z Medicinal Chemistry & Drug Discovery Synthesis ...uomphysics.net/research/pubs/docs/1579236001-chemistry_select.pdf · ligands, which belong to the class of compartmental ligands,

z Medicinal Chemistry & Drug Discovery

Synthesis, Characterization and Anticancer Studies of Rh(I),Rh(III), Pd(II) and Pt(II) Complexes Bearing A DithiooxamideLigandBanafshe Askari,[a] Hadi Amiri Rudbari,*[a] Andreia Valente,*[b] Giuseppe Bruno,[c]

Nicola Micale,[c] Naveen Shivalingegowda,[d] and Lokanath Neratur Krishnappagowda[e]

Breast cancer is the most common type of cancer in women. Inthe current study, six transition-metal complexes were reactedwith a secondary dithiooxamide (H2-isopropyl2DTO) to obtainthe corresponding mononuclear complexes (1-6) and theircytotoxicity was evaluated in two human breast cancer celllines, i. e. MCF-7 and MDA-MB-231. The characterization of thecomplexes, [LnM(H-isopropyl2 DTO k-S,S M)] (LnM= (C5Me5)RhCl,(1); (COD)Rh, (2); (η3-allyl)Pd, (3); (trinpropyl-phosphine)PdCl, (4);(bpy)Pt, (5) and (pph3)PtCl, (6)), and the ion pair form of 1–4,IP1-IP4, were accomplished through NMR spectroscopy and

elemental analysis. The structures of 1 and IP1 were alsodetermined by single crystal XRD technique. In vitro cytotoxicitystudies in MCF-7 and MDA-MB-231 (IC50 determination) showedthat all complexes are cytotoxic for both cell lines, with theexception of 2. Compound 3 was the most cytotoxic in theconditions tested. In addition, the compounds induce celldeath by apoptosis and inhibit the formation of colonies,indicating that these compounds could provide promising newlead derivatives for anticancer drug development.

Introduction

Breast cancer is the second leading cause of cancer death evenamong young women. It is a complex disease that is difficult totreat owing to its heterogeneity, especially for triple-negativepatients.[1] The therapeutic complexity of these tumors under-scores the importance of developing more effective and lesstoxic drugs. The use of transition metal complexes has shownsignificant progresses to treat human diseases like cancer.Among all, platinum-based complexes played a dominant roleas anticancer drugs for over half a century.[2–5] In fact, followingthe success of cisplatin, a large number of other platinum-based drugs have been synthesized and evaluated.[6–11] Also,due to the similarity of Pd(II) to Pt(II) analogs in structure andcoordination chemistry, promising biological properties as well

as chemotherapeutic potential with different mechanism causethat Pd(II) complexes take attention in this field.[12–15] Further-more, in the field of non-platinum compounds exhibitingantitumor properties, arene Ru(II) and Rh(III) complexes with anancillary chloride ligand are promising, showing activity againstcisplatin-resistant tumors.[16–22] However, the rhodium-basedanticancer agents are relatively unexplored compared to theruthenium ones.

In addition to the type of metal, which can affect theanticancer properties, the selection of appropriate monoden-tate or bidentate ligands allows a fine-tune of the pharmaco-logical properties of the intended complexes. Dithiooxamideligands, which belong to the class of compartmental ligands,i. e. compounds with two coordination chambers in closeproximity, have been exploited in the synthesis of hetero- orhomometallic complexes containing two or three metalcenters.[23] Secondary dithiooxamide ligands, H2R2DTO, as wellas the corresponding rubeanate counterparts HR2N2C2S2

� andR2N2C2S2

2� , are made by two thioamide moieties. Thioamidesare a class of drugs that are used to control thyrotoxicosis.[24]

Furthermore, their derivatives are active against a number ofcancer cell lines, such as thioviridamide.[25] This informationsuggests a possible use of the secondary dithiooxamidateligands in chemotherapy. We recently disclosed that complexesbearing the H2R2DTO ligand show anticancer potential throughthe inhibition of important proteasomes and cathepsins.[26]

However, their effect on human cancer cells remains to bedisclosed. Thus, in this work, we synthesized six Rh(I), Rh(III), Pd(II) and Pt(II) complexes embedding the H2-isopropyl2DTOchelating ligand and evaluated their in vitro anticancer activityagainst two human breast cancer cell lines, MCF-7 and MDA-MB-231. Furthermore, compounds which turned out to be

[a] B. Askari, Dr. H. A. RudbariDepartment of Chemistry, University of Isfahan, Isfahan 81746-73441, IranE-mail: [email protected]

[email protected][b] Dr. A. Valente

Centro de Química Estrutural, Faculdade de Ciências da Universidade deLisboa, Campo Grande, 1749-016 Lisboa, PortugalE-mail: [email protected]

[c] Prof. G. Bruno, Prof. N. MicaleDepartment of Chemical, Biological, Pharmaceutical and EnvironmentalSciences, University of Messina, Viale Ferdinando Stagno D’Alcontres 31,I-98166 Messina, Italy.

[d] Dr. N. ShivalingegowdaDepartment of Physics, School of Engineering & Technology, JainUniversity, Bangalore 562 112, India.

[e] Dr. L. N. KrishnappagowdaDepartment of Studies in Physics, University of Mysore, Manasagangotri,Mysore 570 006, India

Supporting information for this article is available on the WWW underhttps://doi.org/10.1002/slct.201903939

Full PapersDOI: 10.1002/slct.201903939

1ChemistrySelect 2020, 5, 1–9 © 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Artikel_Svenja / 155834 [S. 1/9] 1

http://orcid.org/0000-0002-3020-8596

https://doi.org/10.1002/slct.201903939

active against the selected tumor cell lines were also inves-tigated for their cell death mechanism and inhibition of colonyformation in MDA-MB-231 cells.

Results and Discussion

Synthesis of the Complexes

The synthetic routes to prepare complexes 1–6 studied in thiswork are depicted in Schemes 1 and 2. All the characterizationdata 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 PtCl2(dmso)2 (5-6) as starting materials. Complex [(η3-allyl)Pd(H-isopropyl2 DTO k-S,S Pd)] (3), has been previouslyreported by us.[23a] Complexes IP1-IP4 (ion pair intermediates ofcompounds 1–4) and 1–4, [LnM(H-isopropyl2 DTO k-S,S M)](LnM= (C5Me5)RhCl, (1); (COD)Rh, (2); (η3-allyl)Pd, (3); and(trinpropyl-phosphine)PdCl, (4)) respectively, were obtained bythe following process:

H2-isopropyl2 DTO þ 1=2 LnMCl2

½LnMðH2-isopropyl2 DTO k-S,S MÞþ, Cl� �

LnMðH2-isopropyl2 DTO k-S,S MÞ þ HCl

H2-isopropyl2DTO is a bidentate sulfur ligand which, byreacting with chloro bridges, can cleave them and formmononuclear complexes.[23a,f] Structurally, this secondary di-thiooxamide is a chelating binucleating ligand which can alsoform binuclear complexes depending on the stoichiometricratios and the nature of the chlorido-bridged dimers.[23b,26c] Ionpair complexes IP1-IP4 were prepared by the reaction of H2-isopropyl2DTO with half molar of the related chlorido-bridgeddimers. The treatment of these intermediate complexes with anexcess of NaHCO3 afforded the final complexes 1–4, as shownin Scheme 1. Complexes 5 and 6 were prepared by the reactionof [PtCl2(dmso)2] with 1 equiv. of H2-isopropyl2DTO, in chloro-form at room temperature and in the presence of an excess ofsodium bicarbonate, to give the intermediate mononuclearcomplex [Pt(H-isopropyl2DTO k-S,S Pt)(Me2SO)Cl] (I) in goodyield (Scheme 2).[23i] Then, the intermediate I was reacted with1 equiv. of bpy and PPh3 in chloroform, to afford the newcomplexes 5 and 6, respectively. All complexes were precipi-tated from the respective concentrated reaction solution uponaddition of petroleum ether.

Characterization of the Complexes

The ion pair complexes IP1-IP4 and 1–6 were characterized byNMR spectroscopy and elemental analyses. The structures of

Scheme 1. Synthetic routes for the preparation of the four ion paircomplexes IP1-IP4 and the related neutral compounds 1–4.

Scheme 2. Synthetic routes for the preparation of the platinum complexes 5and 6.

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complexes IP1 and 1 were further confirmed by single crystalX-ray crystallography. Complexes 1, 2, 3 and 5 have a plane ofsymmetry and show only one set of signals for the DTO groupin their 1H-NMR spectra, whereas in complexes 4 and 6, theplane of symmetry is absent due to the geometry around themetal center (Figure 1). Therein, the two isopropyl units are notequivalent and therefore they appear as two sets of signals(two septets and two doublets), as shown in Figure 1 forcomplex 4.

N� H protons in the ion pair complexes, IP1-IP4, undergo alarge downfield shift and appear as a broad singlet at δ �13 ppm due to interaction with the Cl

�

anion. This indicatesthat in these complexes there are strong hydrogen interactions.Also, the 1H-NMR spectra of these complexes show a smallextent of downfield shift for the other hydrogens in compar-ison to the neutral ones. Moreover, in the 1H-NMR spectra ofthe ion pair complexes, the hydrogens attached to N are fixedand couple with the hydrogen atoms of isopropyl groups. Thiscoupling causes -CH(CH3)2 and N-CH- hydrogens to appear as adoublet of doublet (instead of one doublet) and a multiplet(instead of one septet), respectively, as shown in Figure 2.

1H-NMR spectra of complexes IP2 and 2 show three broaddistinct signals at δ � 4.44, 2.45 and 2.06 ppm correspondingto the 12 protons of the cyclooctadiene (COD) group. CH2s ofCOD appear as a singlet at δ=31.5 ppm, while the CH groupsnear the Rh center appear as a doublet resonance with JRhC=

10.9 Hz in the 13C-NMR spectrum of complex 2.

In the 1H-NMR spectra of complexes IP4 and 4, the signalsascribed to the hydrocarbon tails of the trinpropyl-phosphinegroup appear as two broad multiplets at δ � 1.57 and1.80 ppm (CH2 groups) and as a triplet at δ � 0.97 ppm (threeterminal methyl groups coupled with CH2 groups with 3JHH=

7.0 Hz). In 13C-NMR spectrum of complex 4 there are threenoticeable signals that are coupled to the phosphorus atom,one doublet at δ=25.32 ppm (coupling to P atom with 1JPC=

27.9 Hz) and the others at δ=18.04 and 15.99 ppm (couplingto P atom with 3JPC=1.3 and 2JPC =14.7 Hz, respectively), whichare attributed to the nearest-neighbor carbon to P atom, thefarthest-neighbor carbon to P atom, and the middle carbon oftrinpropyl-phosphine, respectively.

The observation of a doublet in the 1H-NMR spectrum of 5at δ=8.78 ppm, accompanied by platinum satellites with3JPtH=32 Hz, clearly confirms the coordination of the bpy ligandto the platinum center. The other hydrogens of bpy appear astwo triplets and one doublet in the aromatic region of thisspectrum. The appearance of two broad peaks in the aromaticregion corresponding in intensity to 15 protons, combinedwith two sets of signals for the isopropyl groups of DTO in the1H-NMR spectrum, confirmed the structure of complex 6. In the13C-NMR spectrum of this complex, the phenyl ring carbonsresonated as four doublets due to coupling with phosphorusatom with 1JPC=12 Hz, 2JPC=10.9 Hz, 3JPC=8.6 Hz and 4JPC=

4.7 Hz.

Figure 1. Comparison of 1H-NMR spectra of complexes with symmetry plane (A) (1, 2, 3 and 5) and the complexes without symmetry plane (B) (4 and 6).

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Molecular Structure of {[(C5Me5)ClRh(H2-isopropyl2 DTO k-S,SRh)]+ Cl� }.CHCl3 (IP1.CHCl3)

Structure of the typical complex IP1 was further confirmed bysingle crystal XRD technique. The red crystals having appro-priate X-ray diffraction quality were obtained from a chloroformsolution with slow evaporation. The complex crystallizes in themonoclinic system with P21/c space group. A view of thestructure of this complex is shown in Figure 3 and thecrystallographic data and selected bond lengths and angles arelisted in Tables 1 and 2, respectively. The complex contains apseudo-octahedral rhodium (III) center with a chlorine atom,two S atoms of the chelating DTO ligand and a pentameth-ylcyclopentadienyl ring (Cp*). By considering the Cp* ligand asa unique coordination site represented by the center of thecyclopentadiene ring, the rhodium geometry might bedescribed as a significantly distorted tetrahedral piano-stool.(Fig. 3). This deformation as evidenced by the space-fillingmodel is mainly due to the metal d orbitals orientation (that isoctahedral) that develop bonds toward ligands. As shown infigure 6, the planar DTO makes the angles of 145.76 and 90.38with the centroid of the cyclopentadienyl ring and chlorineatom, respectively. Comparison of the bond lengths ofdithiooxamide in the solid state form of the complex and freeligand[27] shows that there are no significant changes in itsbond lengths in the two situations. The bond lengths and bondangles of RhCp*SS part in the complex are similar to that

reported for Cp*Rh(PySH)(S2C2B10H10)[28] but different from that

for Cp*Rh(PMe3)[(SC5H4)2Fe].[29] The compound co-crystallizes

with a solvent molecule (CHCl3) interacting with the chlorideatom coordinated to the rhodium: H(19)⋅⋅⋅Cl(1) 2.507(9) Å.Figure 4 also shows the intermolecular interactions, C-H⋅⋅⋅Cl-Rhand C-Cl⋅⋅⋅S-C, between two molecules of the complex, IP1, andsolvent. In fact, these important and rather small molecules of

Figure 2. 1H-NMR spectrum of complex {[(C5Me5)ClRh(H2-isopropyl2 DTO k-S,S Rh)]+ Cl� }, IP1.

Figure 3. Perspective view of the molecular structure of IP1 {[(C5Me5)ClRh(H2-isopropyl2 DTO k-S,S Rh)]+ Cl

�

}. Green dotted bonds represent shortintermolecular N-H⋅⋅⋅Cl and C-H⋅⋅⋅Cl interactions.

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CHCl3 interact with their hosts, thus contributing to theintermolecular ‘glue’ that binds molecules in the crystal lattice.Furthermore, two amidic N-H frames of the coordinateddithiooxamide act as hydrogen bond donor groups and makethe ionic hydrogen-bonding (IHB) that have interaction withthe chloride anion (Cl(2)⋅⋅⋅H(1) 2.266(2) Å and Cl(2)⋅⋅⋅H(2)2.197(2) Å).[30] Comparison of the bond lengths, bond anglesand directionality of the ionic hydrogen bond in this complexwith what is reported by Jeffrey and Steiner[31,32] shows that thisIHB classifies as a moderate one in energy and strength. In fact,these interactions are strong enough to form an extensivelyassociated tight ion pair and only polar solvents with donoratoms such as Me2SO, MeOH are able to remove HCl from theion pair. Although, some ion pair complexes of dithiooxamidesand their applications of them were reported before[33] but thisis the first crystal structure description of the ion pair DTOcomplex with observation of the ionic hydrogen-bonding (IHB)interaction with the chloride anion.

Crystal Structure of [(C5Me5)ClRh(H-isopropyl2 DTO k-S,S Rh)](1)

The basic structure of this complex is exactly the same as thatof the ion pair complex IP1, though the former is neutral andhas no chloride counter ion. The Cp* ring (pentameth-ylcyclopentadienyl) which coordinates to the rhodium atom ina η5-fashion, leads to the usual three-legged piano stoolstructure with two sulfur atoms of the dithiooxamide ligandand one chloride ion. Figure 5 gives perspective views of therhodium (III) complex, 1. The distorted tetrahedral piano-stoolgeometry formed around the rhodium (III) center in IP1 isslightly smaller in bond lengths than the ones for 1, as shownin Table 2. In the structure the S� C-C� S skeleton forms a plane

Table 1. Crystal data and structure refinement parameters of the com-plexes IP1 and 1

Complexes IP1 1

Empirical formula C19 H32 Cl5 N2 Rh S2 C18 H30 Cl N2 Rh S2Formula weight 632.74 476.92Temperature (K) 296(2) K 293(2) KWavelength (Å) 0.71073 A 0.71073 ACrystal system Monoclinic MonoclinicSpace group P 21/c P 21/nUnit cell dimensions(Å, °)

a=10.8858(2) A a=10.999(7) A

b=14.7159(3) A b=16.8092(10) Ac=17.4360(3) A c=11.623(7) Aα=90 α=90β=95.6100(10) β=99.849(7)γ=90 γ=90

Volume (Å3) 2779.77(9) 2117.2(19)Z 4 4Calculated density(Mg/m3)

1.512 1.496

Absorption coefficient(mm� 1)

1.255 1.133

F(000) 1288 984Theta range for datacollection (°)

2.725 to 26.996 3.006 to 26.995

Index ranges -13� h �13 -12� h �14-18� k �18 -21� k �20-22� l �22 -12� l �14

Reflections collected 45036 9554Independent reflections 6060 [R(int)=0.0451] 4560 [R(int)=0.0823]Data Completeness (%) 99.8 98.8Refinement method Full-matrix least-

squares on F2Full-matrix least-squares on F2

Data / restraints / pa-rameters

6060 / 0 / 275 4560 / 0 / 226

Goodness-of-fit on F2 1.006 1.087Final R indices [I>2σ (I)] R1=0.0370 R1=0.0464

wR2=0.0834 wR2=0.1232R indices (all data) R1=0.0594 R1=0.0498

wR2=0.0943 wR2=0.1287Largest diff. peak andhole (e.Å� 3)

0.823 and � 0.835 1.605 and � 1.941

CCDC Number 1941931 1941930

Table 2. Selected bond lengths (Å) and angles (°) for complexes IP1 and 1

Complexes IP1 1

Rh(1)-Cl(1) 2.4074(11) 2.4271(16)Rh(1)-C(1) 2.175(3) 2.178(3)Rh(1)-C(2) 2.165(3) 2.161(3)Rh(1)-C(3) 2.173(4) 2.198(4)Rh(1)-C(4) 2.170(4) 2.196(3)Rh(1)-C(5) 2.144(4) 2.164(3)Rh(1)-S(1) 2.3128(9) 2.3401(12)Rh(1)-S(2) 2.3286(9) 2.3632(10)Rh(1)-Xcy 1.799 1.803N(1)-H(1) 0.82(4)N(1)-C(11) 1.303(4) 1.278(4)N(1)-C(16) 1.480(4) 1.468(4)N(2)-H(2) 0.89(4) 0.82(3)N(2)-C(12) 1.306(4) 1.309(4)N(2)-C(13) 1.474(4) 1.472(4)S(1)-C(11) 1.678(3) 1.731(3)S(2)-C(12) 1.684(3) 1.687(4)C(11)-C(12) 1.510(4) 1.519(4)

S(1)-Rh(1)-S(2) 85.41(3) 86.93(4)S(1)-Rh(1)-Cl(1) 90.46(5) 90.61(4)S(2)-Rh(1)-Cl(1) 91.23(4) 93.64(3)Xcy-Rh(1)-S(1) 126.80 125.98Xcy-Rh(1)-S(2) 127.21 124.95C(11)-N(1)-C(16) 124.2(3) 120.1(3)C(12)-N(2)-C(13) 124.7(3) 127.3(3)

Figure 4. Intermolecular interaction between chloroform solvent moleculeand the complex IP1: C-H⋅⋅⋅Cl-Rh and C-Cl⋅⋅⋅S-C interactions.

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and the amidic hydrogens are involved in an N-H⋅⋅⋅N intra-molecular hydrogen interaction. This hydrogen-bonding inter-action is not ionic and according to the reported data ismoderate in energy and strength.[31,32] This intramolecularinteraction has been discussed before and now is confirmed byX-ray diffraction data.[23f–i] As shown in Figure 6, the planardithiooxamide makes an angle of about 139.78° with thecentroid of Cp* in the complex while in complex IP1 this angleis larger but the angle of DTO with chlorine atom is smaller.The XDTO–Rh–Cl bond angles in both complexes are approx-imately same (about 124°). Comparison of the bond angles ofcomplex 1 (S(1)-Rh(1)-S(2) 86.93(4), S(1)-Rh(1)-Cl(1) 90.61(4) andS(2)-Rh(1)-Cl(1) 93.64(3)) with the similar complex containingNN ligand, [(η5-C5Me5)RhCl(C5H4N-2-CH=N–C6H4-p-Cl)]

+, withchelating NN bite angle of 76.17(7)° and N(32)-Rh-Cl(1) 85.13(4)

and N-Rh-Cl(1) 86.76(6) as reported[34] show that the latter onehas three-legs with closer proximity.

Biological Evaluation of the compounds

Analysis of the cytotoxicity in breast cancer cell lines

The cytotoxic activity of compounds 1–6 was assessed in twohuman breast cancer cell lines, MCF-7 and MDA-MB-231 at24 h, using the colorimetric MTT assay. These cell lines presentdifferent responses to treatment with cisplatin (CDDP) andhave important genetic differences (MCF-7 is hormone respon-sive while MDA-MB-231 is hormone independent and invasive).Cells were treated with the compounds within the concen-tration range of 0.1 μM to 200 μM. All the metal complexes,bearing the H2-isopropyl2DTO ligand, are cytotoxic for both celllines, with the exception of 2 (Table 3). Importantly, for theMDA-MB-231 cell line, all the complexes are much better thanCDDP (up to 110 times in the case of complex 3). In regard tothe rhodium compounds 1 and 2, it is clear that the presenceof a Cp* ring and the labile ligand Cl

�

(1) instead of acyclooctadiene ring (2) is vital to the cytotoxicity of thecompounds as 2 turned out to be inactive (IC50 > 100 μM) and1 showed IC50 values of 5.9 μM and 35 μM against MCF-7 andMDA-MB-231, respectively. The same trend of activity wasrecorded for the pair of platinum derivatives 5 and 6, whereinthe complex bearing the labile Cl

�

group (6) is more cytotoxicthan the complex without Cl� group (5) (6: IC50=39.2 μM and13.0 μM vs 5: IC50=123.2 μM and 56.0 μM against MCF-7 andMDA-MB-231, respectively). The palladium compounds 3 and 4are the most cytotoxic in the conditions tested (3: IC50=5.9 μMand 1.1 μM and 4: IC50=29.0 μM and 18.5.0 μM against MCF-7and MDA-MB-231, respectively). In this case, the presence ofthe (η3-allyl) co-ligand (3) imparts more cytotoxicity to thecomplex than the (trinpropyl-phosphine) and Cl� co-ligands (4).

Even if only a qualitative comparison is possible due todifferent incubation times and cell lines, the IC50 valuesobtained for compounds 1–6, with the exception of compound

Figure 5. Perspective view of the molecular structure of 1 [(C5Me5)ClRh(H-isopropyl2 DTO k-S,S Rh)].

Figure 6. Comparison of the orientation of the Cp* rings relative to the DTO in (A) [(C5Me5)ClRh(H-isopropyl2 DTO k-S,S Rh)], 1, and (B) {[(C5Me5)ClRh(H2-isopropyl2 DTO k-S,S Rh)]+ Cl� }, IP1.

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2, are among the best reported for related compounds fromthe literature.[35]

Evaluation of the cell death mechanism induced by selectedcompounds

The cell death mechanism was assessed using Annexin V/Propidium iodide (AV/PI) cytometry-based assay. Annexin V is amarker of early apoptosis, while PI is a marker of necrosis.MDA-MB-231 cells were incubated with compounds 1, 3–6 for24 h at their IC50. The results have shown that all thecompounds led to an increase in the percentage of AV+ /PI-and AV+ /PI+ stained cells (Table 4) in comparison to thenegative control. This increase is particularly evident for doublestaining with both markers (A+ /PI+), indicative of lateapoptosis.

The effects of selected compounds in the colony formationpotential of MDA-MB-231cells

To evaluate the colony formation potential of the compounds1, 3–6, MDA-MB-231 breast cancer derived cell line wereexposed to 1=4 of the IC50 and IC50 values of the differentcompounds for 24 hours, after which the medium wasremoved, and cells were maintained in culture for 7 days. MDA-MB-231 breast cancer derived cell line was used as model ofTriple Negative Breast Cancer (TNBC), a highly metastatic, withpoorer prognosis type of cancer.[37] Our results showed that allthe tested compounds highly reduce the ability of the cells toform colonies in both concentrations studied (Figure 7).

Conclusions

Six mononuclear rhodium-, palladium- and platinum-basedcomplexes of isopropyl-dithiooxamide, M–DTO, were synthe-sized and compared with cisplatin on two different human

breast cancer cell lines, MCF-7 and MDA-MB-231. Resultsshowed that these complexes, with the exception of 2,exhibited excellent cytotoxic activity. Compound 3, showedvery high in vitro cytotoxicity, in particular, against the triple-negative MDA-MB-231 cells which are known to be highlyresistant to the clinically used cisplatin. We believe that ourresults may provide useful information for the design of newcomplexes containing dithiooxamide and Rh(III), Pd(II) and Pt(II)moieties as anticancer agents.

Supporting Information Summary

Experimental section, experimental data and the cif files of 1and IP1 are reported in supporting information.

Acknowledgements

The authors are grateful to the Research Council of the Universityof Isfahan for financial support of this work. Financial support forbiological part was provided by Fundação para a Ciência e aTecnologia (FCT) through the project UID/QUI/00100/2019. A.Valente also acknowledges the CEECIND 2017 Initiative for the

Table 3. IC50 values (μM) for complexes 1–6 and cisplatin (CDDP) at 24 hincubation, in MCF-7 and MDA-MB-231 breast cancer cells.

Compound MCF-7 (μM) MDA-MB-231 (μM)

1 5.9 � 1.1 35.1 � 4.72 > 100 172.4 � 10.63 5.9 � 0.7 1.11 � 0.104 29.0 � 2.0 18.5 � 1.25 123.2 � 12.7 56.0 � 5.06 39.2 � 2.2 13.0 � 0.7CDDP 37.9 � 1.4[36] 122.3 � 24.9[36]

Table 4. Percentage of MDA-MB-231 cells in each state after treatment with compounds 1, 3–6 at IC50 concentration for 24 h of incubation.

% vital cells % early apoptotic cells % late apoptosis % necrotic

Control 82.3 5.0 11.3 1.41 40.2 15.4 40.0 4.43 28.9 9.9 59.6 1.64 19.4 23.7 56.0 0.95 29.2 9.3 60.4 1.16 12.4 7.9 79.1 0.6

Figure 7. Colony formation ability of MDA-MB-231 after being exposed tocompounds 1, 3–6. Analysis of the clonogenic ability, after 24 h incubationwith 1=4 IC50 and IC50 values, in MDA-MB-231 cell line. Values represent mean� SD of two independent experiments.

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project CEECIND/01974/2017 (acknowledging FCT, as well asPOPH and FSE- European Social Fund ).

Keywords: Breast cancer · MCF-7 · MDA-MB-231 · Palladium ·Platinum · Rhodium · Secondary dithiooxamide.

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Submitted: October 18, 2019Accepted: December 27, 2019

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Six mononuclear metal complexes ofa secondary dithiooxamide were syn-thesized and evaluated as anticanceragents against MCF-7 and MDA-MB-231 cells. Most of them turned out to

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B. Askari, Dr. H. A. Rudbari*, Dr. A.Valente*, Prof. G. Bruno, Prof. N.Micale, Dr. N. Shivalingegowda,Dr. L. N. Krishnappagowda

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