Nickel (II) complexes of naphthaquinone thiosemicarbazone and semicarbazone: Synthesis, structure, spectroscopy, and biological activity

JOURNAL OFInorganicBiochemistry

www.elsevier.com/locate/jinorgbio

Journal of Inorganic Biochemistry 99 (2005) 1526–1531

Nickel (II) complexes of naphthaquinone thiosemicarbazone andsemicarbazone: Synthesis, structure, spectroscopy, and

biological activity

Zahra Afrasiabi a,*, Ekk Sinn a, Weisheng Lin a, Yinfa Ma a,Charles Campana b, Subhash Padhye c

a Department of Chemistry, University of Missouri-Rolla, Rolla, MO 65409, USAb Bruker Analytical X-ray Division, Madison 53711, WI, USA

c Department of Chemistry, University of Pune, Pune 411007, India

Received 7 December 2004; received in revised form 11 April 2005; accepted 14 April 2005Available online 31 May 2005

Abstract

Ni(II) complexes of ortho-naphthaquinone thiosemicarbazone and semicarbazone were synthesized and spectroscopically char-acterized. The X-ray crystal structure of both the complexes describe a distorted octahedral coordination with two tridentate mono-deprotonated ligands. In vitro anticancer studies on MCF-7 human breast cancer cells reveal that the semicarbazone derivativealong with its nickel complex is more active in the inhibition of cell proliferation than the thiosemicarbazone analogue.� 2005 Elsevier Inc. All rights reserved.

Keywords: 1,2-Naphthaquinone; Thiosemicarbazone; Nickel complexes; Biological activity; MCF-7 breast cancer cells

1. Introduction

Thiosemicarbazones (TSCs) have received consider-able attention because of their potential therapeuticactivities against bacterial and viral infections [1,2],tuberculosis [3] and leprosy [4]. In addition particularattention has been given to their antitumor activity thatseems to be due to inhibition of DNA synthesis causedby a modification in the reductive conversion of ribonu-cleotides to deoxyribonucleotides [5].

In a number of cases the transition metal complexesof TSCs showed greater biological activity than theuncomplexed ligands [6,7]. This observation furtherencouraged detailed studies on coordination chemistryinvolving TSCs [6,8,9].

0162-0134/$ - see front matter � 2005 Elsevier Inc. All rights reserved.

doi:10.1016/j.jinorgbio.2005.04.012

* Corresponding author. Tel.: +1 573 341 4975; fax: +1 573 341 6033.E-mail address: [email protected] (Z. Afrasiabi).

In contrast to TSCs, less work has been reported onbiological properties of their structural analogue, semic-arbazones (SCs). Recently it has been shown that SCs ofaromatic and unsaturated carbonyl compounds haveanticonvulsants properties and their great advantageover the analogues TSCs is their lesser neurotoxicity[10,11]. It is also reported that naftazone (1,2 naphtha-quinone semicarbazone) has an inhibitory effect on ni-tric oxide (NO) synthesis which protects the vascularsystem [12].

For the past few years we have been working on thestructural and biological properties of metal complexesof the ortho-quinone thiosemicarbazones [13,14]. Re-cently we reported a mechanistical study on antitumoractivity of naphthaquinone thiosemicarbazone (NQTS)metal complexes [15]. The results showed that the metalcomplexes could stabilize the cleavable complex formedby DNA and Topoisomerase II and the nickel (II) com-

Z. Afrasiabi et al. / Journal of Inorganic Biochemistry 99 (2005) 1526–1531 1527

plex was found to be the most active one. Continuingour studies here we report the synthesis and character-ization of naphthaquinone semicarbazone (NQSC) andits nickel(II) complex (Fig. 1), to compare their biologi-cal activity with that of the NQTS analogue and inves-tigate the influence of the nature of the donor atomson biological properties of the complexes. These com-pounds were screened in vitro against MCF-7 breastcancer cell lines for their antiproliferation activity. TheX-ray crystal structure of the two nickel complexes,Ni(NQSC)2 and Ni(NQTS)2, are also discussed.

2. Experimental

2.1. Reagents and measurements

1,2-Naphthaquinone, semicarbazide hydrochloride,and nickelous chloride were purchased from Aldrich,Baker Analytical, and ACROS Organics, respectively.All other chemicals and solvents were of analyticalgrade. The methods of measurements and instrumenta-tion used were as reported previously [14].

2.2. X-ray crystallography of [Ni(NQTS)2] Æ 2DMSO

and [Ni(NQSC)2] Æ 2DMSO Æ 1H2O

Diffraction intensity data were measured with a Bru-ker Smart Apex CCD diffractometer using a graphite-monochromated Mo Ka radiation (k = 0.71073 A) froma sealed tube generator. Absorption corrections weremade using the SADABS program. The structures weresolved by direct methods and all non-hydrogen atomswere refined anisotropically by full-matrix least squares.Hydrogen atoms were inserted in their calculated posi-tions. All computations were carried out using the SHEL-

XTL program package [16]. Details of crystal structuredetermination of both the nickel complexes are summa-rized in Table 1.

2.3. Cell cultures

In vitro cell line: The MCF-7 cell line was purchasedfrom Karmanos Cancer Institute (Detroit, MI). The

O

N

NH2

HN

X

Fig. 1. Chemical diagram for the studied ligands (X = O: NQSC;X = S: NQTS).

cells were cultured in DMEM-F12 medium (InvitrogenCorp.) supplemented with 10% fetal calf serum (GIB-CO-BRL) and 1% penicillin–streptomycin (InvitrogenCorp.) at 37 �C in 5% CO2/95% air.

2.4. Cytotoxicity assay

The cells were collected by trypsinization and resus-pended in the experimental medium which containeddextran-coated charcoal (DCC) stripped DMEM-F12medium [17], 10% fetal calf serum and 1% penicillin–streptomycin. The cells were seeded into 24-well micro-liter plates at 15 · 103 cells/well in 2 ml experimentalmedium and allowed to grow for two days before dos-age. At the end of two days, each drug was preparedfreshly in dimethyl sulfoxide (DMSO) and sequentiallydiluted with experimental medium to 8.0, 6.0, 4.0, 2.0,1.0, and 0.5 lM final concentrations, with each dilutiontested in quadruplicate per assay. The medium in plateswas sucked out and replaced with the experimentalmedium containing drugs. The cell viability was quan-tified after 6 days using 0.2% SRB dissolved in 1% ace-tic acid following a staining protocol described bySkehan et al. [18]. IC50 values for all the test com-pounds were determined graphically using GraphpadPrism software.

2.5. Preparations

2.5.1. Preparation of ligands1,2-naphthaquinone thiosemicarbazone (NQTS) ob-

tained by reacting naphthaquinone and TSC.HCl (1:1ratio) in EtOH/Water following the procedure previ-ously reported [14]. 1,2-naphthaquinone semicarbazone(NQSC) was prepared similarly.

NQTS: Yield = 85%; (Found C, 56.81; H, 3.71; N,17.93. C11H9N3OS requires C, 57.13; H, 3.92; N,18.17%); mmax/cm

�1: (C@O) 1630, (C@N) 1589, (N-H)3140, (NH2) 3410 and 3270, (C@S) 1162; dH(400 MHz, DMSO): 14.22 (1H, N(2)–H), 9.39 and 8.94(2H, N(1)–H), 8.18-6.78 (6H, naphthaquinone ring);mass spectrum (e.i.): m/e 231 (M+), 203 (M+ � CO),189 (M+ � NH2CN), 171 (M+ � CH2NS), 156(M+ � NH2CN � SH), 143 (M+ � CH2N3S), 115(M+ � CH2N3S � CO), 76 (CH4N2S

+), 60 (CH2NS+);UV/VIS/ · 103 cm�1: 28.5, 30.8, 35.2, 48.7

NQSC: Yield = 71%; (Found C, 60.95; H, 4.10; N,19.89%. C11H9N3O2 requires C, 61.39; H, 4.22; N,19.53%); mmax/cm

�1:(C@O) 1708, 1635, (C@N) 1586,(N–H) 3213, (NH2) 3393 and 3301; dH (400 MHz,DMSO): 13.80 (1H, N(2)–H), 8.26 and 8.24 (2H,N(1)–H), 7.83–6.88 (6H, naphthaquinone ring) ; massspectrum (e.i.): m/e 215 (M+), 199 (M+ � NH2), 171(M+ � CH2NO), 156 (M+ � NH2CN–OH), 143(M+ � CH2N3O), 115 (M+ � CH2N3O � CO); UV/VIS/ · 103 cm�1: 19.8, 24.6, 30.5, 36.4.

Table 1Crystal data and structure refinement for [Ni(NQTS)2] Æ 2DMSO and [Ni(NQSC)2] Æ 2DMSO Æ H2O

Empirical formula [NiC22H16N6S2O2] Æ 2DMSO [NiC22H16N6O4] Æ 2DMSO Æ 1H2O

Formula weight 675.40 661.37Space group Monoclinic, C2/c Triclinic, P�1a (A) 29.841(2) 3.4053(4)b (A) 13.5685(10) 14.0824(4)c (A) 14.7739(11) 16.8472(5)a (�) 90 100.6130(1)b (�) 94.284(2) 111.0750(1)c (�) 90 91.8260(1)V (A3) 5965.3(8) 2900.16(2)Z 8 4Density (calculated) (mg/m3) 1.477 1.510Absorption coefficient (mm�1) 0.973 0.868Final R indices [I > 2r(I)] R1 = 0.0696, wR2 = 0.1633 R1 = 0.1186, wR2 = 0.2417R indices (all data) R1 = 0.1370, wR2 = 0.1776 R1 = 0.1535, wR2 = 0.2581

1528 Z. Afrasiabi et al. / Journal of Inorganic Biochemistry 99 (2005) 1526–1531

2.5.2. Preparation of nickel complexes

Both the nickel complexes were synthesized followinga same procedure. A hot solution of NiCl2 Æ 6H2O(0.5 mmol, 0.12 g) in 5 mL hot distilled water was addedto a boiling solution of the ligands NQSC (1.00 mmol,0.22 g) and NQTS (1.00 mmol, 0.24 g) in ethanol. Thereaction mixtures were refluxed on a water bath for4 h and allowed to cool to room temperature overnight.The dark violet precipitate filtered, washed with etherand dried in vacuo.

[Ni(NQTSC)2]: yield = 73%; Dark red crystals suit-able for the single crystal X-ray diffraction analysis wereobtained by slow evaporation of its dimethyl sulfoxide(DMSO) solution. (Found C, 51.07; H, 2.98; N,16.53%. NiC22H16N6O2S2 requires C, 50.89; H, 3.11;N, 16.19); mmax/cm

�1:(C@O) 1625, (C@N) 1580, (NH2)3282 3393, (C@S) 1195, (Ni–S) 323, (Ni–N) 436, (Ni–O) 482; dH (400 MHz, DMSO): 9.17 9.38 (2H, N(1)–H), 8.16–6.74 (6H, naphthaquinone ring); UV/VIS/· 103 cm�1: 11.4, 16.1, 17.7, 21.5, 26.4; leff = 3.28 BM.

[Ni(NQSC)2]: yield = 43%; Dark red crystals suitablefor the single crystal X-ray diffraction analysis were ob-tained by slow evaporation of its DMSO solution.(Found C, 53.64; H, 3.08; N, 16.92%. NiC22H16N6O4 re-quires C, 54.25; H, 3.32; N, 17.25); mmax/cm

�1:(C@O)1694, 1640, (C@N) 1600, (NH2) 3325 3270, (Ni–N)451, (Ni–O) 594 559; dH (400 MHz, DMSO): 8.84(2H, N(1)–H), 7.23–6.80 (6H, naphthaquinone ring);UV/VIS/ · 103 cm�1: 13.1, 17.5, 19.2, 28.4; leff = 3.14BM.

3. Results and discussion

3.1. NMR studies

The high frequency singlets at 14.22 ppm (NQTS)and 13.80 ppm (NQSC) are assigned to hydrazinic(N(2)–H) proton indicating that in solution NQTS and

NQSC exist in thionic and ketonic forms, respectively.These bands are not found in the spectra of the nickelcomplexes, which is consistent with deprotonation ofthese ligands upon metal complexation. The two pro-tons of N(1)H2 group in the spectrum of NQSC freeligand are magnetically non-equivalent and are locatedat 8.24 and 8.26 ppm. These protons became equivalentupon formation of the nickel complex and are shifteddownfield, probably because the hydrogen bondinteraction involving these protons in the free NQSCdisappears after the configuration change of theligand around C(1)–N(2) from E to Z upon metalcomplexation.

3.2. IR studies

Both the NQTS and NQSC ligands can exhibittautomerism since they contain –NH–C@S and –NH–C@O functional groups, respectively. However the ab-sence of the m(S–H) band at 2570 cm�1 from the IRspectrum of NQTS and a band at higher than3500 cm�1 from the spectrum of NQSC (representativeof the hydroxyl form of the enolic structure) indicatethe thionic and ketone nature of these ligands in thesolid state [19,20]. In the 3500–3000 cm�1 region, inaddition to the symmetric and asymmetric stretchingvibrations of the NH2 groups, the bands at ca. 3140and 3213 cm�1 in the spectra of the NQTS and NQSCare attributed to the m(N–H) of thiosemicarbazone andsemicarbazone side chains, respectively [21]. Thesebands are absent in the spectra of nickel complexesdue to the change in the tautomerism and subsequentdeprotonation of the ligands upon coordination. Thestretching vibration bands appearing at 1586 and1635 cm�1 in the spectra of NQSC are assigned tom(C@N) and m(C@O). In Ni(NQSC)2 coordinationthrough imine nitrogen and enolic oxygen shifts thesebands slightly to higher wave numbers (1600 and1640 cm�1, respectively).

Fig. 3. ORTEP diagram and numbering scheme for [Ni(NQS)2] Æ2DMSO Æ H2O.

Z. Afrasiabi et al. / Journal of Inorganic Biochemistry 99 (2005) 1526–1531 1529

3.3. UV–vis spectroscopy and magnetic studies

The magnetic moment for [Ni(NQTS)2] and[Ni(NQSC)2] complexes were found to be 3.28 and3.14 BM, which are compatible with an octahedralNi(II) environment [22]. In the electronic spectra ofthe nickel complexes the bands at 16,120, 21,530 cm�1

[Ni(NQTS)2] and 13,157, 17,513 cm�1 [Ni(NQSC)2] areassigned to 3A2g ! 3T1g and

3A2g ! 3T1g (P) transitions,respectively [23,24]. Calculation of the ligand fieldparameters lead to relative 10Dq values of 7035 cm�1

([Ni(NQTS)2]) and 5737 cm�1 ([Ni(NQSC)2]) while theRacha�s parameters, B, are equal to 1102 and897 cm�1 [25]. These values are in good agreement withthose of octahedral nickel complexes of previously stud-ied tridentate thiosemicarbazones [26].

3.4. X-ray studies

The molecular structure and atom numberingschemes for [Ni(NQTS)2] and [Ni(NQSC)2] complexesare shown in Figs. 2 and 3, respectively. Selected bonddistances and angles are listed in Tables 2 and 3.

3.4.1. The structure of [Ni(NQTS)2] Æ 2DMSO

The nickel(II) atom is in a distorted octahedral envi-ronment surrounded by the two cis carbonyl oxygens,two trans imine nitrogens and two cis thiolato sulfurs.The N(3) and N(6) atoms act as axial ligands andS(1), S(2), O(1), O(2) atoms are considered to form asquare plane where the nickel(II) ion lies 0.001 A abovethe plane toward N(6) nitrogen. Both the coordinatingNQTS ligands are being tridentate and mono-deproto-

Fig. 2. ORTEP diagram and numbering scheme for [Ni(NQTS)2] Æ2DMSO.

nated to coordinate to the metal. The conformation ofthe thiosemicarbazone chain about the C(2)–N(3) andC(1)–N(2) bond changes from Z, E in uncomplexed li-gand to E, Z to facilitate the coordination of thiolatosulfur and imine nitrogen. Least squares planarity anal-ysis shows that the two naphthaquinone rings are almostperpendicular to each other with a dihedral angle of89.8�. The two five membered chelate rings formed uponcoordination are nearly planar with a dihedral angles of4.0� and 1.2� between them in the two coordinatingligands. Nickel–sulfur (2.377 and 2.389 A) and nickel–nitrogen (2.005 and 2.021 A) bond distances are compa-rable to those in the Nickel(II) complexes of otherthiosemicarbazones [27]. Ni(NQTSC)2 shows relativelylonger C@S (1.687 A) and C@O (1.273 A) bond

Table 2Selected bond lengths [A] and angles [�] for [Ni(NQTS)2] Æ 2DMSO

Ni(1)–N(6) 2.005(5) N(4)–C(12) 1.366(8)Ni(1)–N(3) 2.021(5) N(5)–N(6) 1.305(7)Ni(1)–O(2) 2.114(4) N(5)–C(12) 1.345(8)Ni(1)–O(1) 2.121(4) N(6)–C(13) 1.338(7)Ni(1)–S(1) 2.377(2) N(6)–Ni(1)–N(3) 174.8(2)Ni(1)–S(2) 2.389(2) N(6)–Ni(1)–O(2) 79.47(19)S(1)–C(1) 1.658(8) N(3)–Ni(1)–O(2) 97.80(18)S(2)–C(12) 1.687(8) N(6)–Ni(1)–O(1) 96.63(19)O(1)–C(3) 1.251(7) N(3)–Ni(1)–O(1) 78.89(19)O(2)–C(14) 1.273(7) O(2)–Ni(1)–O(1) 89.19(16)N(1)–C(1) 1.341(8) N(6)–Ni(1)–S(1) 102.80(15)N(2)–N(3) 1.319(6) N(3)–Ni(1)–S(1) 81.47(16)N(2)–C(1) 1.376(8) O(2)–Ni(1)–S(1) 89.64(13)N(3)–C(2) 1.322(7) O(1)–Ni(1)–S(1) 159.97(13)N(6)–Ni(1)–S(2) 81.09(17) O(1)–Ni(1)–S(2) 91.99(13)N(3)–Ni(1)–S(2) 101.49(15) S(1)–Ni(1)–S(2) 95.71(8)O(2)–Ni(1)–S(2) 160.53(13)

Table 3Selected bond lengths [A] and angles [�] for [Ni(NQSC)2] Æ2DMSO Æ H2O

Ni(1)–N(3A) 1.988(5) C(14A)–O(4A) 1.264(7)Ni(71)–N(6A) 1.999(5) N(3A)–Ni(1)–N(6A) 178.5(2)Ni(1)–O(3A) 2.067(4) N(3A)–Ni(1)–O(3A) 101.90(19)Ni(1)–O(2A) 2.096(4) N(6A)–Ni(1)–O(3A) 76.74(19)Ni(1)–O(4A) 2.112(4) N(3A)–Ni(1)–O(2A) 80.02(18)Ni(1)–O(1A) 2.137(4) N(6A)–Ni(1)–O(2A) 99.40(17)N(1A)–C(1A) 1.320(8) O(3A)–Ni(1)–O(2A) 92.61(17)C(1A)–O(1A) 1.241(8) N(3A)–Ni(1)–O(4A) 102.12(18)C(1A)–N(2A) 1.415(8) N(6A)–Ni(1)–O(4A) 79.26(18)N(2A)–N(3A) 1.278(6) O(3A)–Ni(1)–O(4A) 155.93(17)N(3A)–C(2A) 1.335(7) O(2A)–Ni(1)–O(4A) 93.05(16)C(3A)–O(2A) 1.260(7) N(3A)–Ni(1)–O(1A) 75.58(19)N(4A)–C(12A) 1.336(8) N(6A)–Ni(1)–O(1A) 104.90(18)C(12A)–O(3A) 1.238(8) O(3A)–Ni(1)–O(1A) 88.81(18)C(12A)–N(5A) 1.402(8) O(2A)–Ni(1)–O(1A) 155.32(18)N(5A)–N(6A) 1.293(6) O(4A)–Ni(1)–O(1A) 95.63(17)N(6A)–C(13A) 1.332(7)

7.14

3. 76

4.94

2.28

0

1

2

3

4

5

6

7

8

NQTS Ni-NQTS NQSC Ni-NQSC

IC50

(uM

)

Fig. 4. Cytotoxic effects of NQTS and NQSC and their nickel(II)complexes on MCF-7 human breast cancer cells.

1530 Z. Afrasiabi et al. / Journal of Inorganic Biochemistry 99 (2005) 1526–1531

distances as compared to those in the free ligand[13,14]. This is the result of deprotonation of thethiohydrazinic nitrogen atoms, which causes a certaindegree of delocalization in the thiosemicarbazone sidechain. The packing is determined by a network of hydro-gen bonds between the terminal thioamide nitrogenatoms and the oxygen atoms from the crystallizationDMSO molecules [N(4)–H(4B)� � �O(31); d(H� � �O) =2.13 A and N(4)� � �H(4A)� � �(O41); d(H� � �O) = 2.06 A].

3.4.2. The structure of 2 {[Ni(NQSC)2] Æ 2DMSO Æ1H2O} complex

The asymmetric crystallographic unit consists of twoNi(NQSC)2 neutral complexes, four DMSO moleculesand two water molecule as solvents of crystallization.Very small differences were found between the structuralparameters of the two Ni(NQSC)2 molecules, thereforethe discussion is centered on the molecule with the lowestnumbered atoms. A pair of tridentate monoanionic li-gands (NQSC) coordinate to the Nickel (II) ion via theenolate oxygen, azomethine nitrogen, and quinone oxy-gen. The two azomethine nitrogen atoms (N3A andN6A) are trans to each other, while the quinone carbonyloxygen atoms (O2A and O4A) and the enolate oxygens(O1A and O3A) are in the cis position. The nickel atomlies 0.0055 A above the O1AO2AO3AO4A plane towardN(6A) atom. The structure is in E conformation with re-spect to C(2A)–N(3A) and C(13A)–N(6A) bonds. Simi-lar to NiNQTS complex the imino nitrogen atoms(N2A and N5A) are deprotonated and the naphthaqui-none moieties from the two coordinated ligands are al-most perpendicular to each other with a dihedral angleof 83.90�. In each ligand the two five-membered chelaterings and the two six-membered naphthaquinone ringsare nearly planar with the dihedral angles between themranging from 2.3� to 14.5�. The Ni–N (1.986 and1.998 A) and the Ni–O (2.140 and 2.068 A) distances fall

in the range normally observed for the analogous semic-arbazone compounds [28].

3.5. Biological activity

Cell proliferation in compound-treated cultures wasevaluated by using a system based on the sulforhoda-mine B (SRB) compound, which can bond with the totalproteins of the living cells and can be assayed colorimet-rically. Fig. 4 shows the IC50 values (lM) for the two li-gands as well as their nickel(II) complexes. It is clearlyobserved that complexation with metal ion in bothNQTS and NQSC ligands increases the inhibitory actionon MCF-7 cell proliferation. Similar effect was observedupon complexation of other thiosemicarbazones withnickel(II) ion [29]. The enhancement of antiproliferationactivity by metal complexes can be related to an increasein the lipophilicity so they can penetrate into the cellsmore easily [30]. It has also been suggested that metalcomplexation may be a vehicle for activation of the li-gand as the cytotoxic agent [5]. This study also showsthat both NQSC and Ni(NQSC)2 have greater inhibi-tory effect on MCF-7 cell growth comparing to theirstructural analogs, NQTS and Ni(NQTS)2, respectively.Semicarbazones may have bestowed important antican-cer properties since they exert IC50 values in 2–5 lMrange and also in general they produce lower side effectthan thiosemicarbazones.

4. Supplementary material

CCDC 257173 and 257174 contain the supplemen-tary crystallographic data for the structures describedin this paper. These data can be obtained free of chargefrom The Cambridge Crystallographic Data Center viawww.ccdc.cam.ac.uk/data_request/cif.

Z. Afrasiabi et al. / Journal of Inorganic Biochemistry 99 (2005) 1526–1531 1531

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