e 67(cid:4)2.3 67(cid:4)2.4 ND 46.0, 50.6, 51.2, 53.0, 64.5 (CH2); 85.1 (Cp* C); 115.2,122.3,134.3,
G2 e 32(cid:4)0.8 25(cid:4)0.1 ND 134.7(CHAr);116.7,164.8(CAr);162.6(CHimine).Elementalanalysis
G
G3
4
e
e
1
3
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7
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(cid:4)
(cid:4)
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5
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42
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(cid:4)
0
4.5
N
N
D
D
(%): calc. for C176H240N14Ir8Cl8O8 $2CH2Cl2 (5246.5): C, 40.29; H,
1 4 55(cid:4)2 126(cid:4)13 ND 4.61; N, 3.74; found: C, 40.20; H, 5.93; N, 3.20. MS (HR-ESI-TOF,
2 8 3.5(cid:4)0.2 4.12(cid:4)0.12 23.6(cid:4)2.5
m/z):990[M(cid:2)4Cp*]4þ .Meltingpoint:159(cid:3)Ce162(cid:3)C.
3 4 40(cid:4)2 60(cid:4)6 ND
4 8 2.6(cid:4)0.5 8.9(cid:4)1.2 10.2(cid:4)0.5 4.3. Synthesisofthecationiccomplexes[5](PF 6)4 e[8](PF 6)8
[5](PF6)4 4 40.8(cid:4)4.4 57.3(cid:4)3.4 ND
[ [ [ 8 6 7 ] ] ] ( ( ( P P P F F F 6 6 6 ) ) ) 8 4 8 8 4 8 3 0 6 . . 6 3 75 (cid:4) (cid:4) (cid:4) 5 0 . . 0 2 6 .01 3 9 3 3 . . 3 5 .8 1 (cid:4) (cid:4) (cid:4) 0 3 . 0 3 . . 8 13 N 2 2 8 2 D . . 6 2 (cid:4) (cid:4) 1 0 . . 3 7 for T 7 h ) e or lig G a 4 n ( d 0. G 05 3 4 (0 g .0 ,0 3 . 2 03 g 7 ,0 m .0 m 48 ol m fo m r o 6 l ; f 0 o . r 07 5 0 ;0 g . , 0 0 3 . 5 04 g 7 ,0 m .0 m 5 o 2 l m fo m r8 o ) l
9 1 105(cid:4)10 38(cid:4)4 ND wasdissolvedinethanol(5.0mL)andaddeddropwisetoastirred
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Cisplatin 1 1.5(cid:4)0.5 25(cid:4)2.5 ND 0.194mmolfor8)in2:1ethanol:dichloromethane(37.5mL).The
solution was allowed to stir for 72 h at room temperature. The
a n¼numberofmetalswithinthecompound.
b ND¼notdetermined;IC50valuesdeterminedforthemostactivecomplexes dichloromethane was removed under reduced pressure. The
againstanormal,non-cancerouscellline. resulting solution was then filtered and the filtrate reduced to
R.Payneetal./JournalofOrganometallicChemistry729(2013)20e27 25
Table3
Crystallographicandstructurerefinementparametersforcomplexes9,10,[11](PF6)and[12](PF6).
9 10 [11](PF6) [12](PF6)
Chemicalformula C20H27ClNORh C20H27ClNOIr C19H27ClF6N2PRh C19H27ClF6N2PIr
Formulaweight 435.79 525.08 566.76 656.05
Crystalsystem Monoclinic Monoclinic Monoclinic Monoclinic
Spacegroup P21/n(no.14) P21/n(no.14) P21/n(no.14) P21/n(no.14)
Crystalcolourandshape Orangeblock Orangeplate Orangeplate Yellowplate
Crystalsize 0.18(cid:5)0.15(cid:5)0.12 0.21(cid:5)0.16(cid:5)0.13 0.24(cid:5)0.19(cid:5)0.16 0.21(cid:5)0.16(cid:5)0.13
(cid:2)
a(A) 7.5500(2) 7.8217(5) 12.9880(5) 12.9766(4)
(cid:2)
b(A) 21.6281(8) 21.5806(19) 11.2305(3) 11.2328(2)
(cid:2)
c(A) 12.4141(4) 12.2917(8) 15.4034(5) 15.4677(4)
b((cid:3)) 106.450(3) 106.816(7) 92.929(3) 93.020(2)
V( (cid:2) A3) 1944.15(11) 1986.1(3) 2243.83(13) 2251.50(10)
Z 4 4 4 4
T(K) 173(2) 173(2) 173(2) 173(2)
Dc(gcm(cid:2)3) 1.489 1.756 1.678 1.935
m(mm(cid:2)1) 1.022 6.863 1.009 6.178
Scanrange(o) 1.88<q<29.18 2.56<q<26.03 1.57<q<29.19 1.57<q<29.17
Uniquereflections 5251 3651 6060 6083
Reflectionsused[I>2s(I)] 4256 2809 5496 5433
Rint 0.0745 0.0492 0.0369 0.0666
FinalRindices[I>2s(I)]a 0.0435,wR20.0679 0.0247,wR20.0548 0.0303,wR20.0573 0.0349,wR20.0807
Rindices(alldata) 0.0618,wR20.0720 0.0367,wR20.0570 0.0361,wR20.0589 0.0417,wR20.0833
Goodness-of-fit 1.094 0.886 1.135 1.083
Max,minDr(e (cid:2) A(cid:2)3) 0.940,(cid:2)0.980 1.045,(cid:2)1.107 1.522,(cid:2)0.736 2.257,(cid:2)2.044
a StructureswererefinedonF0 2:wR2 ¼[S[w(F0 2(cid:2)Fc 2)2]/Sw(F0 2)2]1/2,wherew(cid:2)1¼[S(F0 2)þ(aP)2þbP]andP¼[max(F0 2,0)þ2Fc 2]/3.
about5mL.NaPF6(0.034g,0.205mmolfor5;0.037g,0.219mmol (300MHz,(CD3)2CO):d(ppm)¼1.59(s,8H,NCH2CH2CH2Nbranch),
for7;0.050g,0.300mmolfor6;0.066g,0.391mmolfor8)was 1.71(brm,4H,NCH2CH2core),1.80(d,60H,Cp*CH3),2.39(brm,4H,
addedandthereactionwasstirredat0(cid:3)Cfor3h.Theflaskwasleft NCH2CH2core),3.00(brm,8H,NCH2CH2CH2Nbranch),4.57(brm,8H,
inthefreezerfor12htoprecipitatetheproduct,whichwasfiltered, NCH2CH2CH2Nbranch),7.97(brd,4H,Pyr),8.34(brm,8H,Pyr),9.11
washedwithethanolanddiethylether,anddriedundervacuum. (br t, 4H, Pyr), 9.45 (br s, 4H, HC]N). 13C{1H} NMR (100 MHz,
(CD3)2CO):d(ppm)¼8.1(Cp*CH3);90.2(Cp*C);23.8,24.7,51.0,
4.3.1. [(Cp*RhCl)4 G3 ](PF6)[5](PF 6)4 53.0, 60.9 (CH2); 129.4, 130.0, 140.5, 151.9 (CHpyr); 155.9 (Cpyr);
Yellowsolid,yield:62.8%.IR:KBrpellets,n/cm (cid:2)1:3448(b,NeH), 169.3 (CHimine). Elemental analysis (%): calc. for C80H112N10Ir4
1628(s,imine,C]N),1600(s,pyridyl,C]N),842(s,PeF).1HNMR Cl4P4F24 $1.5CH3CH2OH(3012.0):C,31.90;H,3.75;N,4.65;found:C,
(300MHz,(CD3)2CO):d(ppm)¼1.59(brm,4H,NCH2CH2core),1.76 31.90;H,4.03;N,3.69.MS(HR-ESI-TOF,m/z):531[M]4þ .Melting
(q,8H,NCH2CH2CH2Nbranch),1.81(s,60H,Cp*CH3),2.26(brm,4H, point:209(cid:3)Ce213(cid:3)C.
NCH2CH2core),2.81(brm,8H,NCH2CH2CH2Nbranch),4.30&4.51(br
m,8H,NCH2CH2CH2Nbranch),7.96(brt,4H,Pyr),8.30(brm,8H,Pyr), 4.3.4. [(Cp*IrCl)8 G4 ](PF6)8[8](PF 6)8
8.83(brd,4H,Pyr),9.11(brs,4H,HC]N).13C{1H}NMR(100MHz, Brownsolid,yield:66.9%.IR:KBrpellets,n/cm (cid:2)1:3453(b,NeH),
(CD3)2CO):d(ppm)¼8.5(Cp*CH3);97.5(Cp*C);23.4,24.5,50.8, 1628(s,imine,C]N),1601(s,pyridyl,C]N),840(s,PeF).1HNMR
53.2, 59.9 (CH2); 129.0, 129.5, 140.5, 152.3 (CHpyr); 153.9 (Cpyr); (300MHz,(CD3)2CO):d(ppm)¼1.31(brm,4H,NCH2CH2core),1.51e
167.8 (CHimine). Elemental analysis (%): calc. for C80H112N10Rh4 3.76 (overlapping m, 60H, NCH2CH2core, NCH2CH2CH2N1st branch,
Cl4P4F24 $2CH3CH2OH(2644.4):C,36.98;H,4.34;N,5.39;found:C, NCH2CH2CH2N1st branch, NCH2CH2CH2N1st branch, NCH2CH2CH2N2nd
36.32;H,4.48;N,4.00.MS(HR-ESI-TOF,m/z):441[M]4þ
.Melting branch,NCH2CH2CH2N2ndbranch),1.78(d,120H,Cp*CH3),4.41(brm,
point:184(cid:3)Ce187(cid:3)C. 16H,NCH2CH2CH2N2ndbranch),7.83(brm,8H,Pyr),8.16(brm,16H,
Pyr), 8.96 (br s, 8H, HC]N), 9.18 (br m, 8H, Pyr). 13C{1H} NMR
4.3.2. [(Cp*RhCl)8 G4 ](PF6)8[6](PF 6)8 (100MHz,(CD3)2CO):d(ppm)¼8.0(Cp*CH3);90.4(Cp*C);23.5,
Yellowsolid,yield:72.2%.IR:KBrpellets,n/cm (cid:2)1:3468(b,NeH), 51.1,60.9(CH2);129.3,130.3,140.6,155.5(CHpyr);152.0(Cpyr);169.6
1628(s,imine,C]N),1601(s,pyridyl,C]N),840(s,PeF).1HNMR (CHimine). Elemental analysis (%): calc. for C168H240N22Ir8Cl8P8
(300MHz,(CD3)2CO):d(ppm)¼1.29(brm,4H,NCH2CH2core),1.50e F48 $2CH3CH2OH(6075.8):C,33.21;H,3.98;N,5.07;found:C,33.18;
3.50 (overlapping m, 60H, NCH2CH2core, NCH2CH2CH2N1st branch,
H,4.64;N,4.52.MS(HR-ESI-TOF,m/z):549[M]8þ
.Meltingpoint:
NCH2CH2CH2N1st branch, NCH2CH2CH2N1st branch, NCH2CH2CH2N2nd 216(cid:3)Ce225(cid:3)C.
branch,NCH2CH2CH2N2ndbranch),1.79(s,120H,Cp*CH3),4.28&4.48
(brm,8H,NCH2CH2CH2N2ndbranch),8.10(brm,24H,Pyr),8.80(brm, 4.4. Synthesisofthemononuclearneutralcomplexes9e10
8H,Pyr),9.10(brs,8H,HC]N).13C{1H}NMR(100MHz,(CD3)2CO):
d(ppm)¼8.4(Cp*CH3);97.6(Cp*C);25.7,50.1e52.2,60.4(CH2); Triethylamine(0.094mL,0.679mmol)wasaddeddropwiseto
128.7,129.5,140.4,154.0(CHpyr);152.4(Cpyr);167.1(CHimine).Ele- a stirred solution of the ligand L1 (0.108 g, 0.656 mmol) in
mentalanalysis(%):calc.forC168H240N22Rh8Cl8P8F48 $CH3CH2OH dichloromethane (25 mL). The yellow suspension was stirred at
(5198.7):C,38.81;H,4.65;N,5.93;Found:C,38.66;H,5.28;N,5.32. roomtemperaturefor30min.[Cp*RhCl2]2(0.197g,0.319mmolfor
MS(HR-ESI-TOF,m/z):459[M]8þ .Meltingpoint:196(cid:3)Ce204(cid:3)C. 9) or [Cp*IrCl2]2 (0.258 g, 0.324 mmol for 10) was added to the
reactionmixtureandthereactionallowedtostirfor48hatroom
4.3.3. [(Cp*IrCl)4 G3 ](PF6)4[7](PF 6)4 temperature. The mixture was filtered and the solvent removed
Beigesolid,yield:53.7%.IR:KBrpellets,n/cm (cid:2)1:3447(b,NeH), fromthefiltrate,yieldingthecrudeproduct.Theproductwaspu-
1624(s,imine,C]N),1600(s,pyridyl,C]N),841(s,PeF).1HNMR rified by column chromatography (silica 63-200, 60 A), first
26 R.Payneetal./JournalofOrganometallicChemistry729(2013)20e27
washing through thoroughly with dichloromethane, then eluting 90.9 (Cp* C); 129.5,130.8,141.3,152.8 (CHpyr); 156.7 (Cpyr); 168.9
theproductwith40:1dichloromethane:ethanol.Thesolventwas (CHimine).Elementalanalysis(%):calc.forC19H27N2IrClPF6(656.1):
removedfromtheeluent,yieldingthepureproduct. C, 34.78; H, 4.15; N, 4.27; found: C, 34.51; H, 4.28; N, 3.82. MS
(ESI, m/z): 511 [M] þ where M ¼ [12](PF6) (cid:2) PF6. Melting point:
4.4.1. [Cp*RhClL1](9) 307(cid:3)Ce310(cid:3)C.
Orangesolid,yield:40.4%.IR:KBrpellets,n/cm (cid:2)1:1625(s,imine,
C]N).1HNMR(400MHz,CDCl3):d(ppm)¼1.02(t,3H,CH3),1.58 4.6. Single-crystalX-raystructureanalyses
(s,15H,Cp*CH3),1.79&2.17(brs,1H,NCH2CH2CH3),3.80&4.09(br
s,1H,NCH2CH2CH3),6.48(t,1H,Ar),6.99(d,1H,Ar),7.05(d,1H,Ar), Crystals of compounds 9e12 were mounted on a Stoe Image
7.21(t,1H,Ar),7.84(s,1H,HC]N).13C{1H}NMR(100MHz,CDCl3): PlateDiffractionsystemequippedwithafcirclegoniometer,using
d(ppm)¼8.8(Cp*CH3);11.6(CH3);23.9,65.6(CH2);92.7(Cp*C); Mo-Kagraphitemonochromatedradiation(l¼0.71073 (cid:2) A)withf
114.2,123.9,133.8,134.0(CHAr);122.0,166.7(CAr);162.4(CHimine). range0e200(cid:3).Thestructuresweresolvedbydirectmethodsusing
Elementalanalysis(%):calc.forC20H27NRhClO(435.8):C,55.12;H, theprogramSHELXS-97,whiletherefinementandallfurthercal-
6.24;N,3.21;found:C,54.85;H,6.20;N,2.82.MS(ESI,m/z):400 culationswerecarriedoutusingSHELXL-97[19].TheH-atomswere
[M(cid:2)Cl] þ .Meltingpoint:211(cid:3)Ce215(cid:3)C. foundonFourierdifferencemaporincludedincalculatedpositions
andtreatedasridingatomsusingtheSHELXLdefaultparameters.
4.4.2. [Cp*IrClL1](10) Thenon-Hatomswererefinedanisotropically,usingweightedfull-
Orangesolid,yield:29.1%.IR:KBrpellets,n/cm (cid:2)1:1622(s,imine, matrixleast-squareonF2.Crystallographicdetailsaresummarised
C]N).1HNMR(400MHz,CDCl3):d(ppm)¼1.02(t,3H,CH3),1.55 inTable3.Figs.3and4weredrawnwithORTEP[20].
(s,15H,Cp*CH3),1.92&2.12(brs,1H,NCH2CH2CH3),3.95&4.03(br
s,1H,NCH2CH2CH3),6.47(t,1H,Ar),6.92(d,1H,Ar),7.06(d,1H,Ar), 4.7. Cytotoxicitystudy
7.27(t,1H,Ar),7.79(s,1H,HC]N).13C{1H}NMR(100MHz,CDCl3):
d(ppm)¼9.2(Cp*CH3);11.5(CH3);24.0,68.4(CH2);86.3(Cp*C); ThehumanA2780andA2780cisRovariancarcinomacelllines
115.0,122.8,133.2,134.1(CHAr);121.9,165.2(CAr);159.8(CHimine). were obtained from the European Collection of Cell Cultures
Elementalanalysis(%):calc.forC20H27NIrClO(525.1):C,45.75;H, (Salisbury, UK). Cells were grown routinely in RPMI-1640
5.18;N,2.67;found:C,46.20;H,5.08;N,2.24.MS(ESI,m/z):490 medium with 10% foetal calf serum (FCS) and antibiotics at
[M(cid:2)Cl] þ .Meltingpoint:194(cid:3)Ce203(cid:3)C. 37 (cid:3)C and 5% CO2. Cytotoxicity was determined using the MTT
assay (MTT ¼ 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tet-
4.5. Synthesisofthemononuclearcationiccomplexes[11]PF 6 e[12] razolium bromide). Cells were seeded in 96-well plates
PF 6 as monolayers with 100 mL of cell solution (approximately
20,000 cells) per well and pre-incubated for 24 h in medium
TheligandL2(0.045g,0.306mmolfor11;0.049g,0.330mmol supplementedwith10%FCS.CompoundswerepreparedasDMSO
for 12) was added dropwise to a stirred solution of [Cp*RhCl2]2 solutionthendissolvedintheculturemediumandseriallydiluted
(0.098g,0.159mmolfor11)or[Cp*IrCl2]2(0.134g,0.168mmolfor to the appropriate concentration, to give a final DMSO concen-
12)indichloromethane(25mL).Thesolutionwasallowedtostir tration of 0.5%. A 100 mL portion of drug solution was added to
for 48 h at room temperature. The solvent was removed under each well and the plates were incubated for another 72 h. Sub-
reducedpressureandtheremainingresiduetakenupinethanol. sequently,MTT(5mg/mLsolution)wasaddedtothecellsandthe
The solution was filtered by gravity and the solvent reduced to plateswereincubatedforafurther2h.Theculturemediumwas
about5mL.NaPF6(0.056g,0.335mmolfor11;0.057g,0.339mmol aspirated,andthepurpleformazancrystalsformedbythemito-
for12)wasaddedandthereactionwasallowedtostirat0(cid:3)Cfor chondrial dehydrogenase activity of vital cells were dissolved in
3h.Thereactionvesselwasplacedinthefreezerovernight,pre- DMSO.Theopticaldensity,directlyproportionaltothenumberof
cipitating the product. The product was filtered, washed with survivingcells,wasquantifiedat590nmusingamultiwellplate
ethanolanddiethyletheranddriedundervacuum. readerandthefractionofsurvivingcellswascalculatedfromthe
absorbance of untreated control cells. Evaluation is based on
4.5.1. [Cp*RhClL2]PF6[11]PF 6 means from two independent experiments, each comprising
Yellowsolid,yield:78.4%.IR:KBrpellets,n/cm (cid:2)1:3436(b,NeH), threemicroculturesperconcentrationlevel.
1638(s,imine,C]N),1605(spyridyl,C]N),835(s,PeF).1HNMR
(400MHz,(CD3)2O):d(ppm)¼0.98(t,3H,CH3),1.84(s,15H,Cp* Acknowledgements
CH3), 1.91 & 2.02 (m, 1H, NCH2CH2CH3), 4.16 & 4.48 (m, 1H,
NCH2CH2CH3),7.95(t,1H,Pyr),8.25(d,1H,Pyr),8.35(t,1H,Pyr), Financial support from the University of Cape Town, the Na-
8.87 (s, 1H, HC]N), 9.12 (d, 1H, Pyr). 13C{1H} NMR (100 MHz, tionalResearchFoundation(NRF)ofSouthAfrica,theSouthAfrican
(CD3)2CO):d¼9.0(Cp*CH3);11.5(CH3);23.4,64.9(CH2);98.2(Cp* MedicalResearchCouncil(MRC),andagenerousloanofrhodium
C); 129.5,130.2,141.2,153.3 (CHpyr); 155.0 (Cpyr); 167.4 (CHimine). and iridium trichloride from Johnson Matthey/AngloAmerican
Elementalanalysis(%):calc.forC19H27N2RhClPF6(566.8):C,40.27; Platinum Limited Corporation are gratefully acknowledged. Even
H,4.80;N,4.94;found:C,40.41;H,5.06;N,4.52.MS(ESI,m/z):421 thoughtheworkissupportedbytheMRC,theviewsandopinions
[M] þ whereM¼[11](PF6)(cid:2)PF6.Meltingpoint:234(cid:3)Ce237(cid:3)C. expressedarenotthoseoftheMRCbutoftheauthorsofthema-
terial produced or publicized. The Swiss-South African Joint
4.5.2. [Cp*IrClL2]PF6[12]PF 6 Research Programme is also thanked for a short term exchange
Yellowsolid,yield:79.1%.IR:KBrpellets,n/cm (cid:2)1:3436(b,NeH), grantbetweenthethreelaboratories.
1630(s,imine,C]N),1606(s,pyridyl,C]N),835(s,PeF).1HNMR
(400MHz,(CD3)2O):d(ppm)¼1.01(t,3H,CH3),1.93&2.01(m,1H, AppendixA. Supplementarymaterial
NCH2CH2CH3), 1.82 (s, 15H, Cp* CH3), 4.39 & 4.47 (m, 1H,
NCH2CH2CH3),7.94(d,1H,Pyr),8.33(t,1H,Pyr),8.39(d,1H,Pyr), CCDC 886246 (9), 886247 (10), 886248 (11) and 886249 (12)
9.11 (d, 1H, Pyr), 9.35 (s, 1H, HC]N). 13C{1H} NMR (100 MHz, contain the supplementary crystallographic data for this paper.
(CD3)2CO):d (ppm) ¼ 8.8 (Cp* CH3); 11.5 (CH3); 23.4, 64.9 (CH2); These data can be obtained free of charge from The Cambridge
R.Payneetal./JournalofOrganometallicChemistry729(2013)20e27 27
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_ Organometallics25(2006)4090;
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