Inorganica Chimica Acta 423 (2014) 14–25

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Inorganica Chimica Acta

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Review

Anticancer activity of organotin(IV) carboxylates

Muhammad Kashif Amir has completed his M.PhilInorganic Chemistry from Bahauddin Zakariya Uni-versity Multan, Pakistan. Currently he is PhD scholarin department of Chemistry, Quaid-i-Azam Univer-sity Islamabad, Pakistan under the supervision ofDr. Zia-ur-Rehman. His research is focused on thesynthesis, characterization and medicinal applica-tions of metal based compounds.

Mr. Shahan Zeb Khan is a lecturer in UniversScience and Technology Bannu Khyber Ptunkhwa, Pakistan. He did his M.Sc and M.PhilQuaid-I-Azam University Islamabad and currhe is pursuing his Ph.D. at QAU under the supsion of Dr. Zia-ur-Rehman. His research is focon the synthesis and characterization of metal bcompounds and their Biological applications.

http://dx.doi.org/10.1016/j.ica.2014.07.0530020-1693/� 2014 Elsevier B.V. All rights reserved.

Abbreviations: Bipy, 2,2-bipyridine; Phen, 1,10-phenanthroline; MTT, microcul-ture tetrazolium [3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide,]assay; SRB, sulforhodamine B assay; H2imda, iminodiacetic acid; DBDCT, di-n-butyl-(4 chlorobenzohydroxamate)tin(IV) chloride; PS, phosphatidylserine; PI,propidium iodide; Annexin V-FITC, apoptosis detection kit; CDDP, Cisplatin; 5FU,5-flourouracil; ETO, etoposide; DOX, doxorubicin; MTX, methotrexate; TAX, Taxol.⇑ Corresponding author. Tel.: +92 (051)90642245; fax: +92 (051)90642241.

E-mail addresses: hafizqau@yahoo.com, zrehman@qau.edu.pk ( Zia-ur-Rehman).

Muhammad Kashif Amir a, Shahanzeb Khan a,b, Zia-ur-Rehman a,⇑, Afzal Shah a, Ian S. Butler c

a Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistanb Department of Chemistry, University of Science & Technology Bannu, KPK, Pakistanc Department of Chemistry, McGill University, 801 Sherbrooke St. West, Montreal, Quebec H3A2K6, Canada

a r t i c l e i n f o

Article history:Received 1 May 2014Received in revised form 21 July 2014Accepted 22 July 2014Available online 1 August 2014

Keywords:MetallodrugsCancerOrganotin(IV) carboxylatesAntitumor activity

a b s t r a c t

This article provides a critical review of the anticancer activity of organotin(IV) carboxylates in the lastfive years. Most of the organotin(IV) carboxylates discussed in this review have greater anticancer activ-ity against different cell lines than do the standard drugs. Moreover, some of these organotin(IV) carbox-ylates have pronounced anticancer activity even against cisplatin-resistive cancer cells. The review alsohighlights structure-activity relationships.

� 2014 Elsevier B.V. All rights reserved.

ity ofakh-fromentlyervi-usedased

Dr. Zia-ur-Rehman was educated at the Quaid-i-Azam University (QAU) in Pakistan and McGillUniversity Canada in 2009. He began his academiccareer at QAU in 2009, where he is still teaching anddoing research in metallo-drug, electrochemistry,supramolecular chemistry, environmental and drugdelivery applications of novel surfactants, andnanotechnology. He published 70 research articlesin various journals of international repute, and a co-author of a book entitled ‘‘DNA Binding and DNAExtraction: Methods, Applications and Limitations’’.In his short academic carrier, 11 M.Phil students

obtained their degrees in his direction. His teaching and research efforts havebeen recognized by the Dr. Abus Salam Award from TWAS. He has been marriedto his wife Kausar for 4 years and together they have a son Muhammad Ahm-mad and a daughter Musfira.

Dr. Afzal Shah is an assistant professor at Quaid-i-Azam University, Islamabad, Pakistan. He receivedhis Ph.D. in physical chemistry from QAU in 2010under the indigenous Ph.D. program launched bythe Higher Education Commission of Pakistan. Hisresearch interests include elucidation of electrodereaction mechanism of biologically important mol-ecules and development of new synthetic routes forthe preparation of environmental friendly surfac-tants.

Professor Ian S. Butler was educated at the Uni-versity of Bristol in the U.K. and, following post-doctoral work at Indiana and NorthwesternUniversities in the U.S.A., he began his academiccareer at McGill University in Montreal, Quebec,Canada in 1966, where he is still teaching and doingresearch in a wide range of applications of molecu-lar spectroscopy. Well over 50 M.Sc. and PhD. stu-dents have obtained their degrees under hisdirection and �500 articles and �400 national andinternational conference presentations have ema-nated from their research work to date. He has been

a Visiting Professor in the U.K., France, China, Brazil, Hungary and Australia. Histeaching and research efforts have been recognized by the Gerhard HerzbergAward from the Spectroscopy Society of Canada and the David Thomson Awardfrom McGill University. He has co-authored several textbooks, including Rele-vant Problems for Chemical Principles (with Dr. A.E. Grosser) and InorganicChemistry: Principles and Applications (with Dr. J.F. Harrod). He has beenmarried to his wife, Pamela, a former dancer with American Ballet Theatre inNew York City and now a retired Professor of Political Science, for 48 years andtogether they have four children and fourteen grandchildren.

M.K. Amir et al. / Inorganica Chimica Acta 423 (2014) 14–25 15

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152. Anticancer activity of organotin(IV) carboxylates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

1. Introduction

The first inorganic cancer chemotherapeutic agent was cis-platin, which still remains a front-line treatment for testicular,ovarian and other cancers [1,2]. However, considerable toxicside-effects and the emergence resistance have limited the clinicaleffectiveness of cisplatin and related drugs. There is need to findnew inorganic agents for use in cancer chemotherapy withimproved specificity and decreased toxic side-effects. In vitroscreening of new coordination complexes, followed by selectingthe best performing anticancer active compounds, is still the bestway of identifying potential drug candidates. A great deal of inter-est in platinum and non-platinum metallodrugs has emerged.Among the non-platinum metal complexes with antitumor activ-ity, particular interest has been focused on tin(IV) complexes [3].The potential of organotin(IV) complexes as biologically activemetallopharmaceuticals has been accepted [4–27]. Various studieswith interesting results on the in vitro antitumor properties oforganotin(IV) complexes against a wide panel of tumor cell linesof human origin have been reported [2,9,15,28,29,30]. A largenumber of organotin(IV) compounds have been tested in vitroand in vivo, firstly against murine leukemia cell lines and thenagainst different panels of human cancer cell lines [5,28,31]. Sev-eral organotin(IV) complexes exhibited high antiproliferativeactivity in vitro against a variety of solid and hematologic cancers[9,5]. Organotin(IV) complexes with carboxylato [32–38], thiolato

[19,39–44] and dithiocarbamato [45] ligands have been studiedextensively. In these studies it has been shown that organotin(IV)carboxylates usually present the highest cytotoxic activity [9]. Itis known that organotin(IV) carboxylates have promising in vitroantitumor activities against human tumor cell lines [4,21,22,32].Organotin(IV) carboxylates had been found to be active towardsa number of tumor cells [9,46–48]. The results of such testingshowed that these organotin carboxylates are even more effectivethan cisplatin [9,46–48]. Modification of the carboxylato ligandsand/or the alkyl or aryl substituents at tin(IV) has a notable effecton the antiproliferative effect of di-, tri-alkyl or aryltin(IV) carbox-ylate complexes [9,40]. The higher antitumor activity of triorgano-tin(IV) carboxylates than di- and monoorganotin(IV) counterpartshas been related to their ability to bind to proteins [49–51]. How-ever, the exact mechanism of anti-tumor action of organotin(IV)carboxylates is not yet known. Many reviews are available on theanticancer activity of organotin(IV) carboxylates [5,13,19,32].However, in this review, the anticancer activity of organotin(IV)carboxylates in last five years is being documented. Additionally,some hints are provided to understand the mechanism of anti-tumor action of organotin(IV) carboxylates. This review will behelpful in investigating the chemotherapeutic treatment of cancerswith no or less side effects and drug resistance. Moreover, thereview will emphasize the need to develop non-platinum metal-based anticancer drugs for the treatment of cisplatin-resistive can-cer cells.

16 M.K. Amir et al. / Inorganica Chimica Acta 423 (2014) 14–25

2. Anticancer activity of organotin(IV) carboxylates

The discovery of cisplatin has increased the prominence ofmetal-based drugs for the treatment of various diseases [52]. Fol-lowing the discovery of cisplatin, numerous other metal complexeshave been investigated, especially organotin(IV) complexes [53].Some mononuclear and dinuclear organotin(IV) derivatives wereknown to possess in vitro antitumor activities [54–56]. The dinu-clear complexes (1, 2) were synthesized in which additional a-dii-mine (Bipy or Phen) does not coordinate to metal ion but a-diimineis present in the crystal lattice as spacer, which helps for the for-mation of a supramolecular framework by bringing the two binu-clear species close enough through extensive H-bonding (Fig. 1)[47]. These dinuclear organotin(IV) carboxylates (1, 2) were inves-tigated for their inhibitory effect on the murine leukemia cell lineP388, human leukemia cell line HL-60 and the human non-smallcell lung cancer cell line A549. The results of the in vitro cytotoxic

O O

HN

O

O

Sn

OH2

Bu

Bu

HH

OO

NH

O

O

Sn

H2O

HH

NN

Bu

Bu NN

O O

HN

O

O

Sn

OH2

Bu

Bu

HH

OO

NH

O

O

Sn

H2O

HH

Bu

Bu

(1) (2)

Fig. 1. Structures of dinuclear complexes [n-BuSn(imda)(H2O)]2�Bipy and [n-BuSn(imda)(H2O)]2.Phen having distorted pentagonal bipyramidal (pbp) geometry.

Table 1Inhibition [%] of organotin (IV) carboxylates [dose level of 10.00 lM] against tumor cell li

Complex Coordination mode A-549 P388

(1) seven 72 100(2) seven 74.7 100(3) six(4) six(5) six(6) six(7) six(8) sixCisplatin four 15.1 48.4

a IC50 = 4.9 lM.b IC50 = 5.2 lM.c IC50 = 6.5 lM.d IC50 = 8.1 lM.

Sn OOC CO OR

R

R = Me (3), Et (4), nBu (5), nOct (6), Ph (7)

Cl

Cl

Cl

Cl

Fig. 2. Structures of the organotin(IV) carboxylate compl

effects of the complexes (1) and (2) against the three tumor celllines are compared with those using cisplatin (Table 1).

The inhibitory effect of the complexes (1, 2) is relatively higherthan that exhibited by cisplatin against the two tumor cell lines(Table 1) [47]. The observed higher activities of the complexes (1,2) with reference to that of the cisplatin were correlated in termsof a structural effect, i.e., a long chain of the dinuclear (Sn–Sn) unitsstabilized or controlled via an extensive H-bonding and the pres-ence of additional spacers like Bipy or Phen in the molecular unit(Fig. 1) [20]. The n-butyl group bonded to the tin atom in thesecomplexes (1, 2) may also contribute towards the cytotoxic effects[12]. The results indicated that complexes (1, 2) were highly effec-tive against all the cell lines at higher concentration (10�4 M), butwere not particularly effective at lower concentration (10�7 M).The complexes (1, 2) retained cytotoxic effects against P388 tumorcell line even for the concentration range 10�5–10�6 M [47].

It has been shown that organotin(IV) carboxylates have promis-ing in vitro antitumor activities against human tumor cell lines,[4,21,22,32] and the presence of a 4-chlorophenyl group enhancedthe activity of such complexes [21]. So, the organotin(IV) com-pounds (3–8) containing 1-(4-chlorophenyl)-1-cyclopentanecarb-oxylato ligand (Fig. 2) were synthesized and checked for theirin vitro cytotoxic activities against four different human cell lines[promyelocyticfina leukemic (HL-60), hepatocellular carcinoma(Bel-7402), nasopharyngeal carcinoma (KB), and gastric carcinoma(BGC-823)] [58]. The complex (5) has strong activity against Bel-7402 and BGC-823 cell lines (Table 1) and is slightly more activethan cisplatin against Bel-7402 cell line (Table 1). The IC50 valuesfor the complex (5) and cisplatin were 5.2 and 8.1 lM [57] (forBel-7402), and 4.9 and 6.5 lM [57] (for BGC-823), respectively(Table 2) [58]. It was noted that the organo-ligand R plays a vitalrole in the cytotoxic activity. The di-n-butyltin(IV) complex (5)

nes.

HL-60 BGC-823 Bel-7402 KB Refs.

98.9 [47]98.6 [47]7.8 16.4 10.9 [58]22.4 6.7 16.4 8.7 [58]34.0 89.4a 88.8b 39.2 [58]8.6 12.6 12.8 [58]21.5 17.4 13.3 24.4 [58]26.9 12.7 7.1 19.5 [58]100 90.8c 79.1d 69.4 [47,58]

Sn OO

Sn OSn

O SnSn

O SnO

Ph

OO

O

C

CO

O

CO

O

O

OC

O

C

PhPh

Ph

Ph

Ph

OC

O

Cl

Cl

Cl

Cl

(8)

exes containing 4-chlorophenyl group in the ligand.

Table 2In vitro antiproliferative activity results (IC50, lM) of organotin (IV) carboxylates against different cell lines.

Complex Coordinationmode

IC50 (lM) against cancer cell lines Refs.

L-929 A-549 T-24 MCF-7 8505C A253 A549 DLS1 BGC-823 Bel-7402 LMS cells HL-60 KB

Cisplatin four 0.69 1.53 41.66 7.99 5.0 0.81 1.51 5.1 6.5 8.1 5 2.89 2.65 [58,59,63,65](9) five 0.88 7.2 0.43 0.69 [59]

(10) six 1.02 0.91 19.73 1.24 [59](11) six 0.95 4.83 4.52 0.62 [59](12) five 0.132 0.081 0.094 0.060 [63](13) five 0.172 0.100 0.129 0.178 [63]

(5) six 4.9 5.2 [58](14) six 0.029 0.0224 [65](15) five >20 >20 15.9 [73](16) five 16.05 14.83 4.96 [73](17) five 8.97 5.13 1.94 [73](18) five 0.056 0.049 0.01 [73](19) seven 1.49 0.21 0.13 [73](20) seven 6.55 4.23 2.88 [73]

M.K. Amir et al. / Inorganica Chimica Acta 423 (2014) 14–25 17

had the highest antitumor activity, while the diorganotin(IV) deriv-atives with a too short (methyl) or a too long (n-octyl) carbon chainlength had very low activities. The activity of the diphenyltin(IV)complex (7) was also weak, although usually better than those ofdimethyltin(IV) (3), diethyltin(IV) (4), and di-n-octyltin(IV) (6)complexes. Weak activity of hexanuclear phenyltin(IV) compound(8) (Fig. 2) indicated that polynuclear character of this complex didnot result in a high cytotoxic activity. It was suggested that highcoordination number and steric hindrance around tin were impor-tant factors for the weak activity of complex (8), which limit theaccess of tin to the target [58].

Neutral and cationic organotin(IV) complexes with pyruvic acidthiosemicarbazone (9–11) (Fig. 3) were synthesized and evaluatedfor the in vitro cytotoxic activity against the cells of three humancancer cell lines: MCF-7 (human breast cancer cell line), T-24(bladder cancer cell line), A-549(non-small cell lung carcinoma)and a mouse L-929 (a fibroblast-like cell line cloned from strainL) [59]. The MCF-7, L-929 and A-549 cells were determined bythe SRB assay, while T-24 cells by the MTT assay. The diorgano-tin(IV) complexes (9–11) were similar to cisplatin against L-929cancer cell line and more cytotoxic than cisplatin against theMCF-7 and T-24 cancer cell lines (Table 2). The complex (9) was11.6 and 106 times more active than is cisplatin against MCF-7and T-24 cell lines, respectively, as shown by the IC50 values(Table 2). The complex (10) was 6.4 times more active than is cis-platin against the MCF-7 cell line and 2.7 times more active than iscisplatin against T-24 cell line, as again shown from the IC50 values(Table 2). The complex (11) was 12.9 times more active than is cis-platin against MCF-7 cell line and 9.2 times more active than is cis-platin against the T-24 cell line (Table 2). These results showedthat complexes (9–11) were selectively active against the MCF-7and T-24 cancer cell lines [59]. The complex (9) was highly activeagainst the T-24 bladder cancer cell line at very low concentration,

SnS O

N OH2NN

CH3

SnS O

HN OH2NN

CH3

R RH2O

Cl

(9) (10) R = CH3(11) R = Ph

Fig. 3. Structures of neutral and cationic organotin complexes (9–11) with pyruvicacid thiosemicarbazone.

and can be considered as a future candidate as an anticancer drugand merits further in vivo investigation.

The presence of the xylylthioacetato and mesitylthioacetatoligands was observed to have a positive influence on the cytotoxic-ity of gallium [60] and titanium [61] complexes. In the order toknow the effect of xylylthioacetato and mesitylthioacetato ligandson the cytotoxicity of triphenyltin(IV) complexes, the triphenyl-tin(IV) carboxylate compounds [{SnPh3(O2CCH2SXyl)}1] (12)(Xyl = 3,5-Me2C6H3) and [{SnPh3(O2CCH2SMes)}1] (13) (Mes =2,4,6-Me3C6H2) (Fig. 4) were prepared and tested for in vitro cyto-toxicity against the human tumor cell lines 8505C (anaplastic thy-roid cancer), A253 (head and neck tumor), A549 (lung carcinoma)and DLD-1 (colon carcinoma) using the SRB micro culture colori-metric assay [62,63]. The IC50 values showed that the tin com-plexes (12, 13) studied were more active than is cisplatin againstall the human cancer cell lines examined (Table 2). The IC50 value(0.060 lM) for the complex (12) and IC50 value (0.178 lM) for thecomplex (13) indicated a preference of complex (12) against DLD-1cells [63]. The compounds (12) and (13) had activities up to 285and 2520 times greater than their gallium(III) and titanocene(IV)analogues, respectively [60,61,63]. The cytotoxic activity of com-plexes (12, 13) was from 8 to 85 times greater than is that of cis-platin. It was suggested that greater tolerances of high tinconcentrations in biological systems may be possible (in directcontrast to the large number of side-effects associated with verylow concentrations of platinum). This observation makes thesetin compounds ideal candidates for further studies [63].

It has been shown that triorganotin(IV) compounds show sig-nificant anticancer activity and elongation of survival time oftumor-bearing animals [64]. In view of these findings, the triphen-yltin(IV) carboxylate (14) (Fig. 5), as synthesized previously, was

S

COO

Sn

O

S

COO

Sn

O

H3C CH3

CH3H3C

CH3(12) (13)

Fig. 4. Structures of the triphenyltin(IV) carboxylate complexes containing xylyl-thioacetato and mesitylthioacetato ligands.

SnOC

O

CO

CH3

H3C NSSn

(14)

Fig. 5. Structures of the triorganotin(IV) complex bis[triphenyltin(IV)](3-carboxy-pyridine2-thionato).

18 M.K. Amir et al. / Inorganica Chimica Acta 423 (2014) 14–25

investigated for its anti-proliferative and antitumor activities [65].Trypan blue dye exclusion assay was used to determine cell viabil-ity on leiomyosarcoma cells (LMS) and human breast adenocarci-noma cells (MCF-7). The LMS and MCF-7 cells, which weretreated with various concentrations (0.75–80 nM) of the complex(14), displayed a dose dependent cytotoxicity. For the LMS cells,the IC50 value (22.4 nM) for the complex (14) was 200 times lowerthan is the corresponding IC50 value for cisplatin (5 lM) (Table 2)[65]. These findings are in accordance with previous results [66].For the MCF-7 cells, the IC50 value (29.9 nM) after 48 h of incuba-tion with the complex (14) was much lower than that of cisplatin(6 lM). Cell growth inhibition was analyzed using the MTT assay.For the LMS cell growth proliferation (MTT assay) after 48 h oftreatment, the IC50 value for cisplatin was 25 lM and the IC50 valuefor the complex (14) was 40.7 nM. For MCF-7 cell growth prolifer-ation (MTT assay) after 48 h of treatment, the IC50 value for cis-platin was 28 lM and the IC50 value for the complex (14) was45.3 nM. These findings showed that IC50 values for the complex(14) were much lower than the IC50 values for cisplatin againstthese two cell lines. Cell recovery data (the ability of treated cellsto grow after drug withdrawal-colony efficiency) showed thatLMS and MCF-7 cell cultures treated with the complex 14, losttheir ability to proliferate and growth arrest seemed irreversible.In order to quantify apoptosis or necrosis, the LMS and MCF-7 cellswere treated with the complex 14 and evaluated by flow cytome-try assay. Treated and untreated LMS and MCF-7 cells were stainedwith Annexin V-FITC and PI. The untreated LMS cells showed intotal about 9.26% of background cell death. The LMS cells treatedwith 20, 40 and 60 nM of the complex 14 for 48 h showed16.22%, 35.29% and 70.72% apoptosis, while the necrosis remainedstable at 1.31%, 3.93% and 2.21%, respectively. These resultsshowed that the complex 14 causes a dose-dependent cytotoxicresponse in the LMS cells. Untreated MCF-7 cells showed in totalabout 11.89% of background cell death. The MCF-7 cells treatedwith 20, 40 and 60 nM of the complex 14 for 48 h showed19.84%, 41.88% and 66.1% apoptosis, while the necrosis remainedstable at 2.41%, 1.33% and 1.86%, respectively. These results

SnClO NH

CO R

R = 3,4-F2C6H3 (15), 2,4-F2C6H3 (16),

R = 2,5-F2C6H3 (17), 2,6-F2C6H3 (18)

Fig. 6. Structures of the mononuclear and tetranucle

obtained by flow cytometry assay were confirmed by DNA frag-mentation analyses. The presence of laddering of low molecularweight DNA indicated that the LMS cells treated with the complex14 undergo apoptosis at high concentrations (greater than 20 nM).The in vivo antitumor activity was performed on twenty femaleWistar rats, which were first inoculated with 4 � 106 LMS cells.After the appearance of a palpable tumor mass (smaller than1.5 cm diameter), the inoculated animals were divided into twogroups. The control group (CG) and the experimental group (EG),each consisting of 10 animals. All EG animals were treated with4 � 5.4 mg/kg (body weight) of the complex (14) (dissolved in1 mL of tricapryline) every three days. The CG animals were leftwithout any treatment till death. All animals were observed fortheir behavior once a day. Treatment was terminated after the firstanimal death (from EG) occurred. For both groups, the mean sur-vival time of the animals (MST), the mean tumor weight and meantumor growth rate (MTGR) were calculated. The results showedthat the complex 14 prolonged mean survival time of the animalsby 200% and decreased mean tumor growth rate (MTGR) comparedto the control group. It was observed that the 30% (3 out of 10) ofthe tumour-bearing animals were totally cured [65]. These resultsindicated that the complex 14 might be a promising new antitu-mor agent.

It has also been shown that organotin(IV) hydroxamates pos-sess strong antitumor activity against preneoplastic rat hepato-cytes (RH), Ehrlich ascites (EA), human promyelocytic leukemic(HL-60), human hepatocellular carcinoma (Bel-7402), human gas-tric carcinoma (BGC-823), and human nasopharyngeal carcinoma(KB) cell lines. Di-n-butyltin(IV) hydroxamates are prominent forantitumor activity among the diorganotin(IV) hydroxamates. Itwas seen that the activity of dibutyltin(IV) hydroxamates wasdependent on the type of molecular structure [20–22,67–72]. Inorder to explore further the influence of the nature, the numberand the position of the halo atom and nuclearity, two types ofdibutyltin(IV) arylhydroxamates, mononuclear chloride (15–18)and tetranuclear (19, 20), were prepared [73]. These dibutyltin(IV)hydroxamates (15–20) (Fig. 6) were investigated for cytotoxicityin vitro against the human promyelocytic leukemic (HL-60), humangastric carcinoma (BGC-823), and human nasopharyngeal carci-noma (KB) cell lines by MTT and SRB assay. The complexes 18and 19 exerted strong cytotoxic effects against all tested carcinomacell lines with much lower IC50 values even than that of cisplatin(Table 2). It was seen that almost all complexes show good selec-tivity against KB carcinoma cell lines and the complex 18 withtwo fluorine atoms at C2 and C6 positions of benzene ring wasthe prominent one (Table 2). Three of the complexes (17, 18 and19) were more active than is cisplatin against KB cell lines, andcomplexes 18 and 19 were more active than is cisplatin againstall tested cell lines (Table 2). The cytotoxicity of complex 18 wasgreater than the complex 19 [73]. The antitumor activity of 18

SnONHC

O

R

ONH

OC

R

Bu

Bu

SnONH

CO

R

O

Bu

Bu

HNC

O

R

SnO

O

HN

HN

C

C

R

O

R

OSn

Bu

Bu

R = 3-BrC6H4 (19)R = 4-BrC6H4 (20)

Bu

Bu

ar di-n-butyltin(IV) arylhydroxamate complexes.

(24)

CO

O

Sn

NN

(23)

O

C

H

CO

O

Sn

(21)

O

H3C

HN

N

(22)

CO

O

Sn

O

C

HN

N

CO

O

Sn

NN

OHH3C

Fig. 7. Structures of tributyltin(IV) complexes with 2/4-[(E)-2-(aryl)-1-diazenyl]benzoate ligands.

M.K. Amir et al. / Inorganica Chimica Acta 423 (2014) 14–25 19

was compared with a mixed-ligand complex DBDCT reported pre-viously [74]. Comparison of the IC50 values suggested that complex18 (0.049 lM) with two fluorine atoms was better than the DBDCT(1.0 lM) with one chlorine against HL-60 cell lines [73,74]. Thesestudies indicated that the amount and position of X-substituentstend to affect greatly the antitumor activity. Apoptosis rate oftumor cells was determined in KB cells, which were most sensitiveones to the most cytotoxic tested complexes (18 and 19). Earlystages of apoptosis are characterized by perturbations in the cellu-lar membrane. It leads to a redistribution of PS to the external sideof the cell membrane, which causes a Ca flux. The Annexin V is aCa-dependent phospholipid binding protein with high affinity forPS. Therefore, fluorescently labeled annexin V can be used to iden-tify early apoptosis cells. Late apoptosis and necrotic cells have lostmembrane integrity and can be stained by PI. Untreated KB cellsshowed about 21.2% of background cell death. The KB cells treatedwith 2.5, 10 and 20 lM of complex 18 showed 54.8%, 84.8% and83.9% apoptosis, respectively. These results showed that complex18 causes a dose-dependent cytotoxic response in KB cells. For19, the total apoptosis percentage were 17.7%, 56.2% and 36.7%at concentrations of 2.5, 10 and 20 lM, respectively. Both com-plexes 18 and 19 were more toxic than is cisplatin to KB cells,which even at concentration of 20 lM did not show toxicity, dueto the improved lipophilicity of complexes 18 and 19 [73].

Cell cycle analysis was performed by PI single labeling usingdecreased concentrations of complexes, 18, 19 and cisplatin(0.25, 0.5 and 1 lM) in order to study DNA cell content changesin cell cycle. The phases of the cell cycle can be differentiated onthe basis of content of genetic material which, in non-dividing cellsis limited to one copy of DNA. The cell population in the S phase(DNA replication phase) is synthesizing genetic material and thuscontains more DNA than do quiescent cells. The subsequentG2/M phase (interphase/mitosis) is characterized by the presenceof two copies of DNA. Therefore, the alternations in these phaseswere used as a basis for the comparison of different treatments.It was established that exposure of cells to 18, 19 and cisplatinled to a decrease in the percentages of the S phase and an increasein the percentage of the G0/G1 phase. The complex 18 displayedhigher cells arrest for the G0/G1 phases than did the complex 19and cisplatin. These data demonstrated that complex 18 was evenbetter than complex 19, consistent with the former apoptosis rateof tumor cells and cytotoxicity assays [73]. These results indicatethat the complexes 18 and 19 can be promising antitumor agentsin future.

In another study, it has been shown that triphenyltin (IV) 2-[(E)-2-(aryl)-1-diazenyl] benzoates have high in vitro cytotoxicpotential against human tumor cell lines. Molecular docking stud-ies on these compounds indicated that the azo group nitrogenatoms and formyl, carbonyl, ester and hydroxyl oxygen atoms in

the ligand moiety exhibit hydrogen bonding interactions withthe active site of the amino acids of various enzymes, such asribonucleotide reductase, thymidylate synthase and thymidylatephosphorylase [76,77]. A series of tributyltin(IV) complexes with2/4-[(E)-2-(aryl)-1-diazenyl] benzoate ligands (21–24) (Fig. 7)was synthesized and tested for cytotoxicity studies on the humantumor cell lines A498 (renal cancer), EVSA-T (mammary cancer),H226 (non-small-cell lung cancer), IGROV (ovarian cancer), M19MEL (melanoma), MCF-7 (mammary cancer) and WIDR (colon can-cer) [77]. The cytotoxicity was estimated by the microculture (SRB)test [78]. Usually, complex 21 was more cytotoxic than were theother test complexes (22–24) against all the cell lines tested(Table 3). On increasing the steric bulk at the coupling site of theligand framework by the addition of a tert-butyl group, as in com-pound (22) a marginal decrease in activity was seen. Complex (23)having tributyltin ester at para-position was more cytotoxic(ID50 = 27 ng/ml) than the other test complexes (21–24) againstEVSA-T cell line [77]. These results reveal the importance of sub-stituents in the ligand skeleton in defining the cytotoxic potentialof a complex.

The cytotoxic results of triorganotin(IV) carboxylates (21–24)were superior to CDDP, 5FU and ETO and related dibutyltin(IV)compounds investigated earlier [76]. The higher solubility of thesecomplexes (21–24) makes them prominent in the triorganotin(IV)complexes. Their activity was attributed to the tetrahedral geome-try of the complexes in solution, as well as to the presence of anazo functionality in the ligand framework, as was subsequentlyconfirmed by docking results [75,76]. The cytotoxicity data forcompound 21, together with its better solubility, suggested thatcompound 21 might be a promising candidate for further in vitroand in vivo studies after appropriate modification. [77].

A number of triphenyltin(IV) 4-[(E)-2-(aryl)-1-diazenyl] benzo-ates (25–27) having triphenyltin(IV) carboxylate at para position inthe diazo-forming moiety, and triphenyltin(IV) 2-[(E)-2-(aryl)-1-diazenyl] benzoates (28–29) having a triphenyltin(IV) carboxylategroup at the ortho position in the diazo-forming moiety were pre-pared (Fig. 8) [79]. These complexes were checked for their cyto-toxic potential across the panel of human tumor cell lines A498,EVSA-T, H226, IGROV, M19 MEL, MCF-7 and WIDR. The results ofin vitro cytotoxicity of the tested compounds (25–29) were com-pared with the results from other related triphenyltin(IV) com-plexes (30–31) having triphenyltin (IV) carboxylate at the orthoposition in the diazo-forming moiety. The cytotoxicity resultsshowed that the test complexes (25–31) were more toxic thanstandard drug 5FU (Table 3). The cytotoxicity data (ID50) for thetest complexes (25–31) were of the same order of magnitudeand the change of ligand substitution does not influence the cyto-toxic activity significantly. These results indicated that structuralvariation of the L–R skeletons does not influence the activity. In

Table 3In vitro ID50 values (ng/ml) of organotin (IV) carboxylates against different cell lines.

Complex Coordination mode ID50 (ng/ml) against cancer cell lines Refs.

A498 EVSA-T H226 IGROV M 19 Mel MCF-7 WIDR

(21) four 162 97 148 214 118 113 106 [77](22) four 176 100 165 253 126 120 105 [77](23) four 177 27 167 269 127 112 105 [77](24) four 182 101 163 239 125 118 106 [77](25) four 103 43 102 107 100 53 102 [79](26) four 103 41 101 107 98 43 100 [79](27) four 101 35 102 110 101 41 105 [79](28) four 101 43 102 111 103 79 106 [79](29) four 162 97 148 214 118 113 106 [79](30) four 101 41 104 109 103 92 104 [79](31) four 103 49 101 101 104 78 95 [79]DOX 90 8 199 60 16 10 11 [77,79]CDDP 1503 493 645 229 711 653 576 [79]5-FU 143 475 340 297 442 750 225 [79]MTX 37 5 2287 7 23 18 <3.2 [79]ETO 1314 317 3934 580 505 2594 150 [79]TAX <3.2 <3.2 <3.2 <3.2 <3.2 <3.2 <3.2 [79]

NN

R

OH NN

R

OH

O

Ph3SnO

OOSnPh3

R= Me, 2-OH (25)R= Me, 4-OH (26)R= t-Bu, 2-OH (27)

R= t-Bu, 2-OH (28)R= Me, 2-OH (29)R= Me, 4-OH (30)R= CHO, 4-OH (31)

Fig. 8. Structures of triphenyltin(IV) diazenyl benzoates.

20 M.K. Amir et al. / Inorganica Chimica Acta 423 (2014) 14–25

comparison, the complexes (25–27) having triphenyltin(IV) car-boxylate at para position in the diazo-forming moiety showed bet-ter activity than the complexes (28–30) having triphenyltin(IV)carboxylate at the ortho position, particularly against the MCF-7cell line. The complex (31) showed greater activity than did thecomplexes (25-30) against WIDR cell line (Table 3). However, thecomplex 29 showed less activity than the other complexes testedagainst all cell lines. The lower cytotoxicity of the complex 29might be the result of internal co-ordination of OH with Sn. Thisinternal co-ordination makes the Sn less attractive for co-ordina-tion with DNA or sugar moieties [79]. The ID50 values for the testedcomplexes (25–31) were similar to that of the triphenyltin(IV)complexes of Schiff bases derived from L-leucine and phenylala-nine. The complexes (25–31) were stable for a significantly longer

(33)

Sn

O

OC

C

O

O

CH2

H2C

O

O

CH3

H3C

Sn

O

OC

C

O

O

CH2

H2C

O

O

CH3

H3C

Sn

O

OC

C

O

O

CH2

H2C

O

O

CH3

H3C(32)

S

(34)

Fig. 9. Structures of organotin(IV) carboxylates, [Bu2SnL2] (32), [Et2SnL2] (33), [Me2S

period in both the solid-state and in solution than were triphenyl-tin(IV) complexes containing amino acetate skeletons [80,81].

Among organotin(IV) complexes, organotin(IV) carboxylatesshow significant antifungal, antibacterial and antitumor activities,which are essentially related to the number and nature of theorganic groups attached to the central Sn atom. However, the roleof carboxylate ligand cannot be ignored. So, a series of organotin(IV) carboxylates (32–36) (Fig. 9) were synthesized and evaluatedfor in vitro anticancer assay against prostate cancer cells (PC-3)[82]. The experimental conditions for the in vitro anticancer assaysare described in the literature [82]. The complexes (32, 33, 35)exhibited good anticancer activity as shown by their IC50 values(Table 4).

However, compound (32) was found to be the most active, abehavior normally shown by the dibutyltin(IV) bis(carboxylate)[82]. The activity of the compounds decreased in the order(32) > (35) > (33) > (34) > (36) (Table 4). The results indicated thatorgano-ligand played an important role for the cytotoxic activityof these complexes. The di-n-butyltin carboxylate (32) had thestrongest anticancer activity, while the diorganotin derivativeswith a too short (methyl or ethyl) or a too long (n-octyl) carbonchain length had low activities [82].

The research efforts on the biological activity of new organo-tin(IV) complexes with different RCOOH (R = carbazole) as ligandshave increased recently because the carbazole and its derivativeshave shown pronounced cytotoxicity and anticancer activity [83].Three new organotin(IV) complexes (37–39) (Figs. 10 and 11),

Sn

OCO

OCH3

(35)

OC

On

OH3C

Sn

O

OC

C

O

O

CH2

H2C

O

O

CH3

H3C(36)

nL2] (34), [Me6Sn2L2]n (35), and [Oct2SnL2] (36), where L = O2CCH2C6H4OCH3-4.

Table 4In vitro anticancer results (IC50, lg/ml) of organotin(IV) carboxylates against different cell lines.

Complex Coordination mode IC50 (lg/ml) against cancer cell lines Refs.

PC-3 HepG2 BEL-7402 A549 B16-F10 HeLa HT1080 U87 MCF-7 HEK-293 HCT-15

(32) six 2.53 [82](33) six 5.30 [82](34) six 32.92 [82](35) five 4.21 [82](36) six >100 [82](37) five, six 1.93 0.60 [83](38) six 9.82 8.25 [83](39) five 4.23 3.70 [83](40) five 0.55 0.36 0.08 [90](41) six 2.95 2.48 1.91 [90](42) five, six 0.88 0.52 0.93 [90](43) five 25.72 5.00 0.06 [92](44) five 31.74 6.39 0.60 [92](45) five 2.68 6.13 74.0 [92](46) five 29.76 10.7 0.09 [92](47) five 4.89 279 28.9 [92](48) five 29.69 33.4 5.32 [92](49) five 0.70 5.12 34.5 [97](50) five 5.72 218.6 39.5 [97](51) five 40.63 25.02 42.95 50.65 25.13 [104](52) five 400 238 445 242 98.04 [104](53) five 15.73 54.36 258 317 25.40 [104](54) six 326 498 124 235 471 [104](55) six 40.74 25.21 184 439 20.46 [104](56) six 38.95 25.04 33.06 49.22 9.14 [104](57) five >776 >776 >388 >388 >388 [104](58) six >1086 >543 >543 >543 >2174 [104]Doxorubicin 0.912 [82]5-FU 19.17 17.43 [83]Cisplatin 5.99 5.9 0.87 1.46 3.50 2.60 8.97 6.72 3.71 [90,92,104]

N

CO

OSn

N

CO

O O Sn

Sn OSn

OC O

O CO

N

N

(37)

Bu

Bu

Bu

Bu

Bu

Bu

Bu

Bu

Sn OO

Sn OSn

O SnSn

O SnO

Bu

OO

O

C

CO

O

CO

O

O

OC

O

C

BuBu

Bu

Bu

Bu

OC

O

(38)

N

NN

N

N

N

Fig. 10. Structure of the tetranuclear dibutyltin(IV) complex (37) and the hexanuclear monobutyltin(IV) complex (38) derived from a carbazole carboxylic acid.

M.K. Amir et al. / Inorganica Chimica Acta 423 (2014) 14–25 21

derived from a carbazole carboxylic acid, were prepared and inves-tigated for their in vitro cytotoxicity in hepatocellular carcinoma(BEL-7402) and human hepatocellular liver carcinoma cell line(HepG2) at four different concentrations. It was observed thatthese complexes (37–39) were more cytotoxic than is the standarddrug 5-flurouracil because the IC50 values for these complexes (37–39) were much lower than was that for 5-flurouracil (Table 4). Theresults obtained indicate the order of the antitumor activity as:(37) > (39) > (38) > organotin(IV) precursors [83]. It was proposedthat the di-n-butyltin(IV) derivative 37 with a weaker Sn–O bondwas more active against the two human tumor cell lines than werecomplexes 38 and 39, because further ligand replacement withbiological ligands was possible. The Sn–O bond length (2.771 Å)in complex (37) was much longer than other Sn–O bonds. Ligandreplacement from the Sn–O-core cluster to Sn–DNA complex fol-

lowing the Sn–O cleavage for 37 was expected. The activity ofthe cytotoxic complexes (37–39) was also attributed to the abilityof the ligand to form unobstructed H-bonds and/or p� � �p stackingthat may facilitate an intracellular uptake of complexes [83].

Many ferrocenyl compounds display interesting cytotoxic,anti-tumor, anti-malarial, antifungal and DNA-cleaving activity[82–87]. Recent studies have suggested that combination of a ferr-ocenyl moiety with heterocyclic structures may increase their bio-logical activities or create new medicinal properties [88,89]. Threeorganotin(IV) carboxylate derivatives (40–42) (Figs. 12 and 13)containing a novel ligand ‘‘3-trifluoromethyl-5-ferrocenyl -pyra-zol-1-yl-acetic acid’’ were prepared as a strategy for obtainingnew drug candidates in which the metal and the ligand could actsynergistically [90]. Anti-tumor activities of complexes (40–42)were evaluated using human hepatocellular liver carcinoma cells

Fig. 11. Structure of the hexanuclear tributyltin(IV) complex (39) derived from acarbazole carboxylic acid.

Sn

NN

CO

O

OSn

SnO Sn

O CO

N

Bu

Bu

Bu

Bu

Bu

Bu

Bu

Bu

F

FF

Fe

NF

FF Fe

(42)

N N

CO

O

FF

F

Fe

OCO

N NF

F FFe

Fig. 13. Structure of the tetranuclear organotin(IV) complex containing3-trifluoromethyl-5-ferrocenyl-pyrazol-1-yl-acetic acid as ligand.

22 M.K. Amir et al. / Inorganica Chimica Acta 423 (2014) 14–25

(HepG2), human lung carcinoma cells (A549) and melanoma cells(B16-F10) as described elsewhere with some modifications [91].5-Fluorouracil and cisplatin were used as positive controls. Theorder of the anti-tumor activity of the studied complexes was as40 > 42 > 41. The complexes (40) and (42) had greater inhibitoryeffect than did cisplatin against the three tumors cell lines(Table 4). The greater inhibitory effect of the complex (40) (IC50

0.08 lg/ml) than cisplatin (IC50 1.46 lg/ml) against B16-F10 cellline would make this complex a potent anti-tumor agent. Theligand alone exhibited low inhibition of cellular proliferationagainst each tumor cell line indicating organotin(IV) complexes(40–42) are responsible for the inhibitory effect [90].

Six new organotin(IV) carboxylates (43–48) (Fig. 14), based on1,3-benzenedicarboxylic acid and 1,4-benzenedicarboxylic acidligands, were synthesized and evaluated for antitumor activityagainst (HeLa) cervical cells, (HT1080) fibrosarcoma cells and(U87) glioma cells [92]. The (MTT) assay that differentiates deadfrom living cells was adapted [92,93]. It was observed from IC50

values that the complex (45) was the most efficient antitumoragent for HeLa having greater antitumor activity than cisplatin(Table 4) [94]. Complexes (43), (44) and (46) were the most effi-cient antitumor agents for U87 having greater antitumor activities

OH3C

Sn

NN

CO

OO

Sn

SnO SnO

CH3

OC

O

N

Ph

Ph

Ph

Ph

Ph

Ph

Ph

Ph

F

FF

Fe

NF

FF Fe

(40)

FFF

Fe

Fig. 12. Structures of the tetranuclear and hexanuclear organotin(IV) complexes

than cisplatin (Table 4) [95]. Cisplatin had no effect on HT1080cancer cells [96], but the complexes (43–48) had an effect onHT1080 cancer cells and the complexes (43–45) stood out in thiscase [92]. The selectivity in antitumor activity against differentcancer cells can be attributed to different structures and differentsubstituents on the ligand of these complexes.

Two organotin(IV) carboxylates (49–50) (Fig. 15) with (E)-3(2-nitrophenyl) propionic acid were prepared and examined for anti-tumor activity against HeLa, HT1080 and U87 cell lines using MTTassay [97]. Selectivity was observed in the complexes (49–50) forantitumor activity against different cell lines. It was observed fromIC50 values that the activities of complex (49) against three cancercell lines were better than complex (50) (Table 4). The complex(49) presented lower IC50 value for HeLa than did cisplatin (Table 4)[97]. These results indicated that complex (49) had the better anti-tumor activity and could be future candidate as anticancer agentafter in vivo study.

In living organisms orotic acid is very much important in the ‘denuovo’ biosynthesis of pyrimidine bases of nucleic acids [98]. Somemetal orotates are widely used in medicine due to therapeuticproperties [99,100]. Platinum orotates, palladium orotates, andzinc orotates have interesting anticancer properties [101–103]. Inorder to know the anticancer activity of organotin(IV) orotates,complexes (51–58) were prepared (Fig. 16). These complexes(51–58) along with standard drugs were screened in vitro againstfive cancer cell lines of human origin, MCF-7 mammary cancer,HEK-293 kidney cancer, PC-3 prostate cancer, HCT-15 colon cancerand HepG-2 liver cancer. In vitro anti-cancer screening data

Sn OO

Sn OSn

O SnSn

O SnO

Bu

OO

OC

CO

O

CO

O

O

OCOC

BuBu

BuBu

Bu

OC

O

(41)

NN

N NFF

F Fe

NNF

F FFe

N NFFF Fe

NN

FFF

Fe

NNF

F FFe

containing 3-trifluoromethyl-5 ferrocenyl-pyrazol-1-yl-acetic acid as ligand.

O

O

OO

OO

Sn

HO

OH

(43)

OO

O

O

OO

Sn

HO

OH

CH3

CH3

(44)

OO

O

O

O

O

Sn

HO

OH(45)

OH

SnO

Sn

SnO

SnO

OCO

Bu

Bu

Bu

Bu

Bu

Bu

Bu

Bu

O

SnO

Sn

SnO

Sn

HO

OC

O

Bu

Bu

Bu

Bu

Bu

Bu

Bu

Bu

OO

OC

O

O

CO

OO

(47)

OH

SnO

Sn

SnO

SnO

OCO

Bu

Bu

Bu

Bu

Bu

Bu

Bu

Bu

O

SnO

Sn

SnO

Sn

HO O

CO

Bu

Bu

Bu

Bu

Bu

Bu

Bu

Bu

OO

OC

O

O

CO

OO

(46)

OH

SnO

Sn

SnO

SnO

OCO

Bu

Bu

Bu

Bu

Bu

Bu

Bu

Bu

OSn

OSn

SnO

Sn

HO O

CO

Bu

BuBu

Bu

Bu

Bu

Bu

Bu

OO

OC

O

OCO

OO

(48)H3C

CH3

CH3

H3C

Fig. 14. Structures of the dinuclear and octanuclear organotin(IV) complexes based on 1,3-benzenedicarboxylic acid and 1,4-benzenedicarboxylic acid ligands.

COO

Sn

O

O2N

n

(49)

COO

Sn

O2N

CO

OSn O2N

O

O Sn

OCO

Sn

O2N

CO

O

NO2

Bu Bu

BuBu

BuBu

(50)

Bu

Bu

Fig. 15. Structures of the organotin(IV) carboxylates with (E)-3(2-nitrophenyl) propionic acid.

M.K. Amir et al. / Inorganica Chimica Acta 423 (2014) 14–25 23

showed that these complexes (51–58) had low to moderate cyto-toxicity against these five cancer cell lines (Table 4). It wasobserved that the complex (56) was most active against all the celllines, followed by the complex (51). These complexes (51–58) wereless active in comparison to cisplatin, 5-fluorouracil and metho-trexate, except the complex (56) and the complex (53) (Table 4).The complex (56) exhibited comparable activity against HCT-15in comparison to 5-fluorouracil and the complex (53) exhibited

comparable activity against PC-3 in comparison to methotrexate[104]. The low to moderate cytotoxicity of the studied organo-tin(IV) orotates (51–58) was explained on the basis of structure-activity relationship. It was proposed that the activity of theorganotin complexes mainly depends mainly on the hydrolytic sta-bility of Sn–X bond (X = O, N, Cl, F and S), whereas the Sn–C bond ishydrolytically more stable. It was reported that either organo-tin(IV) compounds as whole or R3Sn+ and R2Sn2+ produced on

SnR

RR

O O

HN

HN

O O

OO

NH

NH

OO

SnR

O RO OH

HN

HN

O O

OHO

NH

NH

OO

O

OO

HN

NH

NH

HN

O

O

O

O

SnBu

BuO

O

OO

NH

NH

OO

(57)

N NH

O

O

(58)R= Ph, (51)R= n-Bu, (52)R= Me (53)

R= Ph, (54)R= Me, (55)R= n-Oct, (56)

SnBu

Bu O

O

O

O

HNNH

O

O

N NH

O

O

Fig. 16. Structures of the organotin(IV) carboxylates with orotic acid.

SnBu

O

BuBuO

NHO

H3CO

SnPh

O

PhPhO

NHO

H3CO

(59) (60)

Fig. 17. Structures of triorganotin complexes with the carboxylate ligand derivedfrom maleic anhydride and p-aminoacetophenone.

24 M.K. Amir et al. / Inorganica Chimica Acta 423 (2014) 14–25

hydrolysis/dissociation might be the final active species responsi-ble for the anti-cancer activity of tri- and diorganotin compounds[23,105]. Since the studied organotin(IV) orotates (51–58) werevery stable to air and moisture, and may had relatively strongSn–X (O/N) bond, this may be correlated to the observed low-to-moderate activity of these organotin(IV) orotates (51–58) [104].

Triorganotin(IV) complexes (59–60) with the carboxylate ligandderived from maleic anhydride and p-aminoacetophenone havealso been synthesized (Fig. 17) and screened for antitumor activityby potato disc antitumor assay [106].

The IC50 values showed that these complexes (59–60) weremore active than the free ligand. The complex (60) exhibited besttumor inhibitory activity with the lowest IC50 value of 7.37 lgml�1

[107].

3. Conclusions

In this review on anticancer activity of organotin(IV) carboxyl-ates, it is noted that most of the organotin carboxylates such asthe complexes (1, 2, 5, 9–14, 17–19, 21–31, 37–46, 49) have greaterantitumor activity than do the standard drugs against different celllines, indicating that these complexes have great potential forfuture use as medicine. Different organotin(IV) carboxylates haveselectivity for different cell lines. This selectivity in antitumoractivity against different cancer cells can be attributed to the dif-ferent structures and different substituents on the ligand of thesecomplexes. Some of the organotin(IV) carboxylates are active evenagainst cancer cells where cisplatin is inactive. These studies haveshown that the cytotoxicity of organotin(IV) carboxylates dependsupon the chain length of the alkyl groups. The butyltin(IV) carbox-ylates have greater anticancer activity, while the organotin(IV) car-boxylates with a too short (methyl or ethyl) or a too long (n-octyl)carbon chain length have low activity. The polynuclear character oforganotin(IV) carboxylates results in poor anticancer activity dueto high coordination number and steric hindrance around tin,which limit the access of tin to the target. Some structural effectsmay increase the antitumor activity of organotin(IV) carboxylates.

It is concluded that organotin(IV) carboxylates will be promisingcandidates for use as anticancer agents. Future research shouldbe undertaken to determine the exact mechanism of action oforganotin(IV) carboxylates.

Acknowledgement

We thank the TWAS and Higher Education Commission of Paki-stan for financial support.

References

[1] V. Cepeda, M.A. Fuertes, J. Castilla, C. Alonso, C. Quevedo, J.M. Perez,Anticancer Agents Med. Chem. 7 (2007) 3.

[2] P. Yang, M. Guo, Coord. Chem. Rev. 185–186 (1999) 189.[3] P.J. Barnard, S.J. Berners-Price, Coord. Chem. Rev. 251 (2007) 1889.[4] A.M. Pizarro, A. Habtemariam, P.J. Sadler, Activation mechanisms for

organometallic anticancer complexes, in: G. Jaouen, N. Metzler-Nolte (Eds.),Med. Organomet. Chem. Topics in Organometallic Chemistry, vol. 32, 2010, p.21.

[5] M. Gielen, E.R.T. Tiekink, Metallotherapeutic Drugs and MetalBasedDiagnostic Agents: The Use of Metals in Medicine, John Wiley & Sons Ltd.,New York, 2005, p. 421.

[6] G. Gasser, I. Otto, N. Metzler-Nolte, J. Med. Chem. 54 (2011) 3.[7] T. Gianferrara, I. Bratsos, E. Alessio, Dalton Trans. 37 (2009) 7588.[8] M. LaMaryet, A.A. Holder, Annu. Rep. Prog. Chem. Sect. A: Inorg. Chem. 105

(2009) 505.[9] S.K. Hadjikakou, N. Hadjiliadis, Coord. Chem. Rev. 253 (2009) 235.

[10] S. Tabassum, C. Pettinari, J. Organomet. Chem. 691 (2006) 1761.[11] C. Pellerito, L. Nagy, L. Pellerito, A. Szorcsik, J. Organomet. Chem. 691 (2006)

1733.[12] M. Gielen, M. Biesemans, R. Willem, Appl. Organomet. Chem. 19 (2005) 440.[13] L. Pellerito, L. Nagy, Coord. Chem. Rev. 224 (2002) 111.[14] M.J. Clarke, F. Zhu, D.R. Frasca, Chem. Rev. 99 (1999) 2511.[15] M. Gielen, Coord. Chem. Rev. 151 (1996) 41.[16] P.J. Sadler, Adv. Inorg. Chem. 36 (1991) 1.[17] E.R.T. Tiekink, Crit. Rev. Oncol. Hematol. 42 (2002) 217.[18] Z. Guo, P.J. Sadler, Angew. Chem., Int. Ed. 38 (1999) 1512.[19] M.N. Xanthopoulou, S.K. Hadjikakou, N. Hadjiliadis, E.R. Milaeva, J.A.

Gracheva, V.-Y. Tyurin, N. Kourkoumelis, K.C. Christoforidis, A.K. Metsios, S.Karkabounas, K. Charalabopoulos, Eur. J. Med. Chem. 43 (2008) 327.

[20] X.M. Shang, J.R. Cui, J.Z. Wu, A.J.L. Pombeiro, Q.S. Li, J. Inorg. Biochem. 102(2008) 901.

[21] Q. Li, M.F.C. Guedes da Silva, A.J.L. Pombeiro, Chem. Eur. J. 10 (2004) 1456.[22] Q. Li, M.F.C. Guedes da Silva, Z. Jinghua, A.J.L. Pombeiro, J. Organomet. Chem.

689 (2004) 4584.[23] M. Nath, S. Pokharia, X. Song, G. Eng, M. Gielen, M. Kemmer, M. Biesemans, R.

Willem, D. de Vos, Appl. Organomet. Chem. 17 (2003) 305.[24] M. Gielen, M. Biesemans, D. de Vos, R. Willem, J. Inorg. Biochem. 79 (2000)

139.[25] D. de Vos, R. Willem, M. Gielen, K.E. van Wingerden, K. Nooter, Met.-Based

Drugs 5 (1998) 179.[26] M. Gielen, H. Dalil, B. Mahieu, D. de Vos, M. Biesemans, R. Willem, Met.-Based

Drugs 5 (1998) 275.[27] E.R.T. Tiekink, M. Gielen, A. Bouhdid, R. Willem, V.I. Bregadze, L.V. Ermanson,

S.A. Glazun, Met.-Based Drugs 4 (1997) 75.[28] M. Gielen (Ed.), Tin-Based Antitumor Drugs, Springer-Verlag, Berlin, 1990. p.

139.[29] M. Gielen, Appl. Organomet. Chem. 16 (2002) 481.

M.K. Amir et al. / Inorganica Chimica Acta 423 (2014) 14–25 25

[30] M. Gielen, A.G. Davies, K. Pannell, E. Tiekink, Tin Chemistry: Fundamentals,Frontiers, and Applications, John Wiley and Sons, Wiltshire, 2008.

[31] A.J. Crowe, Drugs. Fut. 12 (1987) 255.[32] A.K. Saxena, F. Huber, Coord. Chem. Rev. 95 (1989) 109.[33] J. Susperregui, M. Bayle, G. Lain, C. Giroud, T. Baltz, G. Deleris, Eur. J. Med.

Chem. 34 (1999) 617.[34] T.S. Basu Baul, W. Rynjah, E. Rivarola, A. Lycka, M. Holcapek, R. Jirásko, D. de

Vos, R.J. Butcher, A. Linden, J. Organomet. Chem. 691 (2006) 4850.[35] L. Tian, Y. Sun, H. Li, X. Zheng, Y. Cheng, X. Liu, B. Qian, J. Inorg. Biochem. 99

(2005) 1646.[36] G. Han, P. Yang, J. Inorg. Biochem. 91 (2002) 230.[37] S. Gómez-Ruiz, G.N. Kalu -derovic, Z.D. Juranic, S. Prashar, E. Hey-Hawkins, A.

Eric, Z. Zizak, Z.D. Juranic, J. Inorg. Biochem. 102 (2008) 2087.[38] D. Tzimopoulos, I. Sanidas, A.-C. Varvogli, A. Czapik, M. Gdaniec, E. Nikolakaki,

P.D. Akrivos, J. Inorg. Biochem. 104 (2010) 423.[39] M.N. Xanthopoulou, S.K. Hadjikakou, N. Hadjiliadis, M. Schurmann, K.

Jurkschat, A. Michaelides, S. Skoulika, T. Bakas, J.J. Binolis, S. Karkabounas,K. Charalabopoulos, J. Inorg. Biochem. 96 (2003) 425.

[40] M.N. Xanthopoulou, S.K. Hadjikakou, N. Hadjiliadis, M. Kubicki, S. Skoulika, T.Bakas, M. Baril, I.S. Butler, Inorg. Chem. 46 (2007) 1187.

[41] M.N. Xanthopoulou, S.K. Hadjikakou, N. Hadjiliadis, N. Kourkoumelis, E.R.Milaeva, J.A. Gracheva, V.-Y. Tyurin, I.I. Verginadis, S. Karkabounas, M. Baril,I.S. Butler, Russ. Chem. Bull. 56 (2007) 767.

[42] C. Ma, Q. Jiang, R. Zhang, Appl. Organomet. Chem. 17 (2003) 623.[43] C. Ma, J. Zhang, Appl. Organomet. Chem. 17 (2003) 788.[44] F. Barbieri, F. Sparatore, R. Bonavia, C. Bruzzo, G. Schettini, A. Alama, J. Neurol.

Oncol. 60 (2002) 109.[45] E.R.T. Tiekink, Appl. Organometal. Chem. 22 (2008) 533.[46] B. Ruan, Y. Tian, H. Zhou, J. Wu, R. Hu, C. Zhu, J. Yang, H. Zhu, Inorg. Chim. Acta

365 (2011) 302.[47] Z.A. Siddiqi, M. Shahid, S. Kumar, M. Khalid, S. Noor, J. Organomet. Chem. 694

(2009) 3768.[48] A. Chaudhary, A.K. Singh, R.V. Singh, J. Inorg. Biochem. 100 (2006) 1632.[49] A.G. Davies, P.J. Smith, Adv. Inorg. Chem. Radiochem. 23 (1980) 1.[50] W.N. Aldridge, in: J.J. Zuckerman (Ed.), Organotin Compounds. New

Chemistry and Applications, Adv. Chem. Ser, vol. 168, Am. Chem. Soc,Washington, 1976, p. 157.

[51] B.M. Elliot, W.N. Aldridge, J.M. Bridges, Biochem. J. 177 (1979) 461.[52] (a) G. Ciarimboli, T. Ludwig, D. Lang, H. Pavenstädt, H. Koepsell, H.-J. Piechota,

J. Haier, U. Jaehde, J. Zisowsky, E. Schlatter, Am. J. Pathol. 167 (2005) 1477;(b) S. Terstriep, A. Grothey, Expert Rev. Anticancer Ther. 6 (2006) 921;(c) A. Gelasco, S.J. Lippard, Top. Biol. Inorg. Chem. 1 (1999) 1;(d) E.R. Jamieson, S.J. Lippard, Chem. Rev. 99 (1999) 2467.

[53] V. Narayanan, M. Nasr, K.D. Paull, in: M. Gielen (Ed.), Tin-based AntitumourDrugs, 1, Springer, Berlin, 1990, pp. 201–216.

[54] S.W. Ng, V.G. Kumar, Appl. Organomet. Chem. 11 (1997) 39.[55] M. Gielen, T. Joosen, T. Mancilla, K. Jurkschat, R. Willem, C. Roobol, J.

Bernheim, G. Atassi, F. Huber, E. Hoffman, H. Preut, B. Mahieu, Main GroupMet. Chem. 10 (1987) 147.

[56] R. Willem, M. Biesemans, M. Bouâlam, A. Delmotte, A. El Khloufi, M. Gielen,Appl. Organomet. Chem. 7 (1993) 311.

[57] J. Zhang, L. Li, L. Wang, F. Zhang, X. Li, Eur. J. Med. Chem. 45 (2010) 5337.[58] X. Shang, X. Meng, E.C.B.A. Alegria, Q. Li, M.F.C. Guedes da Silva, M.L.

Kuznetsov, A.J.L. Pombeiro, Inorg. Chem. 50 (2011) 8158.[59] J. Wiecek, V. Dokorou, Z. Ciunik, D. Kovala-Demertzi, Polyhedron 28 (2009)

3298.[60] M.R. Kalu -derovic, S. Gómez-Ruiz, B. Gallego, E. Hey-Hawkins, R. Paschke, G.N.

Kalu -derovic, Eur. J. Med. Chem. 45 (2010) 519.[61] S. Gómez-Ruiz, B. Gallego, Z. Zizak, E. Hey-Hawkins, Z.D. Juranic, N.

Kalu -derovic, Polyhedron 29 (2010) 354.[62] P. Skehan, R. Storeng, D. Scudiero, A. Monks, J. McMahon, D. Vistica, J.T.

Warren, H. Bokesch, S. Kenney, M.R. Boyd, J. Natl Cancer Inst. 82 (1990) 1107.[63] G.N. Kalu -derovic, R. Paschke, S. Prashar, S. Gómez-Ruiz, J. Organomet. Chem.

695 (2010) 1883.[64] F. Barbieri, M. Viale, F. Sparatore, A. Favre, M. Cagnoli, C. Bruzzo, F. Novelli, A.

Alama, Anticancer Res. 20 (2000) 977.[65] I.I. Verginadis, S. Karkabounas, Y. Simos, E. Kontargiris, S.K. Hadjikakou, A.

Batistatou, A. Evangelou, K. Charalabopoulos, Eur. J Pharm. Sc. 42 (2011) 253.

[66] S.K. Hadjikakou, I.I. Ozturk, M.N. Xanthopoulou, P.C. Zachariadis, S. Zartilas, S.Karkabounas, N. Hadjiliadis, J. Inorg. Biochem. 102 (2008) 1007.

[67] S.K. Choudhuri, S.D. Dutta, R. Chatterjee, J.R. Chowdhury, Chemotherapy 37(1991) 122.

[68] V.S. Petrosyan, N.S. Yashina, S.V. Ponomarev, Met.-Based Drugs 5 (1998) 237.[69] X. Shang, Q. Li, J. Wu, J. Organomet. Chem. 690 (2005) 3997.[70] X. Shang, J. Wu, Q. Li, Eur. J. Inorg. Chem. (2006) 4143.[71] X. Shang, J. Wu, A.J.L. Pombeiro, Q. Li, Appl. Organomet. Chem. 21 (2007) 919.[72] M. Gajewska, K.V. Luzyanin, M.F.C.G. da Silva, Q. Li, J. Cui, A.J.L. Pombeiro, Eur.

J. Inorg. Chem. 25 (2009) 3765.[73] X. Shang, N. Ding, G. Xiang, Eur. J. Med. Chem. 48 (2012) 305.[74] Y. Li, Y. Li, X. Niu, L. Jie, X. Shang, J. Guo, Q. Li, J. Inorg. Biochem. 102 (2008)

1731.[75] T.S. Basu Baul, A. Paul, L. Pellerito, M. Scopelliti, P. Singh, P. Verma, D. De Vos,

Inves. New Drugs. 27 (2009) 587.[76] T.S. Basu Baul, A. Paul, L. Pellerito, M. Scopelliti, P. Singh, P. Verma, A. Duthie,

D. de Vos, E.R.T. Tiekink, Invest. New Drugs 29 (2011) 285.[77] T.S. Basu Baul, A. Paul, L. Pellerito, M. Scopelliti, C. Pellerito, P. Singh, P. Verma,

A. Duthie, D. de Vos, R.P. Verma, U. Englert, J. Inorg. Biochem. 104 (2010) 950.[78] Y.P. Keepers, P.R. Pizao, G.J. Peters, J. VanArk-Otte, B. Winograd, H.M. Pinedo,

Eur. J. Cancer 27 (1991) 897.[79] T.S. Basu Baul, A. Paul, L. Pellerito, M. Scopelliti, D. de Vos, R.P. Verma, U.

Englert, A. Duthie, J. Inorg. Biochem. 107 (2012) 119.[80] T.S. Basu Baul, C. Masharing, G. Ruisi, R. Jirásko, M. Holcapek, D. de Vos, D.

Wolstenholme, A. Linden, J. Organomet. Chem. 692 (2007) 4849.[81] T.S. Basu Baul, S. Basu, D. de Vos, A. Linden, Invest. New Drugs 27 (2009) 419.[82] N. Muhammad, Zia-ur-Rehman, S. Ali, A. Meetsma, F. Shaheen, Inorg. Chim.

Acta 362 (2009) 2842.[83] B. Ruan, Y. Tian, H. Zhou, J. Wu, R. Hu, J. Yang, H. Zhu, C. Zhu, Inorg. Chim. Acta

365 (2011) 302.[84] U. Schatzschneider, N. Metzler-Nolte, Angew. Chem., Int. Ed. 45 (2006) 1504.[85] D.R. Van Staveren, N. Metzler-Nolte, Chem. Rev. 104 (2004) 5931.[86] D. Dive, C. Biot, Chem. Med. Chem. 3 (2008) 383.[87] P.C.A. Bruijnincx, P.J. Sadler, Curr. Opin. Chem. Biol. 12 (2008) 197.[88] H. Yu, L. Shao, J. Fang, J. Organomet. Chem. 692 (2007) 991.[89] B. Maity, M. Roy, A.R. Chakravarty, J. Organomet. Chem. 693 (2008) 1395.[90] M.-L. Sun, B.-F. Ruan, Q. Zhang, Z.-D. Liu, S.-L. Li, J.-Y. Wu, B.-K. Jin, J.-X. Yang,

S.-Y. Zhang, Y.-P. Tian, J. Organomet. Chem. 696 (2011) 3180.[91] X. Chen, C. Plasencia, Y. Hou, N. Neamati, J. Med. Chem. 48 (2005) 1098.[92] D. Du, Z. Jiang, C. Liu, A.M. Sakho, D. Zhu, L. Xu, J. Organomet. Chem. 696

(2011) 2549.[93] A. Varvaresou, K. Iakovou, Anticancer Res. 25 (2005) 2253.[94] G.N. Kalu -derovic, V.M. Ðinovic, Z.D. Juranic, T.P. Stanojkovic, T.J. Sabo, J. Inorg.

Biochem. 99 (2005) 488.[95] T. Servidei, A. Riccardi, M. Sanguinetti, C. Dominici, R. Riccardi, J. Cell. Physiol.

208 (2006) 220.[96] B. Law, L. Quinti, Y. Choi, R. Weissleder, C.-H. Tung, Mol. Cancer Ther. 5 (2006)

1944.[97] C. Liu, S. Liu, D. Du, D. Zhu, L. Xu, J. Mol. Struct. 1003 (2011) 134.[98] (a) A. Lehninger, Principles of Biochemistry, Worth Publishers Inc., New York,

1970. p. 661;(b) Available from: <http://www.whatislife.com/reader2/Metabolism/pathway/nucleicacids.html> (accessed in May 2011).

[99] H.A. Nieper, German Patent: 2, 507, 974.[100] A. Cihak, W. Reutter, Orotic Acid, MTP Press Ltd., Lancaster, 1980.[101] P. Castan, S. Wimmer, E. Colacio-Rodriguez, A.L. Beauchamp, S. Cros, J. Inorg.

Biochem. 38 (1990) 225.[102] K. Matsumoto, Inorg. Chim. Acta 151 (1988) 9.[103] O. Kumberger, J. Riede, H. Schmidbaur, Z. Naturforsch. B 48 (1993) 961.[104] M. Nath, M. Vats, P. Roy, Eur. J. Med. Chem. 59 (2013) 310.[105] C. Pettinari, F. Marchetti, Chemical and biological developments in organotin,

Cancer Chemotherapy, in: Tin Chemistry; Fundamentals, Frontiers andApplications, Wiley, 2010, p. 454.

[106] J.L. McLaughlin, L.L. Rogers, Drug Inf. J. 32 (1998) 513.[107] N. Arshad, S.I. Farooqi, M.H. Bhatti, S. Saleem, B. Mirza, J. Photochem.

PhotoBiol. B: Biol. 125 (2013) 70.