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Synthesis, Characterization and Anticancer Studies of Rh(I), Rh(III), Pd(II) and Pt(II) Complexes Bearing A Dithiooxamide Ligand
DOI: 10.1002/slct.201903939 Full Papers
z
Medicinal Chemistry & Drug Discovery
Synthesis, Characterization and Anticancer Studies of Rh(I),
Rh(III), Pd(II) and Pt(II) Complexes Bearing A Dithiooxamide
Ligand
Banafshe Askari,[a] Hadi Amiri Rudbari,*[a] Andreia Valente,*[b] Giuseppe Bruno,[c]
Nicola Micale,[c] Naveen Shivalingegowda,[d] and Lokanath Neratur Krishnappagowda[e]
Breastcanceristhemostcommontypeofcancerinwomen.In elemental analysis. The structures of 1 and IP1 were also
the current study, six transition-metal complexes were reacted determinedbysinglecrystalXRDtechnique.Invitrocytotoxicity
with a secondary dithiooxamide (H-isopropylDTO) to obtain studiesinMCF-7andMDA-MB-231(IC determination)showed
2 2 50
the corresponding mononuclear complexes (1-6) and their that all complexes are cytotoxic for both cell lines, with the
cytotoxicity was evaluated in two human breast cancer cell exception of 2. Compound 3 was the most cytotoxic in the
lines, i.e. MCF-7 and MDA-MB-231. The characterization of the conditions tested. In addition, the compounds induce cell
complexes,[L M(H-isopropyl DTOk-S,SM)](L M=(CMe)RhCl, death by apoptosis and inhibit the formation of colonies,
n 2 n 5 5
(1);(COD)Rh,(2);(η3-allyl)Pd,(3);(trinpropyl-phosphine)PdCl,(4); indicatingthatthesecompoundscouldprovidepromisingnew
(bpy)Pt, (5) and (pph)PtCl, (6)), and the ion pair form of 1–4, leadderivativesforanticancerdrugdevelopment.
3
IP1-IP4, were accomplished through NMR spectroscopy and
Introduction
aschemotherapeuticpotentialwithdifferentmechanismcause
Breastcanceristhesecondleadingcauseofcancerdeatheven that Pd(II) complexes take attention in this field.[12–15] Further-
amongyoungwomen.Itisacomplexdiseasethatisdifficultto more, in the field of non-platinum compounds exhibiting
treat owing to its heterogeneity, especially for triple-negative antitumorproperties,areneRu(II)andRh(III)complexeswithan
patients.[1] The therapeutic complexity of these tumors under- ancillarychlorideligandarepromising,showingactivityagainst
scores the importance of developing more effective and less cisplatin-resistant tumors.[16–22] However, the rhodium-based
toxic drugs. The use of transition metal complexes has shown anticancer agents are relatively unexplored compared to the
significant progresses to treat human diseases like cancer. rutheniumones.
Among all, platinum-based complexes played a dominant role In addition to the type of metal, which can affect the
asanticancerdrugsforoverhalfacentury.[2–5]Infact,following anticancer properties, the selection of appropriate monoden-
the success of cisplatin, a large number of other platinum- tate or bidentate ligands allows a fine-tune of the pharmaco-
based drugs have been synthesized and evaluated.[6–11] Also, logical properties of the intended complexes. Dithiooxamide
due to the similarity of Pd(II) to Pt(II) analogs in structure and ligands, which belong to the class of compartmental ligands,
coordinationchemistry, promisingbiologicalproperties aswell i.e. compounds with two coordination chambers in close
proximity, have been exploited in the synthesis of hetero- or
homometallic complexes containing two or three metal
[a] B.Askari,Dr.H.A.Rudbari centers.[23] Secondary dithiooxamide ligands, HRDTO, as well
DepartmentofChemistry,UniversityofIsfahan,Isfahan81746-73441,Iran 2 2
as the corresponding rubeanate counterparts HRNCS(cid:0) and
E-mail:h.a.rudbari@sci.ui.ac.ir 2 2 2 2
hamiri1358@gmail.com R 2 N 2 C 2 S 2 2(cid:0), are made by two thioamide moieties. Thioamides
[b] Dr.A.Valente are a class of drugs that are used to control thyrotoxicosis.[24]
CentrodeQuímicaEstrutural,FaculdadedeCiênciasdaUniversidadede
Furthermore, their derivatives are active against a number of
Lisboa,CampoGrande,1749-016Lisboa,Portugal
cancer cell lines, such as thioviridamide.[25] This information
E-mail:amvalente@fc.ul.pt
[c] Prof.G.Bruno,Prof.N.Micale suggests a possible use of the secondary dithiooxamidate
Department of Chemical, Biological, Pharmaceutical and Environmental ligandsinchemotherapy.Werecentlydisclosedthatcomplexes
Sciences,UniversityofMessina,VialeFerdinandoStagnoD’Alcontres31,
bearingtheHRDTOligandshowanticancerpotentialthrough
I-98166Messina,Italy. 2 2
the inhibition of important proteasomes and cathepsins.[26]
[d] Dr.N.Shivalingegowda
Department of Physics, School of Engineering & Technology, Jain However, their effect on human cancer cells remains to be
University,Bangalore562112,India. disclosed.Thus,inthiswork,wesynthesizedsixRh(I),Rh(III),Pd
[e] Dr.L.N.Krishnappagowda
(II) and Pt(II) complexes embedding the H-isopropylDTO
DepartmentofStudiesinPhysics,UniversityofMysore,Manasagangotri, 2 2
chelating ligand and evaluated their invitro anticancer activity
Mysore570006,India
against two human breast cancer cell lines, MCF-7 and MDA-
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/slct.201903939 MB-231. Furthermore, compounds which turned out to be
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active against the selected tumor cell lines were also inves-
tigatedfortheircelldeathmechanismandinhibitionofcolony
formationinMDA-MB-231cells.
Results and Discussion
SynthesisoftheComplexes
The synthetic routes to prepare complexes 1–6 studied in this
work are depicted inSchemes1 and 2. All the characterization
data are reported within the Experimental Section. Six mono-
nuclear complexes of Rh(III) (1), Rh(I) (2), Pd(II) (3-4) and Pt(II)
(5-6) were prepared using a (μ-chloro)-bridged metal complex
(1-4) or PtCl(dmso) (5-6) as starting materials. Complex [(η3-
2 2
allyl)Pd(H-isopropyl DTO k-S,S Pd)] (3), has been previously
2
reportedbyus.[23a]ComplexesIP1-IP4(ionpairintermediatesof
compounds 1–4) and 1–4, [L M(H-isopropyl DTO k-S,S M)]
n 2
(L M=(CMe)RhCl, (1); (COD)Rh, (2); (η3-allyl)Pd, (3); and
n 5 5
(trinpropyl-phosphine)PdCl, (4)) respectively, were obtained by
thefollowingprocess:
Scheme2.Syntheticroutesforthepreparationoftheplatinumcomplexes5
and6.
H-isopropylDTO is a bidentate sulfur ligand which, by
2 2
reacting with chloro bridges, can cleave them and form
mononuclear complexes.[23a,f] Structurally, this secondary di-
thiooxamide is a chelating binucleating ligand which can also
form binuclear complexes depending on the stoichiometric
ratios and the nature of the chlorido-bridged dimers.[23b,26c] Ion
pair complexes IP1-IP4 were prepared by the reaction of H-
2
isopropylDTO with half molar of the related chlorido-bridged
2
dimers.Thetreatmentoftheseintermediatecomplexeswithan
excess of NaHCO afforded the final complexes 1–4, as shown
3
inScheme1.Complexes5and6werepreparedbythereaction
of [PtCl(dmso)] with 1equiv. of H-isopropylDTO, in chloro-
2 2 2 2
formatroomtemperatureandinthepresenceofanexcessof
sodium bicarbonate, to give the intermediate mononuclear
complex [Pt(H-isopropylDTO k-S,S Pt)(MeSO)Cl] (I) in good
2 2
yield (Scheme2).[23i] Then, the intermediate I was reacted with
1equiv. of bpy and PPh in chloroform, to afford the new
3
complexes 5 and 6, respectively. All complexes were precipi-
tated from the respective concentrated reaction solution upon
additionofpetroleumether.
Scheme1.Syntheticroutesforthepreparationofthefourionpair
complexesIP1-IP4andtherelatedneutralcompounds1–4.
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CharacterizationoftheComplexes 1H-NMR spectra of complexes IP2 and 2 show three broad
distinct signals at δ � 4.44, 2.45 and 2.06ppm corresponding
Theionpair complexesIP1-IP4and 1–6werecharacterized by to the 12 protons of the cyclooctadiene (COD) group. CHs of
2
NMR spectroscopy and elemental analyses. The structures of COD appear as a singlet at δ=31.5ppm, while the CH groups
complexes IP1 and 1 were further confirmed by single crystal near the Rh center appear as a doublet resonance with J =
RhC
X-ray crystallography.Complexes1, 2,3and 5have aplane of 10.9Hzinthe13C-NMRspectrumofcomplex2.
symmetryandshowonlyonesetofsignalsfortheDTO group In the 1H-NMR spectra of complexes IP4 and 4, the signals
in their 1H-NMR spectra, whereas in complexes 4 and 6, the ascribed to the hydrocarbon tails of the trinpropyl-phosphine
plane of symmetry is absent due to the geometry around the group appear as two broad multiplets at δ � 1.57 and
metalcenter(Figure1).Therein,thetwoisopropylunitsarenot 1.80ppm(CH groups)andasatripletatδ � 0.97ppm(three
2
equivalent and therefore they appear as two sets of signals terminal methyl groups coupled with CH groups with 3J =
2 HH
(two septets and two doublets), as shown in Figure1 for 7.0Hz). In 13C-NMR spectrum of complex 4 there are three
complex4. noticeable signals that are coupled to the phosphorus atom,
N(cid:0) Hprotons in the ion pair complexes, IP1-IP4, undergo a one doublet at δ=25.32ppm (coupling to P atom with 1J =
PC
large downfield shift and appear as a broad singlet at δ � 27.9Hz) and the others at δ=18.04 and 15.99ppm (coupling
13ppm due to interaction with the Cl(cid:0) anion. This indicates toPatomwith3J =1.3and2J =14.7Hz,respectively),which
PC PC
thatinthesecomplexestherearestronghydrogeninteractions. are attributed to the nearest-neighbor carbon to P atom, the
Also, the 1H-NMR spectra of these complexes show a small farthest-neighbor carbon to P atom, and the middle carbon of
extent of downfield shift for the other hydrogens in compar- trinpropyl-phosphine,respectively.
ison to the neutral ones. Moreover, in the 1H-NMR spectra of The observation of a doublet in the 1H-NMR spectrum of 5
the ion pair complexes, the hydrogens attached to N are fixed at δ=8.78ppm, accompanied by platinum satellites with
andcouplewiththehydrogenatomsofisopropylgroups.This 3J =32Hz,clearlyconfirmsthecoordinationofthebpyligand
PtH
couplingcauses-CH(CH) andN-CH-hydrogenstoappearasa to the platinum center. The other hydrogens of bpy appear as
32
doublet of doublet (instead of one doublet) and a multiplet two triplets and one doublet in the aromatic region of this
(insteadofoneseptet),respectively,asshowninFigure2. spectrum. The appearance of two broad peaks in the aromatic
region corresponding in intensity to 15 protons, combined
Figure1.Comparisonof1H-NMRspectraofcomplexeswithsymmetryplane(A)(1,2,3and5)andthecomplexeswithoutsymmetryplane(B)(4and6).
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Figure2.1H-NMRspectrumofcomplex{[(CMe)ClRh(H-isopropyl DTOk-S,SRh)]+Cl(cid:0)},IP1.
5 5 2 2
withtwosetsofsignalsfortheisopropylgroupsofDTOinthe
1H-NMRspectrum,confirmedthestructureofcomplex6.Inthe
13C-NMR spectrum of this complex, the phenyl ring carbons
resonated as four doublets due to coupling with phosphorus
atom with 1J =12Hz, 2J =10.9Hz, 3J =8.6Hz and 4J =
PC PC PC PC
4.7Hz.
MolecularStructureof{[(CMe)ClRh(H-isopropyl DTOk-S,S
5 5 2 2
Rh)]+ Cl(cid:0)}.CHCl (IP1.CHCl)
3 3
Structure of the typical complex IP1 was further confirmed by
single crystal XRD technique. The red crystals having appro-
priateX-raydiffractionqualitywereobtainedfromachloroform
solutionwith slowevaporation. Thecomplexcrystallizesinthe
monoclinic system with P2/c space group. A view of the
1
structure of this complex is shown in Figure3 and the
Figure3.PerspectiveviewofthemolecularstructureofIP1{[(CMe)ClRh(H-
5 5 2
crystallographicdataandselectedbondlengthsandanglesare isopropyl DTOk-S,SRh)]+Cl(cid:0)}.Greendottedbondsrepresentshort
2
listed in Tables1 and 2, respectively. The complex contains a intermolecularN-H⋅⋅⋅ClandC-H⋅⋅⋅Clinteractions.
pseudo-octahedral rhodium (III) center with a chlorine atom,
two S atoms of the chelating DTO ligand and a pentameth-
ylcyclopentadienylring(Cp*). Byconsidering theCp* ligandas figure6,theplanar DTO makesthe anglesof145.76and 90.38
a unique coordination site represented by the center of the with the centroid of the cyclopentadienyl ring and chlorine
cyclopentadiene ring, the rhodium geometry might be atom, respectively. Comparison of the bond lengths of
described as a significantly distorted tetrahedral piano-stool. dithiooxamide in the solid state form of the complex and free
(Fig. 3). This deformation as evidenced by the space-filling ligand[27] shows that there are no significant changes in its
modelismainlyduetothemetaldorbitalsorientation(thatis bondlengthsinthetwosituations.Thebondlengthsandbond
octahedral) that develop bonds toward ligands. As shown in angles of RhCp*SS part in the complex are similar to that
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Table1. Crystaldataandstructurerefinementparametersofthecom- Table2. Selectedbondlengths(Å)andangles(°)forcomplexesIP1and1
plexesIP1and1
Complexes IP1 1
Complexes IP1 1
Rh(1)-Cl(1) 2.4074(11) 2.4271(16)
Empiricalformula C H Cl N RhS C H ClN RhS Rh(1)-C(1) 2.175(3) 2.178(3)
19 32 5 2 2 18 30 2 2
Formulaweight 632.74 476.92 Rh(1)-C(2) 2.165(3) 2.161(3)
Temperature(K) 296(2)K 293(2)K Rh(1)-C(3) 2.173(4) 2.198(4)
Wavelength(Å) 0.71073A 0.71073A Rh(1)-C(4) 2.170(4) 2.196(3)
Crystalsystem Monoclinic Monoclinic Rh(1)-C(5) 2.144(4) 2.164(3)
Spacegroup P21/c P21/n Rh(1)-S(1) 2.3128(9) 2.3401(12)
Unitcelldimensions a=10.8858(2)A a=10.999(7)A Rh(1)-S(2) 2.3286(9) 2.3632(10)
(Å,°) Rh(1)-Xcy 1.799 1.803
b=14.7159(3)A b=16.8092(10)A N(1)-H(1) 0.82(4)
c=17.4360(3)A c=11.623(7)A N(1)-C(11) 1.303(4) 1.278(4)
α=90 α=90 N(1)-C(16) 1.480(4) 1.468(4)
β=95.6100(10) β=99.849(7) N(2)-H(2) 0.89(4) 0.82(3)
γ=90 γ=90 N(2)-C(12) 1.306(4) 1.309(4)
Volume(Å3) 2779.77(9) 2117.2(19) N(2)-C(13) 1.474(4) 1.472(4)
Z 4 4 S(1)-C(11) 1.678(3) 1.731(3)
Calculateddensity 1.512 1.496 S(2)-C(12) 1.684(3) 1.687(4)
(Mg/m3) C(11)-C(12) 1.510(4) 1.519(4)
Absorptioncoefficient 1.255 1.133
(mm(cid:0)1) S(1)-Rh(1)-S(2) 85.41(3) 86.93(4)
F(000) 1288 984 S(1)-Rh(1)-Cl(1) 90.46(5) 90.61(4)
Thetarangefordata 2.725to26.996 3.006to26.995 S(2)-Rh(1)-Cl(1) 91.23(4) 93.64(3)
collection(°) Xcy-Rh(1)-S(1) 126.80 125.98
Indexranges -13�h�13 -12�h�14 Xcy-Rh(1)-S(2) 127.21 124.95
-18�k�18 -21�k�20 C(11)-N(1)-C(16) 124.2(3) 120.1(3)
-22�l�22 -12�l�14 C(12)-N(2)-C(13) 124.7(3) 127.3(3)
Reflectionscollected 45036 9554
Independentreflections 6060[R =0.0451] 4560[R =0.0823]
(int) (int)
DataCompleteness(%) 99.8 98.8
Refinementmethod Full-matrixleast- Full-matrixleast-
squaresonF2 squaresonF2
Data/restraints/pa- 6060/0/275 4560/0/226
rameters
Goodness-of-fitonF2 1.006 1.087
FinalRindices[I>2σ(I)] R =0.0370 R =0.0464
1 1
wR =0.0834 wR =0.1232
2 2
Rindices(alldata) R =0.0594 R =0.0498
1 1
wR =0.0943 wR =0.1287
2 2
Largestdiff.peakand 0.823and(cid:0) 0.835 1.605and(cid:0) 1.941
hole(e.Å(cid:0)3)
CCDCNumber 1941931 1941930
Figure4.Intermolecularinteractionbetweenchloroformsolventmolecule
reported for Cp*Rh(PySH)(S
2
C
2
B
10
H
10
)[28] but different from that andthecomplexIP1:C-H⋅⋅⋅Cl-RhandC-Cl⋅⋅⋅S-Cinteractions.
for Cp*Rh(PMe)[(SCH)Fe].[29] The compound co-crystallizes
3 5 42
with a solvent molecule (CHCl) interacting with the chloride
3
atom coordinated to the rhodium: H(19)⋅⋅⋅Cl(1) 2.507(9) Å.
Figure4 also shows the intermolecular interactions, C-H⋅⋅⋅Cl-Rh associated tight ion pair and only polar solvents with donor
andC-Cl⋅⋅⋅S-C,betweentwomoleculesofthecomplex,IP1,and atoms such as MeSO, MeOH are able to remove HCl from the
2
solvent. In fact, these important and rather small molecules of ionpair.Although,someionpaircomplexesofdithiooxamides
CHCl interact with their hosts, thus contributing to the andtheirapplicationsofthemwerereportedbefore[33]butthis
3
intermolecular‘glue’thatbindsmoleculesinthecrystallattice. is the first crystal structure description of the ion pair DTO
Furthermore, two amidic N-H frames of the coordinated complexwithobservationoftheionichydrogen-bonding(IHB)
dithiooxamide act as hydrogen bond donor groups and make interactionwiththechlorideanion.
the ionic hydrogen-bonding (IHB) that have interaction with
the chloride anion (Cl(2)⋅⋅⋅H(1) 2.266(2) Å and Cl(2)⋅⋅⋅H(2)
CrystalStructureof[(CMe)ClRh(H-isopropyl DTOk-S,SRh)]
2.197(2) Å).[30] Comparison of the bond lengths, bond angles 5 5 2
(1)
and directionality of the ionic hydrogen bond in this complex
withwhatisreportedbyJeffreyandSteiner[31,32]showsthatthis The basic structure of this complex is exactly the same as that
IHBclassifiesasamoderateoneinenergyandstrength.Infact, of the ion pair complex IP1, though the former is neutral and
these interactions are strong enough to form an extensively has no chloride counter ion. The Cp* ring (pentameth-
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ylcyclopentadienyl) which coordinates to the rhodium atom in approximately same (about 124°). Comparison of the bond
a η5-fashion, leads to the usual three-legged piano stool angles of complex 1 (S(1)-Rh(1)-S(2) 86.93(4), S(1)-Rh(1)-Cl(1)
structure with two sulfur atoms of the dithiooxamide ligand 90.61(4) and S(2)-Rh(1)-Cl(1) 93.64(3)) with the similar complex
and one chloride ion. Figure5 gives perspective views of the containing NN ligand, [(η5-CMe)RhCl(CHN-2-CH=N–CH-p-
5 5 5 4 6 4
rhodium (III) complex, 1. The distorted tetrahedral piano-stool Cl)]+,withchelatingNNbiteangleof76.17(7)°andN(32)-Rh-Cl
geometry formed around the rhodium (III) center in IP1 is (1)85.13(4)andN-Rh-Cl(1)86.76(6)asreported[34]showthatthe
slightly smaller in bond lengths than the ones for 1, as shown latteronehasthree-legswithcloserproximity.
inTable2.InthestructuretheS(cid:0) C(cid:0) C(cid:0) Sskeletonformsaplane
and the amidic hydrogens are involved in an N-H⋅⋅⋅N intra-
molecular hydrogen interaction. This hydrogen-bonding inter- Biological Evaluation of the compounds
action is not ionic and according to the reported data is
Analysisofthecytotoxicityinbreastcancercelllines
moderate in energy and strength.[31,32] This intramolecular
interactionhasbeendiscussedbeforeandnowisconfirmedby The cytotoxic activity of compounds 1–6 was assessed in two
X-ray diffraction data.[23f–i] As shown in Figure6, the planar human breast cancer cell lines, MCF-7 and MDA-MB-231 at
dithiooxamide makes an angle of about 139.78° with the 24h,using thecolorimetricMTTassay.Thesecelllinespresent
centroid of Cp* in the complex 1 while in complex IP1 this different responses to treatment with cisplatin (CDDP) and
angle is larger but the angle of DTO with chlorine atom is haveimportantgeneticdifferences(MCF-7ishormonerespon-
smaller. The X –Rh–Cl bond angles in both complexes are sivewhileMDA-MB-231ishormoneindependentandinvasive).
DTO
Cells were treated with the compounds within the concen-
tration range of 0.1μM to 200μM. All the metal complexes,
bearingtheH-isopropylDTOligand,arecytotoxicforbothcell
2 2
lines, with the exception of 2 (Table3). Importantly, for the
MDA-MB-231cell line, all the complexes are much better than
CDDP (up to 110 times in the case of complex 3). In regard to
the rhodium compounds 1 and 2, it is clear that the presence
of a Cp* ring and the labile ligand Cl(cid:0) (1) instead of a
cyclooctadiene ring (2) is vital to the cytotoxicity of the
compoundsas2turnedouttobeinactive(IC >100μM)and
50
1 showed IC values of 5.9μM and 35μM against MCF-7 and
50
MDA-MB-231, respectively. The same trend of activity was
recorded for the pair of platinum derivatives 5 and 6, wherein
the complex bearing the labile Cl(cid:0) group (6) is more cytotoxic
than the complex without Cl(cid:0) group (5) (6: IC =39.2μM and
50
13.0μM vs 5: IC =123.2μM and 56.0μM against MCF-7 and
50
MDA-MB-231,respectively).Thepalladiumcompounds3and4
arethemostcytotoxicintheconditionstested(3:IC =5.9μM
50
and 1.1μM and 4: IC =29.0μM and 18.5.0μM against MCF-7
50
Figure5.Perspectiveviewofthemolecularstructureof1[(C 5 Me 5 )ClRh(H- and MDA-MB-231, respectively). In this case, the presence of
isopropyl DTOk-S,SRh)].
2
Figure6.ComparisonoftheorientationoftheCp*ringsrelativetotheDTOin(A)[(CMe)ClRh(H-isopropyl DTOk-S,SRh)],1,and(B){[(CMe)ClRh(H-
5 5 2 5 5 2
isopropyl DTOk-S,SRh)]+Cl(cid:0)},IP1.
2
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the (η3-allyl) co-ligand (3) imparts more cytotoxicity to the
complexthanthe(trinpropyl-phosphine)andCl(cid:0) co-ligands(4).
Even if only a qualitative comparison is possible due to
different incubation times and cell lines, the IC values
50
obtainedforcompounds1–6,withtheexceptionofcompound
2, are among the best reported for related compounds from
theliterature.[35]
Evaluationofthecelldeathmechanisminducedbyselected
compounds
The cell death mechanism was assessed using Annexin V/
Propidiumiodide(AV/PI)cytometry-basedassay.AnnexinVisa
marker of early apoptosis, while PI is a marker of necrosis.
MDA-MB-231 cells were incubated with compounds 1, 3–6 for
24h at their IC . The results have shown that all the
50
compounds led to an increase in the percentage of AV+/PI-
and AV+/PI+ stained cells (Table4) in comparison to the
negativecontrol.Thisincreaseisparticularlyevidentfordouble
staining with both markers (A+/PI+), indicative of late
Figure7.ColonyformationabilityofMDA-MB-231afterbeingexposedto
apoptosis. compounds1,3–6.Analysisoftheclonogenicability,after24hincubation
with1= IC andIC values,inMDA-MB-231cellline.Valuesrepresentmean
4 50 50
�SDoftwoindependentexperiments.
Theeffectsofselectedcompoundsinthecolonyformation
potentialofMDA-MB-231cells
To evaluate the colony formation potential of the compounds
Conclusions
1, 3–6, MDA-MB-231 breast cancer derived cell line was
exposed to 1= of the IC and IC values of the different Six mononuclear rhodium-, palladium- and platinum-based
4 50 50
compounds for 24hours, after which the medium was complexes of isopropyl-dithiooxamide, M–DTO, were synthe-
removed,andcellsweremaintainedinculturefor7days.MDA- sized and compared with cisplatin on two different human
MB-231 breast cancer derived cell line was used as model of breast cancer cell lines, MCF-7 and MDA-MB-231. Results
Triple Negative Breast Cancer (TNBC), a highly metastatic, with showed that these complexes, with the exception of 2,
poorer prognosis type of cancer.[37] Our results showed that all exhibited excellent cytotoxic activity. Compound 3, showed
the tested compounds highly reduce the ability of the cells to very high invitro cytotoxicity, in particular, against the triple-
formcoloniesinbothconcentrationsstudied(Figure7). negative MDA-MB-231 cells which are known to be highly
resistant to the clinically used cisplatin. We believe that our
results may provide useful information for the design of new
complexescontainingdithiooxamideandRh(III),Pd(II)andPt(II)
Table3. IC values(μM)forcomplexes1–6andcisplatin(CDDP)at24h moietiesasanticanceragents.
50
incubation,inMCF-7andMDA-MB-231breastcancercells.
Compound MCF-7(μM) MDA-MB-231(μM)
SupportingInformationSummary
1 5.9�1.1 35.1�4.7
Experimental section, experimental data and the cif files of 1
2 >100 172.4�10.6
3 5.9�0.7 1.11�0.10 andIP1arereportedinsupportinginformation.
4 29.0�2.0 18.5�1.2
5 123.2�12.7 56.0�5.0
6 39.2�2.2 13.0�0.7
CDDP 37.9�1.4[36] 122.3�24.9[36]
Table4. PercentageofMDA-MB-231cellsineachstateaftertreatmentwithcompounds1,3–6atIC concentrationfor24hofincubation.
50
%vitalcells %earlyapoptoticcells %lateapoptosis %necrotic
Control 82.3 5.0 11.3 1.4
1 40.2 15.4 40.0 4.4
3 28.9 9.9 59.6 1.6
4 19.4 23.7 56.0 0.9
5 29.2 9.3 60.4 1.1
6 12.4 7.9 79.1 0.6
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