Synthesis, characterization and biological activity of antimony(III)

8/11/2019 Synthesis, characterization and biological activity of antimony(III)

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Synthesis, characterization and biological activity of antimony(III)or bismuth(III) chloride complexes with dithiocarbamate ligandsderived from thiuram degradation

I.I. Ozturk a,b,, C.N. Banti b, N. Kourkoumelis c,, M.J. Manos d, A.J. Tasiopoulos d, A.M. Owczarzak e,M. Kubicki e, S.K. Hadjikakou b,

a Department of Chemistry, Namk Kemal University, 59030 Tekirdag, Turkeyb Section of Inorganic and Analytical Chemistry, Department of Chemistry, University of Ioannina, 45110 Ioannina, Greecec Medical Physics Laboratory, Medical School, University of Ioannina, 45110 Ioannina, Greece

d Department of Chemistry, University of Cyprus, Nicosia, Cypruse Faculty of Chemistry, Adam Mickiewicz University, Grunwaldzka 6, 60-780 Poznan, Poland

a r t i c l e i n f o

Article history:Received 14 June 2013Accepted 22 August 2013Available online 4 September 2013

Keywords:Bioinorganic chemistryAntimony(III) and bismuth(III) complexesPolymorphsStructure activity relationship (SAR)

CytotoxicityPCAMolecular docking

a b s t r a c t

Antimony(III) or bismuth(III) complexes of formulae {[SbCl(Me2DTC)2]n} (1), {[BiCl(Me2DTC)2]n} (2) and{[Bi(Et2DTC)3]2} (3) (Me2DTCH = dimethyldithiocarbamate, C3H7NS2 and Et2DTCH = diethyldithiocarba-mate, C5H11NS2) were isolated from the reactions between SbCl3or BiCl3with tetramethylthiuram mono-sulfide (Me4tms), tetramethylthiuram disulfide (Me4tds) or tetraethylthiuram disulfide (Et4tds). In thecase of1 two polymorphs were isolated depending on the synthetic procedure followed. Crystal growthfrom the reaction of antimony(III)chloride with Me4tms in methanol produced 1a polymorph, whilethose derived from Me4tds in acetonitrile/dichloromethane produced 1bform. The complexes 13werecharacterized by m.p., e.a., FT-IR, FT-Raman, 1H, 13C NMR spectroscopy and Thermal GravimetryDiffer-ential Thermal Analysis (TGADTA). Moreover, single crystal X-ray diffraction analysis was carried out for

1a,1b,2and 3. X-ray powder diffraction data confirm the existence of one polymorph in the bulk of eachsample of1aand1b. 1H NMR spectra in the DMSO-d6solutions of1aand1bsuggest the retention of thestructural variations. Complexes 1and 2 are polymers with distorted square pyramidal (SPY) geometry ineach monomeric unit. The known structure of3 was re-determined to be used for the theoretical andstructure activity relationship studies (SAR).

Complexes13 were evaluated for their in vitro cytotoxic activity against human breast adenocarci-noma (MCF-7) and human cervix adenocarcinoma (HeLa) cells. Complex 3 is more active against HeLacells whereas1a,1band2against MCF-7. Compound 1ashows slightly higher activity than1b. Principalcomponents analysis (PCA) was performed to discriminate the significant physicochemical moleculardescriptors while regression analysis successfully related the experimental inhibitory concentration,(IC50) to the independent variables indexed by PCA. The calculated IC50values are satisfactorily comparedwith the measured inhibitory activity of the complexes.

2013 Elsevier Ltd. All rights reserved.

1. Introduction

The bis(N,N-dialkylthiocarbamoyl)sulfide and bis(N,N-dial-kylthiocarbamoyl)disulfide derivatives, (thiuram sulfides orthiuram disulfides) of the general formula R2NC(S)SnC(S)NR2 arethe thiocarbamoyl esters of dialkyldithiocarbamic acids [1]. Thebiological applications of thiuram disulfides varied within a broad

spectrum. Thiuram disulfides (R4tds) have been used as fungicides,

as therapy against alcoholism, and as arrestors of human immu-nodefficiency virus infections such as AIDS[14]. Studies on thethiuram monosulfides (R4tms), on the other hand, are rare [5].Thiuram monosulfides inhibit peptidyl-prolylcis/trans isomeraseactivity, in HeLa cells. Flow Cytometry Data Analysis (FACS)showed that thiuram monosulfides induce G0 arrest of theHCT116 cells. These results suggest that thiuram monosulfideshave the potential to guide the development of novel anticancerdrugs[5].

Reactions of thiuram monosulfides or disulfides lead to threedifferent categories of products: (a) adducts; (b) thiuram oxidationproducts and (c) ligand reduction with concomitant degradation todithiocarbamate and/or thiocarboxamide ligands (Fig. 1)[6].

0277-5387/$ - see front matter 2013 Elsevier Ltd. All rights reserved.http://dx.doi.org/10.1016/j.poly.2013.08.052

Corresponding authors at: Department of Chemistry, Namk Kemal University,59030 Tekirdag, Turkey (I.I. Ozturk), Medical Physics Laboratory, Medical School,University of Ioannina, Ioannina, Greece (N. Kourkoumelis), Section of Inorganic andAnalytical Chemistry, Department of Chemistry, University of Ioannina, Greece.Tel.: +30 26510 08374; fax.:+ 30 26510 08786 (S.K. Hadjikakou).

E-mail addresses: [email protected] (I.I. Ozturk), [email protected](N. Kourkoumelis), [email protected](S.K. Hadjikakou).

Polyhedron 67 (2014) 89103

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Examples of thiuram monosulfides or disulfides adducts(Fig. 1a), include the complexes: [Zn(Me4tms)I2] (Me4tms: Tetram-ethylthiuram monosulfide)[7], [Hg(Et4tds)I2] (Et4tds: Tetraethyl-thiuram disulfide) [8a], [CuCl(Me4tms)]2, [CuBr(Me4tms)]n,[CuI(Me4tms)]2, [CuCl(Et4tms)] (Et4tms: Tetraethylthiuram mono-sulfide) [8b]. Besides, five membered dicationic cyclic derivativeswhich are neutralized by metal halides counter anions (Fig. 1b)may obtained; e.g. [Et4biit-3]

2+[Hg2I6]2 (Et4biit-3: 3,5-bis(N,

N0diethylimonium)-1,2,4-trithiolane) [9a], [Et4biit-3]2+2[FeCl4]

and [Bu4biit-3]2+[Cu2X6]

2 (Bu4biit-3: 3,5-bis(N,N0dibutylimoni-um)-1,2,4-trithiolane, X:Cl, Br) [9b]. In the case of ligands degrada-tion (Fig. 1c), the SS bond are cleaved resulting in the formation ofdithiocarbamate and/or thiocarboximade fragments. These frag-ments can then coordinate to metal ions. Examples of ligand reduc-

tion with simultaneous ligand degradation include: Tl(Me2dtc)3[10a], [Me3Sb(dtc)2] [10b], [V2(l-S2)2(Et2dtc)4] [10c], [Mo(R2dtc)4](R: Me, Et, Ph) [10df], [Cu(Et2dtc)]4and [Cu{(i-Pr)2dtc}Br2] [8b].

Dithiocarbamates, on the other hand, already play an importantrole in medicine, as antidotes in heavy-metal detoxification[11].Dithiocarbamates exhibit strong tendency for metal ions com-plexetion with a variety of coordination modes (Fig. 2), especiallywith antimony(III) and bismuth(III)[12,13].

Metaldithiocarbamate complexes have also been investigatedfor their anti-cancer potential, most notably with platinum(IV) pal-ladium(II), tin(IV) and gold(I/III)[11]. Diethyldithiocarbamates caninhibit tumor induction caused by benzo[a]pyrene[11]. Recently,the bismuth diethyldithiocarbamate complex Bi(Et2DTC)3 wasshown to be a potent in vitro cytotoxin against seven human cancer

cell lines: (i) breast cancer (MCF-7, estrogen receptor (ER)+/proges-terone receptor (PgR)+), (ii) breast cancer (EVSA-T, estrogen recep-tor (ER)/progesterone receptor (PgR), (iii) renal cancer (A498),(iv) non-small cell lung cancer (H226), (v) ovarian cancer (IGROV),(vi) melanoma (M19 MEL) and (vii) colon cancer (WIDR) [11]. Thecomplex Bi(S2CNEt2)3shows selective activity towards MCF-7 (ERpositives) cells[11]. The steroid receptors (ER-aand ER-b) are lo-cated in human breast cancer cells (MCF-7), since estrogen recep-tors (ERs) are expressed in human breast cancer [14a]. This sexsteroid plays an important role in the development and propaga-tion of the disease [14a]. ERs are also of special interest becausetheir protein levels are elevated in premalignant and malignantbreast lesions as opposed to normal tissue [14b]. Consequently,inhibition of the ERs has become one of the major strategies forthe prevention and treatment of breast cancer [14b]. In contrastHeLa cells are devoid of estrogen receptors (ERs) [14c].

In the progress of our research on the design and developmentof new metallotherapeutics containing metal ions of group 15 [15],we have synthesized and characterized new antimony(III) and bis-muth(III) chloride complexes with the tetramethylthiuram mono-sulfide (Me4tms), tetramethylthiuram disulfide (Me4tds) andtetraethylthiuram disulfide (Et4tds) ligands (Fig. 3). Reactions ofthiuram sulfides with antimony(III) and bismuth(III) chlorides leadto the ligand degradation with the simultaneous formation of thecomplexes 13. Thus, tetramethylthiuram monosulfide (Me4tms)and tetramethylthiuram disulfide (Me4tds) react with anti-mony(III) chloride to form two different polymorphs of formula{[SbCl(Me2DTC)2]n} (1aand1b). Bismuth(III) chloride on the otherhand, reacts with Me4tds or Et4tds to produce {[BiCl(Me2DTC)2]n}(2) and {[Bi(Et2DTC)3]2} (3) complexes. Complexes 13have been

characterized by a variety of analytical methods; FT-IR, FT-Raman,1H, 13C NMR, TGADTA, X-ray powder diffraction (XRPD) and sin-gle crystal X-ray diffraction (XRD) analysis. Although, the crystalstructure of3 has been deposited four times up to now[16], how-ever, its structure was re-determined for the subsequent theoreti-cal and structure activity relationship studies (SAR). Compounds13were also tested forin vitrocytotoxicity against human breastadenocarcinoma (MCF-7) and human cervix adenocarcinoma(HeLa) cell lines. The high activity observed for the known com-pound 3 against MCF-7, (estrogen receptor (ER)+/progesteronereceptor (PgR)+) (IC50= 6 nM), and EVSA-T, (estrogen receptor(ER)/progesterone receptor (PgR)) (IC50= 9 nM),[11]promptedus to undertake a comparison study with 1a, 1b and 2. Multivariatestatistical and regression analysis were employed in order to eval-

uate the experimental activity results in relation to conformationrelated molecular descriptors.

2. Results and discussion

2.1. General aspects

Complex 1 was derived by two different routes which lead totwo polymorphs (1aand1b): reacting tetramethylthiuram mono-sulfide with antimony(III) chloride in methanol solution (1a) or byreacting tetramethylthiuram disulfide with antimony(III) chloridein acetonitrile/dichloromethane solutions (1b) in 1:1 ligand to me-tal ratio (Scheme 1). 2 was obtained when bismuth(III) chloridewas used instead of SbCl3 under the same conditions (Scheme 1).

In contrast,3 was isolated only by reacting methanol solutions oftetraethylthiuram disulfide with bismuth(III) chloride in 1:1 ligand

S

S

S

NN

R

R

R

R

M

M

S

SS

S

N

R

R

R

RS S

S

NR2R2N2+

[MXn]2-

(a) (c)(b)

Fig. 1. Possible products obtained from the reactions of thiuram sulfides with metal ion; (a) adduct; (b) thiuram oxidation products and (c) products derived from ligandreduction with concomitant degradation to dithiocarbamates and/or thiocarboxamides.

N

R

R

S

S

M N

R

R

S

S

M N

R

R

S

S M

N

R

R

S

S

M

M

Isobidentate Anisobidentate Monodentate Triconnective

Fig. 2. Possible coordination modes to a metal ion of the dialkyldithiocarbamate ligands.

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to metal molar ratio (Scheme 1). During this reaction the SS or CS bonds are clipped and dithiocarbamate and/or thiocarboximadefragments formed coordinate to the metal ions.

The products13, were characterized by e.a.; FT-IR, FT-Raman,1H, 13C NMR, TGADTA, XRPD and single crystal by X-ray diffrac-tion crystallography. Crystals of complex3 were found to be iden-tical with those already reported[16]. Compound3 crystallized inP21/c space group with a= 12.3965(8), b= 13.5006(8), c=14.7833(9) and b= 99.942(6), while the crystal data of thoseprevious reported are: space group P21/c with a= 12.55,

b= 13.58,c= 14.86 andb = 100.2[16a]; space groupP21/awith

a= 14.825(4), b= 13.640(2), c= 12.605(3) and b= 100.01(3)[16b]; space group P21/c with a= 12.625(2), b= 13.628(3),c = 14.835(3) andb = 100.002(2) [16c]; space group P21/cwitha= 12.4824(6),b= 13.5486(7),c= 14.7668(7) andb = 99.979(1)[16d].

The solubility of the complexes 1a and 1b in DMSO/H2O (0.5%DMSO in water) was checked by UVVis spectroscopy (Fig. S1).The stability of 1a and 1b in DMSO-d6 solutions was confirmedby 1H NMR spectra (Fig. S2). Slight changes between the initial1H NMR spectra and those after 48 h were probably due to solva-

tion effects (Fig. S2inset). The thermal stability of complexes 13

S

S

S

N N

CH3

CH3

CH3

H3C

S

SN S

S

N

CH3

H3C

CH3

CH3

S

SN S

S

N

CH2

H2C

H2C

H2C

H3C

H3 CC H3

CH3

Tetramethylthiuram monosulfide

(Me4tms, C6H12N2S3)

Tetramethylthiuram disulfide

(Me4tds, C6H12N2S4)

Tetraethylthiuram disulfide

(Et4tds, C10H20N2S4)

Fig. 3. Precursors used in this work.

S

S

S

N N

CH3

CH3

CH3

H3C

Me4tms

+ MCl3

S

S

N

H3C

H3C

M

S

S

N

CH3

CH3

Cl

M= Sb, (1)

M= Bi, (2)

1: M=Sb; MeOH

2: M=Bi;

MeOH/MeCN

S

SN S

S

N

CH3

H3C

CH3

CH3

Me4tds

+ MCl3 2: M=Bi;

MeOH/MeCN

S

SN S

S

N

CH2

H2C

H2C

H2C

H3C

H3C CH3

CH3

Et4tds

+BiCl3S

SN

CH2

H2C

H3C

H3C

S

S N

H2C

H2C

CH3

CH3

Bi

SS

N

H2C CH2

CH3

CH3

(3)

MeOH

1: M=Sb;

MeCN/CH2Cl2

Scheme 1. Reactions scheme for the synthesis of14.

I.I. Ozturk et al. / Polyhedron 67 (2014) 89103 91
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was also tested by TG-DTA analysis (under nitrogen flow). The datashows that compounds 13 remain stable up to 154 (1), 185 (2)and 145 (3) C, while beyond this temperature decomposition oc-curs by endothermic steps 154319 (1), 185328 (2) and 145415 (3) C, respectively (seeSI, Figs. S3S5).

2.2. Vibrational spectroscopy

Significant vibrational bands are listed in Table 1 (Figs. S6S16).The characteristic IR bands that are sensitive to molecular struc-ture are the stretching modes for the m(CN), m(CS), m(MS) andm(MCl) bands (M = Sb or Bi)[15].The IR spectra of complexes showdistinct vibrational bands at 1528 (1), 1519 (2) and 1508 (3) cm1

respectively, which are attributed to them(CN) vibrations and at964882 cm1 (1), 965879 cm1 (2) and 982841 cm1 (3) whichare assigned to the m(CS) vibrations. The IR spectra of complexes1

3show twom(CS) vibration bands and one strongm(CN) band. Thisis an indication of the anisobidentate character of the S2CNR2 li-gands[17]. The correspondingm(CN) andm(CS) vibration bands ofthe free ligands are found at 15171499, 962 and 861 cm1 forMe4tms, 1498, 978 and 848 cm

1 forMe4tds and 1496, 999 and817 cm1 forEt4tds, respectively[18].

Far-IR spectra of1 and 2 show distinct vibration bands at 304and 423 cm1, which are assigned to m(SbCl) and m(BiCl) [67,15,19]. The m(SbS) vibration band at 384 cm1 (1) [15]and them(BiS) vibration bands are 202 cm1 for complex 2 and 247 cm1

for complex3, respectively[19].Vibration bandsm(MS) andm(MCl) (M: Sb or Bi) are also Ra-

man active[15,20]. Thus, bands at 183 and 229 cm1 in the Ramanspectra of complexes 2and 3are due to the m(BiS) vibrations[20],

while the band at 448 cm1

is assigned to them(BiCl) vibration forcomplex 2[20]. The m(SbS) vibration band in the Raman spectrum

is at 388 cm1 while the m(SbCl) vibration band is 310 cm1 forcomplex1.

2.3. NMR spectroscopy

The 1H and 13C NMR spectral data of 13 and of free ligandsMe4tms, Me4tds and Et4tds have been recorded in DMSO-d6 on aBruker AC250 MHz FT NMR spectrometer (Figs. S17S28). Signifi-cant resonances are summarized inTable 2. The 1H NMR spectralof1a and1b in DMSO-d6 are also recorded on a Bruker AvanceAV-500 MHz LC NMR spectrometer. The resonance signal for themethyl protons, of 1a and 1b complexes is at 3.352 (1a) and3.355 (1b) ppm respectively, while the singlet at 3.415 ppm isdue to DMSO-d6. The differences observed for the methyl protonsin the case of1aand1b(Fig. 4) suggest the retention of the struc-tural variations in solution as well.

The 13C NMR spectra of Me4tms and Me4tds ligands show sig-

nals at 186.98 ppm and 192.60 ppm, respectively, due to the>C(@S) carbons. The 13C(NCS2) resonance signals in the 13C NMR

spectra of 13 are observed at 197.03, 200.82 and 198.99 ppm,respectively compared to similar dithiocarbamate complexes. Themethyl carbons were observed at 44.24 ppm (1), 44.16 ppm (2)and 12.95 ppm (3), respectively. The signal at 48.74 ppm in thespectrum of3 is assigned to the methylene carbon.

2.4. Crystal and molecular structure {[SbCl(Me2DTC)2]n} (1aand 1b),{[BiCl(Me2DTC)2]n} (2) and {[Bi(Et2DTC)3]2} (3)

Selected bond distances and angles of complexes 1a, 1b and 2are given in Table3, whiletheir ORTEP diagrams are shownin Figs. 57.

Two polymorphs of1 were isolated, 1a and 1b (Figs. 5 and 6)depending on the preparative procedure followed. Crystals from

Table 1

Vibrational (IR, far-IR and Raman) spectra data (cm1) of complexes 13and the corresponding ones of the ligands that complexes 13derived.

Compound Far-IR Raman

m(CN) m(C@S) m(CS) m(MS) m(MCl) m(MS) m(MCl)

Me4tms 15171499 s 962 s 861 m Me4tds 1498 s 978 s 848 m Et4tds 1496 s 999 s 817 m 1 1528 s 964 s 882 w 384 304 388 3102 1519 s 965 s 879 w 202 423 183 4483 1508 s 982 s 841 w 247 229

Table 2

Chemical shifts (ppm) of the resonance signals observed in 1H and 13C NMR spectra of starting compounds (Me4tms, Me4tds and Et4tds)and complexes 13in DMSO-d6.

Compounds 1H NMR chemical shift (ppm) 13C NMR chemical shift (dppm)

Me4tms 3.383.42, d, 12H, (CH3 of Me4tms) 44.63 (CH3, Me4tms)45.31 (CH3, Me4tms)186.98 (C@S, Me4tms)

Me4tds 3.503.59, d, 12H, (CH3 of Me4tds) 42.60 (CH3, Me4tds)47.90 (CH3, Me4tds)192.60 (C@S, Me4tds)

Et4tds 1.161.21, t, 6H, (CH

3 of Et

4tds) 12.01 (CH

3, Et

4tds)

1.361.41, t, 6H, (CH3 of Et4tds) 14.12 (CH3, Et4tds)3.943.99, q, 8H, (CH2 of Et4tds) 48.08 (CH2, Et4tds)

52.36 (CH2, Et4tds)191.69 (C@S, Et4tds)

1 3.352, s, 12H, (CH3 of 1a) 44.24 (CH3, 1)3.355, s, 12H, (CH3 of 1b) 197.03 (CS2, 1)

2 3.30, s, 12H, (CH3 of 2) 44.16 (CH3, 2)200.82 (CS2, 2)

3 1.231.28, t, 12H, (CH3 of 3) 12.95 (CH3, 3)3.653.74, q, 8H, (CH2 of 3) 48.74 (CH2, 3)

198.99 (CS2, 3)

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the reaction of antimony(III) chloride with Me4tms in methanolwere of1a polymorphic form (space group:P21/c,a= 10.0276(5),b= 16.4718(7), c= 8.3203(4) , a= 90.00, b= 100.598(5),c= 90.00), while those derived from Me4tds in acetonitrile/dichloromethane were of 1b form (space group: P21/c,a= 14.3425(5), b= 10.5007(3), c= 9.0543(3) , a= 90.00,b= 97.154(3),c = 90.00). In order to assure the existence of eachpolymorphic form in the bulk samples, X-ray powder diffraction(XRPD) data were collected. The two measured patterns are clearly

different (Fig. 8) but similar to the theoretical patterns calculatedfrom single crystal X-ray data (Fig. S29). Both patterns show anamorphous phase which is attributed to the holder substrate. Thisis more evident for1adue to the extremely small amount of crys-talline powder available. Therefore, the variations in preparativeprocedures lead to polymorphic forms.

The metal centers of complexes1(1aand1b) and2with eitherSb or Bi are five coordinated (Figs. 57). Complexes 1a, 1b and 2 arepolymers with distorted square pyramidal (SPY) geometry in each

Fig. 4. 1H NMR spectra of1a and1b in DMSO-d6.

Table 3

Selected bond lengths () and angles () 13complexes.

1a 1b 2

Bond length ()Sb1Cl 2.7061(13) Sb1Cl3 2.6096(7) BiCl 2.8159(17)Sb1S1 2.5486(13) Sb1S1 2.4665(6) BiS1 2.6834(19)Sb1S3 2.6243(13) Sb1S11 2.5485(6) BiS2 2.7014(18)Sb1S11 2.5098(12) Sb1S13 2.6399(7) BiS3 2.6481(18)S1C2 1.723(5) S1C2 1.751(2) BiS4 2.937(2)S3C2 1.717(5) S3C2 1.702(2) S1C1 1.714(7)S11C12 1.750(5) S11C12 1.729(3) S2C1 1.744(8)S13C12 1.676(5) S13C12 1.714(3) S3C4 1.740(8)

S4C4 1.709(8)

Bond angles ()ClSb1S1 81.56(4) Cl3Sb1S1 85.20(2) ClBiS1 80.33(5)ClSb1S3 150.64(4) Cl3Sb1S11 81.68(2) ClBiS2 147.38(6)ClSb1S11 83.97(4) Cl3Sb1S13 150.23(2) ClBiS3 79.99(5)S1Sb1S3 69.09(4) S1Sb1S11 88.34(2) ClBiS4 124.94(6)S1Sb1S11 84.95(4) S1Sb1S13 90.36(2) S1BiS2 67.07(5)

S3Sb1S11 92.93(4) S11Sb1S13 68.75(2) S1BiS3 82.80(6)S1BiS4 129.83(6)S2BiS3 96.39(6)S2BiS4 79.97(6)S3BiS4 63.87(6)

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monomeric unit. The ligand is anisobidentate l2-bridging in bothcomplexes1and2. One l2S Sb bridging interaction in1aformsa highly distorted octahedral (Oh) geometry around antimony,while twol2S Sb bridges in 1bleads to a pentagonal bi-pyrami-dal (PBP) (Figs. 5 and 6). These differences in the intermolecular

interactions between1a and1b establish the two different poly-morphs in the solid state (Figs. 5B and 5B). Two l2S Bi andonel2Cl Bi bridging interaction also lead to pentagonal bipyra-midal (PBP) geometry around bismuth ions in case of2 (Fig. 7).

Two stronger metalsulfur bonds, with shorter MS bondlengths (Sb1S1 = 2.5486(13) , Sb1S11 = 2.5098(12) (1a),Sb1S1 = 2.4665(6), Sb1S11 = 2.5485(6) (1b),BiS3 = 2.6481(18) , BiS1 = 2.6834(19) (2)) and two weakerbond with longer MS distances (Sb1S3 = 2.6243(13), Sb1S13 =2.924 (1a) and Sb1S3 = 2.923, Sb1S13 = 2.6399(7) (1b), Bi1S2 = 2.7014(18) and Bi1S4 = 2.937(2) (2)) are formed. Thesebonds in 1a and1b are in the range of the corresponding SbSlengths (varying from 2.482 to 3.009 ) found in {[SbCl2(-MBZIM)4]

+Cl2H2O(CH3OH)} [15b], {[SbCl2(MBZIM)4]

+Cl3H2-

O(CH3CN)} [15b], a,b,c-Cl-[SbCl3(MBZIM)2] [15b], a,b,d-Cl-

[SbCl3(EtMBZIM)2] [15b], a,b,c-Cl-[SbCl3(MTZD)2] [15b], and b,c,d-Cl-[SbCl3(tHPMT)2] [15b] complexes. The equatorial angles in 1a,1b and 2 are: ClSb1S1 = 81.56, ClSb1S13 = 124.13, S13Sb1S3 = 79.62, S1Sb1S3 = 69.09 (1a), Cl3SbS11 = 81.68,S11SbS13 = 68.75, S13SbS3 = 80.06, S3SbCl3 = 123.95

(1b) and ClBS1 = 80.33, S1BiS2 = 67.07, S2BiS4 = 79.97,S4BiCl = 124.94 (2), while the corresponding basal SaxialMXbasal (M = Sb or Bi and X = S or Cl) angles lie between: S11SbS13 = 65.09 to S11SbS3 = 92.93 (1a) S1SbS3 = 66.19 toS1SbS13 = 90.36 (1b) and between S3BiS4 = 63.87 to S3BiS1 = 96.39 (2), indicating high deviation from their idealgeometry. This deviations from the 90of the ideal SPY geometryare due to the repulsions between the free electrons pair locatedon the M (Sb or Bi) and those of the covalent MX bonds (X = S orCl) in accordance to the Valance Shell Electron Pair Repulsion(VSEPR) theory.

The MCl bond distances are 2.7061(13) and 2.6096(7) in1aand 1b respectively and 2.8159(17) in 2. These distances areshorter than the sum of metal and chloride van der Waals radii

(SbCl = 4.04.46 and BiCl = 4.105.57 ) [21a]. The SbCl bond

Fig. 5. (A) ORTEPdiagram together with labeling scheme of two polymorphs 1a (B) Intermolecularl2S Sb interactions leading to polymerization of1a.



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distances are similar to those found in {[SbCl2(MBZIM)4]+Cl2H2-

O(CH3OH)} [15b], {[SbCl2(MBZIM)4]+Cl3H2O(CH3CN)} [15b],

a,b,c-Cl-[SbCl3(MBZIM)2] [15b], a,b,d-Cl-[SbCl3(EtMBZIM)2] [15b],a,b,c-Cl-[SbCl3(MTZD)2] [15b], and b,c,d-Cl-[SbCl3(tHPMT)2] [15b]where the SbCl bond lengths lie between 2.376 and 3.010 . Wehave previously shown that the shorter SbCl bond correspondsto the apical chlorine, while the SbCl bond, for the terminal chlo-rine atom in the equatorial plane, is longer than that of SbClapicalwhile the SbClbridgingbond distances are longer [15h]. Based onthese findings the SbCl bonds of 1a or 1b are classified to theSbClterminalbonds.

The CS bonds varied between 1.676 and 1.751 in complexes

1a,1b and2; this distance is in the range of the free tetramethyl-thiuram monosulfide (1.655 ) and tetramethylthiuram disulfide(1.647 ) [21b,c]. The CS single bonds in free ligands are 1.7871.807 for tetramethylthiuram monosulfide and 1.805 fortetramethylthiuram disulfide [21b,c].

Complex 3 is dimeric (Fig. 9). Two bridging l2SBi bonds of3.188(1) lead to dimeric molecular conformation in the crystalstructure. The geometry of each monomer is pentagonal bipyrami-dal (PBP) around bismuth. The central bismuth atom is six coordi-nated. Five sulfur atoms occupy the equatorial plane while onesulfur atom lies in axial position. The resulting BiS6 coordinationpolyhedron approximates a pentagonal pyramid (Fig. 9).

The volumes of Hirshfeld surfaces of13(Fig. 10) and the cor-responding related antimony(III) chloride compounds of formulae

{[SbCl2(MBZIM)4]Cl3H2O(CH3CN)} (MBZIM = 2-mercapto-benz-imidazole [15b], {[SbCl2(MBZIM)4]Cl2H2O(CH3OH)} [15b],

[SbCl3(MBZIM)2] [15b], [SbCl3(EtMBIM)2] (EtMBIM = 5-ethoxy-2-mercapto-benzimidazole) [19b], [SbCl3(MTZD)2] (MTZD = 2-mer-capto-thiazolidine) [15b], [SbCl3(tHPMT)2], (tHPMT = 2-mercapto-3,4,5,6-tetrahydro-pyrimidine) [15b] and [SbCl3(Hthcl)2]n(Hthcl = x-thiocaprolactam) [15h] are also determined and aresummarized inTable 4among with MW and IC50values used fortheoretical studies.

2.5. Biological studies

The cytotoxicity of complexes 13against human breast adeno-carcinoma (MCF-7) and human cervix adenocarcinoma (HeLa) cells

have been evaluated by means of Trypan blue method. Table 4summarizes the IC50values of13 against HeLa and MCF-7 cellsand the corresponding ones of other related antimony(III) chloridecompounds. The IC50 values of the two polymorphs 1a and 1bslightly vary (Table 4). Although, both1aand1bpossess the samechemical composition, they affect the cell viability differently dueto the retention of the structure diversity in their solutions (seeNMR studies).

Antimony(III) and bismuth(III) complexes 13 show higheractivity than the standard anti-cancer agents; cisplatin [15e,i],doxorubicin [11,22a] (the most active agent in advanced breastcancer [22b]) and tamoxifen [22c] (an antiestrogen drug whichinhibits the growth of MCF-7 cells by blocking the steroid receptors(ER-aand ER-b) [22d]) (Table 4). Compounds,13exhibit 2153-

fold higher activity than cisplatin against HeLa cells, while againstMCF-7 cells, 158340 fold higher activity (Table 4). Moreover,1a

Fig. 6. (A)ORTEPdiagram together with labeling scheme of two polymorphs 1b (B) Intermolecularl2S Sb interactions leading to polymerization of1b.

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has almost similar IC50 value with doxorubicin against MCF-7,while1b,2 and3 are less active (0.8 to 0.4-fold) than doxorubicinagainst the same cell line. Against HeLa cells, however, complexes

13 are more potent from 2 to 6 times, than doxorubicin. Com-plexes 13are also more effective than tamoxifen. Thus,1aexhibit2 times higher activity than the corresponding one of tamoxifenagainst MCF-7.

Antimony(III) and bismuth(III) complexes 13exhibit strongeranti-proliferative activity against MCF-7 than against HeLa whichis: 23 (1a) ,21(1b), 14 (2) a nd 4 (3) foldhigher (Table 4). Moreover,complex3with higher molecular volume (MV) (Table 4,Fig. 10) ismore active against HeLa cells whereas 1a, 1b and 2 with lower MVare more active against MCF-7. Furthermore, antimony(III) com-plexes1aand 1bwith the non-cyclic thiocarbamates ligands (withtwo sulfur donor atoms) show higher activity against HeLa cellsthan the corresponding one of other related antimony(III) chloridecompounds of the heterocyclic thioamides (Table 4).

2.6. Computational studies

The physicochemical characteristics of some biologically active

compounds are related with pharmaceutical properties like bio-availability, stability and distribution profile via the qualitativeconcept of drug-likeness. The physicochemical characteristics ofsome biologically active compounds are related with pharmaceuti-cal properties like bioavailability, stability and distribution profilevia the qualitative concept of drug-likeness. There are many bio-logically active compounds that cannot fulfill the requirementsfor potential drugs. These however can be valuable agents foruncovering the hypotheses driven modeling of biological mecha-nisms [23a]. Lipinskis Rule of Five [23b,c] is currently the goldstandard to evaluate a chemical compound as a potential drug, uti-lizing four rules related to the calculated octanolwater partitioncoefficient (clogP), the molecular mass and the hydrogen donorsand acceptors. In addition to these molecular descriptors, other

Fig. 7. (A) ORTEPdiagram together with labeling scheme of2 (B) Intermolecularl2S Bi andl2Cl Bi interactions leading to polymerization in complex 2.



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researchers have also shown that molecular weight and molarrefractivity are crucial [23d] while others [23e,f] suggested thatrotatable bonds and polar surface area are related to increased oral

bioavailability. In our case, given the excellent IC50 values of thestudied complexes, we assessed 11 conformation-dependent prop-erties which have been successfully used (among others) as molec-ular descriptors for drug-likeness [23g]. Most of these descriptorsare sums of structural features and only two were calculated: logof the octanolwater partition coefficient (AlogP) using the Ghoseand Crippens method [23h] and molar refractivity (ALogP_MR).The rest of the descriptors, used in this study, are: molecularweight (MW), number of rotatable bonds (NRB), number of aro-matic rings (NAR), number of rings (NR), hydrogen bond acceptors(HBA) and hydrogen bond donors (HBD), molecular volume (MV),surface area (SA) and polar surface area (PSA). The physicochemicalproperties attributed to these descriptors contribute to the conceptof molecular property spaces [23i] which relates molecular sensi-

tivity with topological flexibility. Table 5shows the mean values

of the calculated properties for the complexes 1a, 1b, 2,3 and forthe related antimony(III) chloride compounds.

Multivariate statistical analysis of the descriptors was carriedout with principal components analysis (PCA) using the Unscram-bler (CAMO Software AS, Norway) software package. PCA is a sta-tistical modeling technique which effectively removes theredundancy of the original dataset by compressing it into a feworthogonal uncorrelated principal components (PCs) which arean effective indicator of the chemical diversity related to the con-formation of each compound. 98% of the total variance was ex-plained by the first two PCs (the 3rd PC contributes by 1%).Table 6shows the eigenvectors found after the diagonalization ofthe covariance matrix.

The results (Table 6) indicate high loading values from MW, MV,SA and PSA. The first PC, which explains 93% of the total variance,contains particularly high loadings from MW and SA. The twodimensional loadings plot of PC1 versus PC2 is shown in Fig. 11(The overlapping labels inFig. 11are due to software limitations,since there is not an option to manipulate the image in the multi-variate analysis software. Nevertheless, we also believe that this isnot necessary since the overlapping labels are near zero (minimalloadings) and therefore they have no statistical significance in ouranalysis. In contrast, the significant high loadings values (MW, MV,SA and PSA) are clearly labeled).

Fig. 11describes the data structure in terms of variable correla-tions. PSA and MV show a strong positive correlation (specific forthese ligands) while they are inversely correlated with MW. Inthe analysis, compound 3could be treated as an outlier since someof its specific molecular descriptors are vastly different comparedto the others. However, no significant discrepancy is found regard-ing the final PC loadings.

The correlation loadings plot indicates that all variables arehighly correlated; therefore the distinct significance of each vari-able may not be apparent (especially with our small dataset). Torelate the variation of the IC50 values for HeLa cells (dependent var-iable) to the variations of the molecular descriptors (independentvariables) statistically indexed by PCA, we have carried out partialleast squares (PLS) regression analysis which performs well whenthex-data are correlated like in this case. The PLS regression modelwith 3 latent components constructed from the set of the descrip-tors with high PC loadings was not satisfactory due to the lowPear-son correlated coefficient (R2 = 0.5). However, a similar regressionmodel predicting the activity of these compounds was successfully

Fig. 8. The two clearly different XRPD patterns of1a and1b measured.

Fig. 9. Molecular formula of complex3.

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constructed from the following descriptors: MW, PSA, SA, MV,

AlogP_MR, HBA and HBD where the latter was considered as highlysignificant followed by PSA and described by the equation:IC50

(HeLa) = 0.02 ALogP_MR + 0.002 MW 0.74 HBA + 1.23HBD + 0.01 MV+ 0.003 SA 0.04 PSA + 2.2.Fig. 12depicts thegraphical representation of the linear model and the correspondingfitting parameters.

Our statistical analysis concentrated on important moleculardescriptors closely related to the comparable geometric parame-ters of the two polymorphs. Therefore, we have particularlyemphasized to structural terms although energetic terms, solva-tion effects and toxicity studies are crucial evaluation parameters.

2.7. Docking studies

To clarify the possible involvement of estrogen receptors (ERs)which are present in MCF-7 cells [14a] in the mechanism of action

of 1a, 1b and 2 in contrast to 3 (Table 4) molecular docking studies

were performed. Estrogen receptors (ER) are of two forms, alpha(a) andbeta(b) and play a crucial role in mammary gland develop-ment and morphogenesis [24a]. The crystal structure of estrogenreceptora (ERa) complexed with 17b-estradiol (1A52) [24b] wasobtained from Protein Data Bank (PDB). Estradiol is a natural estro-gen which can bind in ERs [24a]. Complexes1a,1b,2 and3 wereexamined regarding their ability to be docked into the ligand bind-ing domains. Validation docking was performed and the root meansquare deviation (RMSD) between the co-crystallized and thedocked ligand and was found 0.59 (Fig. 13A).

Both 1aand 1b compounds were docked into the ligand bindingdomains specified by the two larger cavities of volume 142 and133 3 (Fig. 13B). They also adopt the same conformation havingslightly different interaction energies of83.5 and 84.7 (in scor-ing arbitrary units) respectively with the receptor which probablyexplains their similar activity. The corresponding ligandprotein

Fig. 10. Hirshfeld surfaces of1 (A),2 (B) and3 (C).



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Table 4

Hirshfeld surfaces Volumes, Molecular weights and IC 50against MCF-7 and HeLa cell lines of13and the corresponding ones of other related antimony(III) chloride compounds.

Compound Volume (3) MW (gr/mol) IC50(lM) Refs.

HeLa MCF-7

1a 330.6 397.61 0.46 0.07 0.020 0.003 1b 331.19 397.61 0.51 0.10 0.024 0.004

2 414.73 484.84 0.33 0.03 0.023 0.003 3 1207.07 1307.47 0.19 0.02 0.043 0.008

{[SbCl2(MBZIM)4] Cl 3H2O(CH3CN)} 754.26 911.94 6.4 1.6 [15b]{[SbCl2(MBZIM)4] Cl 2H2O(CH3OH)} 739.79 896.93 7.0 2.0 [15b][SbCl3(MBZIM)2] 460.02 528.49 7.7 1.2 [15b][SbCl3(EtMBIM)2] 572.77 616.58 6.9 1.1 [15b][SbCl3(MTZD)2] 360.9 466.50 6.8 4.4 [15b][SbCl3(tHPMT)2] 418.77 460.49 7.7 2.5 [15b][SbCl3(Hthcl)2]n 471.6 484.51 12.23 2.27 [15h]Cisplatin 10 6.81 0.32 [15e,i]Doxorubicin 1.12 0.018 [11,22a]Tamoxifen 0.0455 [22c]

* This work, MBZIM = 2-mercapto-benzimidazole, EtMBIM = 5-ethoxy-2-mercapto-benzimidazole, MTZD = 2-mercapto-thiazolidine, tHPMT = 2-mercapto-3,4,5,6-tetrahy-dro-pyrimidine, Hthcl =x-thiocaprolactam.

Table 5

Molecular descriptors mean values.

Property Mean value

AlogP 4.78ALogP_MR 124.2MW 632.1NRB 6NR 4NAR 1HBA 8HBD 4MV 500.8SA 453.8PSA 185.6

Table 6

Normalized X- loadings for the first two PCs.

PC1 PC2

ALogP 7.826e-03 3.237e-02ALogP_MR 0.168 9.962e-03MW 0.730 0.487NRT 1.039e-02 1.959e-02NR 6.522e-03 9.310e-03NAR 2.237e-03 1.412e-02HBA 1.239e-02 9.499e-03HBD 6.147e-03 3.312e-02MV 0.363 0.726SA 0.501 4.142e-02PSA 0.237 0.481

Fig. 11. X-Loadings plot (x-expl: 93%, 5%).

Fig. 12. Pls regression analysis for the activity against HeLa cells.

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interaction in the case of estradiol was found 113.8 while this li-gand was further stabilized by hydrogen bonding interactions. Inthe case of1a and 1b the complexes are stabilized in the hydro-phobic core by van der Waals interactions. Hydrophobic van derWaals contacts are also responsible for the docking of2 into thesame pocket with almost the same interaction energy with 1aand1b (78.3). 3, due to its bulk dimensions, cannot reach thebinding sites and therefore interacts with the residues present atthe receptors surface exhibiting hydrogen bonding interactionwith the N atom of Leu462.

Tamoxifen is a well-known breast cancer drug which acts as anestrogen antagonist inhibiting the growth of tumours dependenton estrogen stimulation. The crystal structure (PDB ID: 3ERT) ofthe ERacomplex with 4-hydroxytamoxifen (an active metabolite

of tamoxifen) shows that ligand binding causes a conformational

shift of helix 12 into an adjacent coactivator site and shows aremarkable resemblance with docking results with 1A52 of 1aand1b complexes regarding their binding conformation (Fig. 14).Although the two structures (complex versus 4-hydroxytamoxifen)present critical differences (hydroxyl groups, phenyl rings, size)they adopt similar conformation. The dimethyl-amino-ethyl side-chain extends to the space also available for the thiuram moietywhile the phenyl ring moves deeper into the binding pocket likethe Cl atom of1a and 1b. Complexes 1a and 1b show significanthydrophobic interactions into the binding pocket while of 4-hydroxytamoxifen also exhibits significant hydrogen bondinginteractions with Glu353, Thr347, Phe404 and Arg394. The similarbinding is probably indicative of a similar action mechanism to-wards ERs and it might be explain the same IC50values between

tamoxifen and1a.

Fig. 13. (A) Validation docking results of 1A52 with 17b-estradiol. Drawn with LIGOPLOT+ [24c]. (B) The ERabinding pocket with1a and1b.



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3. Conclusions

Three antimony(III) or bismuth(III) chloride complexes of for-mulae {[SbCl(Me2DTC)2]n} (1), {[BiCl(Me2DTC)2]n} (2) and {[Bi(Et2-DTC)3]2} (3) were synthesized. Alterations in preparation of1 bythe use of different processor reagents (Me4tms instead of Me4tds)and solvation effect (Scheme 1), lead to different polymorphicforms in the solid state (1aand1b).

The cytotoxicity of complexes 13against human cervix adeno-carcinoma (HeLa) and human breast adenocarcinoma (MCF-7) cellshave been evaluated. Although both 1a and 1b possess the samechemical composition, the IC50 values of the two polymorphs 1aand1b varies slightly (Table 4). Furthermore, antimony(III) com-plexes 1a and 1b with thiocarbamates exhibit higher activityagainst HeLa cells than that of other related antimony(III) chloride

compounds of the heterocyclic thioamide (Table 4). Complex 3occupied the higher molecular volume (MV) (Table 4, Fig. 10)and is more active against HeLa cells, while 1a, 1b and 2 with lowerMV are more active against MCF-7.

Complexes 13 show higher activity against MCF-7 than HeLa(Table 4). Tiekink et.al, have shown that bismuth dithiocarbamatecomplexes of general formula Bi(S2CNR2)3 demonstrate potentactivity against breast cancer (MCF-7, estrogen receptor (ER)+/pro-gesterone receptor (PgR)+) in contrast to breast cancer (EVSA-T),estrogen receptor (ER)/progesterone receptor (PgR)) cells[11].The higher activity of these complexes (Bi(S2CNR2)3) againstMCF-7 reveals the involvement of estrogen receptors (ERs) in theirmechanism of cytostasis together with progesterone receptors(PgR) [progesterone is a precursor for the major steroid hormones

(androgens, estrogens, corticosteroids) which adjust ERs concen-trations among with estradiol [25]]. These findings support ourhypothesis for the involvement of ERs in the mechanism of cytos-tasis of1a,1band2. However, the higher activity of13observedagainst MCF-7 than HeLa cells may be also due to the different tis-sues origin (breast or cervix). Molecular docking studies haveshown that 1a, 1b and 2 are docked in the same pocket with theERs modulators (like 17b-estradiol, a natural estrogen [24a]).Tamoxifen, a known anti-estrogen drug, on the other hand, whichinhibits the growth of MCF-7 cells by blocking the steroid receptors(ER-aand ER-b) [22d], is also docked in the same pocket as 1a,1band 2 (Fig. S28). This might be due to the same mechanism ofcytostasis towards MCF-7 cells adopted either by 1a, 1b and 2 ortamoxifen. 3 cannot reach this binding site due to its bulk dimen-

sions. This inability to enter the binding sites is compatible with itsreduced activity against MFC-7 cells in regards to1a, 1b and2.

Multivariate analysis studies of 11 conformation-dependentmolecular descriptors have shown (Table 6) high loading valuesfrom molecular weight (MW), molecular volume (MV), surfacearea (SA) and polar surface area (PSA). Molecular docking studiesexplained the experimental IC50values in terms of the known li-gand binding domains of ER (1A52) while PLS analysis with onlythree latent components constructed a linear theoretical modelwhich effectively predicts the experimental inhibitory activity ofthe studied complexes.

4. Experimental

4.1. Materials and instruments

All solvents used were of reagent grade; antimony(III) chloride(Aldrich), bismuth(III) chloride (Aldrich), tetramethylthiurammonosulfide (Aldrich), tetramethylthiuram disulfide (Aldrich) andtetraethylthiuram disulfide (Aldrich) were used with no other puri-fication. Elemental analyses for C, H, N, and S were carried out witha Carlo Erba EA MODEL 1108 elemental analyzer. Melting pointswere measured in open tubes with a STUART-SMP10 scientificapparatus and are uncorrected. IR spectra from 4000 to 370 cm1

were obtained in KBr pellets while far-IR spectra (40050 cm1)were obtained in polyethylene discs with a Perkin-Elmer SpectrumGX FT-IR spectrometer. The FT-Raman spectra were recorded witha Bruker IFS 66 spectrometer with an FRA 106 Raman moduleattachment and Nd3+/YAG laser excitation at 1064 nm. 1H and13C NMR spectra were recorded with a Bruker AC250 MHz FTNMR and Bruker Avance AV-500 MHz LC NMR instruments inDMSO-d6with chemical shifts given in parts per million referencedto internal TMS (H). Thermal studies were carried out on a Shima-dzu DTG-60 simultaneous and Thermal GravimetryDifferentialThermal Analysis (TGDTA) apparatus for complexes 1, 2 and aSeteram Labsys TG-DTA for3 under N2flow (50 cm

3 min1) witha heating rate of 10 C min1. X-ray powder diffraction patterns,

from the powder derived from crystals, were obtained using a Bru-ker AXS D8 Advance diffractometer in BraggBrentano geometryequipped with a Cu sealed-tube radiation source (k= 1.54178 )and a secondary beam graphite monochromator.

4.2. Synthesis and crystallization of {[SbCl(Me2DTC)2]n} (1),{[BiCl(Me2DTC)2]n} (2) and {[Bi(Et2DTC)3]2} (3)

4.2.1. {[SbCl(Me2DTC)2]n} (1)A solution of tetramethylthiuram monosulfide (0.25 mmol,

0.052 g) in methanol (1a) or tetramethylthiuram disulfide

(0.25 mmol, 0.060 g) in acetonitrile (1b) (10 mL) was added to asolution of SbCl3(0.25 mmol, 0.057 g) in methanol (1a) or dichlo-romethane solution (1b) 10 mL, under stirring for 30 min. After-wards, the solutions were filtered off. The clear yellow solutionswere kept in darkness at room temperature to give light yellowcrystals.

4.2.2. {[BiCl(Me2DTC)2]n} (2)A solution of BiCl3 (0.25 mmol, 0.079 g) in methanol (10 ml)

was added to an acetonitirile solution (10 mL) of 0 tetramethyl-thiuram monosulfide (.25 mmol, 0.052 g) or tetramethylthiuramdisulfide (0.25 mmol, 0.060 g) under stirring for 30 min. After-wards, the solutions were filtered off. The resulting clear yellow

solutions were kept in darkness at room temperature to give yel-low crystals.

Fig. 14. Docking results of 1A52 with 4-hydroxytamoxifen (a known anti-estrogendrug) vs. 1a complex.

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4.2.3. {[Bi(Et2DTC)3]2} (3)0.25 mmol bismuth(III) chloride (0.079 g) were dissolved in

methanol (10 ml) and the resulting solution is added to a methanolsolution (10 mL) of tetraethylthiuram disulfide (0.25 mmol,0.074 g). The solution was stirred 30 min and then was filteredoff. The clear light yellow solution was kept in darkness at roomtemperature to give yellow crystals.

1:Light yellow crystals, yield: 70% (method A), 75% (method B),

melting point: 224226 C. ElementalAnal. Calc. for C6H12ClN2S4-Sb: C, 18.12; H, 3.04; N, 7.04; S, 32.25. Found: C, 18.17; H, 3.09;N, 7.12; S, 32.33%. IR (cm1): 2927w, 1524s, 1383s, 1241s, 1148s,1043 m, 1016w, 972s, 830w, 570m, 444m, 385w, 374m.

2:Yellow crystals, yield 80% (method A), yield 73% (method B),melting point: >300 C. ElementalAnal.Calc. for C6H12ClN2S4Bi: C,14.86; H, 2.49; N, 5.78; S, 26.45. Found: C, 14.90; H, 2.53; N, 5.82; S,26.54%. IR (cm1): 2925w, 1520s, 1383s, 1240s, 1147s, 1042m,965s, 568m, 445m.

3: Yellow crystal, yield 75%, melting point: 133135C. Elemen-talAnal.Calc. for C15H30N3S6Bi: C, 27.56; H, 4.63; N, 6.43; S, 29.43.Found: C, 27.63; H, 4.70; N, 6.38; S, 29.52: IR (cm1): 2974w,2931w, 1506s, 1457w, 1432s, 1378w, 1354m, 1297w, 1273s,1200m, 1147m, 1093w, 1075m, 982m, 908m, 841m, 778w,561w, 375w.

4.3. X-ray structure determination

Intensity data for 1aand 1bwere collected on a KUMA KM4CCDfour-circle diffractometer [26a] witha CCD detector, usinggraphitemonochromated Mo Karadiation (k= 0.71073 ). Cell parameterswere determined by a least squares fit [26b]. All data were cor-rected for Lorentz-polarization effects and absorption [26b]. Thestructures were solved with direct methods with SHELXS97 [26c]and refined by full-matrix least squares procedures onF2 with SHEL-XL97 [26d].

Intensity data for the crystals of23were collected on an Ox-ford Diffraction CCD instrument, using graphite monochromated

Mo radiation (k= 0.71073 ). Cell parameters were determinedby least-squares refinement of the diffraction data from 25 reflec-tions [26b]. All data were corrected for Lorentz-polarization effectsand absorption [26b,e]. The structures were solved with directmethods with SHELXS97 [26c] and refined by full-matrix least-squares procedures onF2 with SHELXL97 [26d]. All non-hydrogenatoms were refined anisotropically, hydrogen atoms were locatedat calculated positions and refined via the riding model with iso-tropic thermal parameters fixed at 1.2 (1.3 for CH3 groups) timesthe Ueq value of the appropriate carrier atom.

The molecular volumes defined as the areas in the crystalwhere the electron density which originates from a given moleculeis higher than the density from the rest of the crystal (the surfacelimiting this space is called Hirshfeld surface [26f]) were calcu-

lated with the CrystalExplorer program [26g].Significant crystallographic data for antimony(III) chloride and

bismuth(III) chloride complexes:1a: C6H12ClN2S4Sb: MW = 397.61, monoclinic, P21/c,

a= 10.0276(5), b= 16.4718(7), c= 8.3203(4) , b= 100.598(5),V= 1350.84(11) 3, Z= 4, Dcalc= 1.955 g cm

3, l= 2.8mm1,reflections collected: 5741, independent: 2805, R int= 0.030. FinalRindices [I> 2r(I)];R1= 0.0385,wR2= 0.0776,S= 1.06.

1b: C6H12ClN2S4Sb: MW = 397.61, monoclinic, P21/c,a= 14.3425(5), b= 10.5007(3), c= 9.0543(3) , b= 97.154(3),V= 1353.02(8) 3,Z= 4,Dcalc= 1.952 g cm

3, l = 2.8mm1, reflec-tions collected: 25233, independent: 2833, Rint= 0.032, Final Rindices [I> 2r(I)];R1= 0.0213,wR2= 0.0564,S= 1.11.

2: C6H12ClN2S4Bi: MW = 484.84, monoclinic, P21/c,

a= 10.0523(3), b= 16.1457(6), c= 8.1648(3) , b= 99.668(3),V= 1306.34(8) 3, Z = 4, Dcalc= 2.465 g cm3, l= 14.3 mm1,

reflections collected: 5026, independent: 2297, R int= 0.035, FinalRindices [I> 2r(I)];R1= 0.0333,wR2= 0.0657,S= 1.17.

3: (C15H30N3S6Bi)2: MW = 1307.47, monoclinic, P21/c, a=12.3965(8), b= 13.5006(8), c= 14.7833(9) , b= 99.942(6), V=2437.0(3) 3, Z = 4, Dcalc= 1.782 g cm

3, l= 7.8 mm1, reflectionscollected: 9390, independent: 4290, Rint= 0.057, Final R indices[ I > 2r(I)];R1= 0.0431,wR2= 0.1081, S = 1.03.

4.4. Biological tests

Cell viability was determined as previously described [15h].Biological experiments were carried in dimethyl sulfoxide in Dul-beccos Modified Eagles Medium solutions (DMEM)DMSO/DMEM(0.000050.0055% v/v) for the complexes 13. In case of 1a and1b, the DMSO/DMEM solutions were 0.000050.006% v/v. Stocksolutions of the complexes 13, (0.01 M) in DMSO were freshlyprepared and diluted in with cell culture medium to the desiredconcentration (0.0050.800lM). The low concentration of thecomplexes used for the cells screening tests allow the formationof clear solution. MCF-7 and HeLa cells were seeded onto 24-wellplates at a density of 3 104 cells per well, respectively, and incu-bated for 24 h before the experiment. Results are expressed interms of IC50values, which is the concentration of drug requiredto inhibit cell growth by 50% compared to control, after of 48 hincubation of the complexes towards cell lines.

4.5. Computational studies

We have performed in silico and molecular docking studiesaccording to Refs. [14a,14d].

Acknowledgements

The NMR spectra of compounds1aand1bwere recorded by DrC.G. Tsiafoulis, who is acknowledged. The NMR Centre of the Net-

work of Research Supporting Laboratories of the University ofIoannina and the Greek Community Support Framework III, Regio-nal Operational Program of Epirus 20002006 (MIS 91629), forsupporting the purchase of an LC-NMR cryo instrument are alsoacknowledged. This research was carried out in partial fulfillmentof the requirements for the master thesis of Mrs C.N.B. under thesupervision of S.K.H. within the graduate program in BioinorganicChemistry. The research of I.I.O was supported by the Namik KemalUniversity Scientific Research Projects Fund (Project No.NKUBAP.00.10.AR.10.1).

Appendix A. Supplementary data

CCDC 909398, 909399, 910135, and 910136 contain the supple-

mentary crystallographic data for compounds 1a, 1b, 2 and 3,respectively. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html , or from the CambridgeCrystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ,UK; fax: (+44) 1223-336-033; or e-mail: [email protected] data associated with this article can be found, inthe online version, at http://dx.doi.org/10.1016/j.poly.2013.08.052.

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