Anticancer activity of organotin(IV) carboxylates

Inorganica Chimica Acta xxx (2014) xxx–xxx

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Inorganica Chimica Acta journal homepage: www.elsevier.com/locate/ica

Review

Anticancer activity of organotin(IV) carboxylates 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, Pakistan Department of Chemistry, University of Science & Technology Bannu, KPK, Pakistan c Department of Chemistry, McGill University, 801 Sherbrooke St. West, Montreal, Quebec H3A2K6, Canada b

a r t i c l e

i n f o

Article history: Received 1 May 2014 Received in revised form 21 July 2014 Accepted 22 July 2014 Available online xxxx Keywords: Metallodrugs Cancer Organotin(IV) carboxylates Antitumor 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 last five years. Most of the organotin(IV) carboxylates discussed in this review have greater anticancer activity against different cell lines than do the standard drugs. Moreover, some of these organotin(IV) carboxylates have pronounced anticancer activity even against cisplatin-resistive cancer cells. The review also highlights structure-activity relationships. Ó 2014 Published by Elsevier B.V.

Muhammad Kashif Amir has completed his M.Phil Inorganic Chemistry from Bahauddin Zakariya University Multan, Pakistan. Currently he is PhD scholar in department of Chemistry, Quaid-i-Azam University Islamabad, Pakistan under the supervision of Dr. Zia-ur-Rehman. His research is focused on the synthesis, characterization and medicinal applications of metal based compounds.

Mr. Shahan Zeb Khan is a lecturer in University of Science and Technology Bannu Khyber Pakhtunkhwa, Pakistan. He did his M.Sc and M.Phil from Quaid-I-Azam University Islamabad and currently he is pursuing his Ph.D. at QAU under the supervision of Dr. Zia-ur-Rehman. His research is focused on the synthesis and characterization of metal based compounds and their Biological applications.

Abbreviations: Bipy, 2,2-bipyridine; Phen, 1,10-phenanthroline; MTT, microculture tetrazolium [3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide,] assay; SRB, sulforhodamine B assay; H2imda, iminodiacetic acid; DBDCT, di-nbutyl-(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: hafi[email protected], [email protected] ( Zia-ur-Rehman). http://dx.doi.org/10.1016/j.ica.2014.07.053 0020-1693/Ó 2014 Published by Elsevier B.V.

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Dr. Zia-ur-Rehman was educated at the Quaid-iAzam University (QAU) in Pakistan and McGill University Canada in 2009. He began his academic career at QAU in 2009, where he is still teaching and doing research in metallo-drug, electrochemistry, supramolecular chemistry, environmental and drug delivery applications of novel surfactants, and nanotechnology. He published 70 research articles in various journals of international repute, and a coauthor of a book entitled ‘‘DNA Binding and DNA Extraction: Methods, Applications and Limitations’’. In his short academic carrier, 11 M.Phil students obtained their degrees in his direction. His teaching and research efforts have been recognized by the Dr. Abus Salam Award from TWAS. He has been married to his wife Kausar for 4 years and together they have a son Muhammad Ahmmad and a daughter Musfira.

Professor Ian S. Butler was educated at the University of Bristol in the U.K. and, following postdoctoral work at Indiana and Northwestern Universities in the U.S.A., he began his academic career at McGill University in Montreal, Quebec, Canada in 1966, where he is still teaching and doing research in a wide range of applications of molecular spectroscopy. Well over 50 M.Sc. and PhD. students have obtained their degrees under his direction and 500 articles and 400 national and international conference presentations have emanated from their research work to date. He has been a Visiting Professor in the U.K., France, China, Brazil, Hungary and Australia. His teaching and research efforts have been recognized by the Gerhard Herzberg Award from the Spectroscopy Society of Canada and the David Thomson Award from McGill University. He has co-authored several textbooks, including Relevant Problems for Chemical Principles (with Dr. A.E. Grosser) and Inorganic Chemistry: Principles and Applications (with Dr. J.F. Harrod). He has been married to his wife, Pamela, a former dancer with American Ballet Theatre in New York City and now a retired Professor of Political Science, for 48 years and together they have four children and fourteen grandchildren.

Dr. Afzal Shah is an assistant professor at Quaid-iAzam University, Islamabad, Pakistan. He received his Ph.D. in physical chemistry from QAU in 2010 under the indigenous Ph.D. program launched by the Higher Education Commission of Pakistan. His research interests include elucidation of electrode reaction mechanism of biologically important molecules and development of new synthetic routes for the preparation of environmental friendly surfactants.

Contents 1. 2. 3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anticancer activity of organotin(IV) carboxylates Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction The first inorganic cancer chemotherapeutic agent was cisplatin, which still remains a front-line treatment for testicular, ovarian and other cancers [1,2]. However, considerable toxic side-effects and the emergence resistance have limited the clinical effectiveness of cisplatin and related drugs. There is need to find new inorganic agents for use in cancer chemotherapy with improved specificity and decreased toxic side-effects. In vitro screening of new coordination complexes, followed by selecting the best performing anticancer active compounds, is still the best way of identifying potential drug candidates. A great deal of interest in platinum and non-platinum metallodrugs has emerged. Among the non-platinum metal complexes with antitumor activity, particular interest has been focused on tin(IV) complexes [3]. The potential of organotin(IV) complexes as biologically active metallopharmaceuticals has been accepted [4–27]. Various studies with interesting results on the in vitro antitumor properties of organotin(IV) complexes against a wide panel of tumor cell lines of human origin have been reported [2,9,15,28,29,30]. A large number of organotin(IV) compounds have been tested in vitro and in vivo, firstly against murine leukemia cell lines and then against different panels of human cancer cell lines [5,28,31]. Several organotin(IV) complexes exhibited high antiproliferative activity in vitro against a variety of solid and hematologic cancers [9,5]. Organotin(IV) complexes with carboxylato [32–38], thiolato

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[19,39–44] and dithiocarbamato [45] ligands have been studied extensively. In these studies it has been shown that organotin(IV) carboxylates usually present the highest cytotoxic activity [9]. It is known that organotin(IV) carboxylates have promising in vitro antitumor activities against human tumor cell lines [4,21,22,32]. Organotin(IV) carboxylates had been found to be active towards a number of tumor cells [9,46–48]. The results of such testing showed that these organotin carboxylates are even more effective than cisplatin [9,46–48]. Modification of the carboxylato ligands and/or the alkyl or aryl substituents at tin(IV) has a notable effect on the antiproliferative effect of di-, tri-alkyl or aryltin(IV) carboxylate complexes [9,40]. The higher antitumor activity of triorganotin(IV) carboxylates than di- and monoorganotin(IV) counterparts has been related to their ability to bind to proteins [49–51]. However, the exact mechanism of anti-tumor action of organotin(IV) carboxylates is not yet known. Many reviews are available on the anticancer 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 antitumor action of organotin(IV) carboxylates. This review will be helpful in investigating the chemotherapeutic treatment of cancers with no or less side effects and drug resistance. Moreover, the review will emphasize the need to develop non-platinum metalbased anticancer drugs for the treatment of cisplatin-resistive cancer cells.

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effects of the complexes (1) and (2) against the three tumor cell lines are compared with those using cisplatin (Table 1). The inhibitory effect of the complexes (1, 2) is relatively higher than 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 terms of a structural effect, i.e., a long chain of the dinuclear (Sn–Sn) units stabilized or controlled via an extensive H-bonding and the presence of additional spacers like Bipy or Phen in the molecular unit (Fig. 1) [20]. The n-butyl group bonded to the tin atom in these complexes (1, 2) may also contribute towards the cytotoxic effects [12]. The results indicated that complexes (1, 2) were highly effective against all the cell lines at higher concentration (104 M), but were not particularly effective at lower concentration (107 M). The complexes (1, 2) retained cytotoxic effects against P388 tumor cell line even for the concentration range 105–106 M [47]. It has been shown that organotin(IV) carboxylates have promising in vitro antitumor activities against human tumor cell lines, [4,21,22,32] and the presence of a 4-chlorophenyl group enhanced the activity of such complexes [21]. So, the organotin(IV) compounds (3–8) containing 1-(4-chlorophenyl)-1-cyclopentanecarboxylato ligand (Fig. 2) were synthesized and checked for their in 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 Bel7402 and BGC-823 cell lines (Table 1) and is slightly more active than cisplatin against Bel-7402 cell line (Table 1). The IC50 values for the complex (5) and cisplatin were 5.2 and 8.1 lM [57] (for Bel-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 vital role in the cytotoxic activity. The di-n-butyltin(IV) complex (5)

2. Anticancer activity of organotin(IV) carboxylates The discovery of cisplatin has increased the prominence of metal-based drugs for the treatment of various diseases [52]. Following the discovery of cisplatin, numerous other metal complexes have been investigated, especially organotin(IV) complexes [53]. Some mononuclear and dinuclear organotin(IV) derivatives were known to possess in vitro antitumor activities [54–56]. The dinuclear complexes (1, 2) were synthesized in which additional a-diimine (Bipy or Phen) does not coordinate to metal ion but a-diimine is present in the crystal lattice as spacer, which helps for the formation of a supramolecular framework by bringing the two binuclear species close enough through extensive H-bonding (Fig. 1) [47]. These dinuclear organotin(IV) carboxylates (1, 2) were investigated for their inhibitory effect on the murine leukemia cell line P388, human leukemia cell line HL-60 and the human non-small cell lung cancer cell line A549. The results of the in vitro cytotoxic

Bu

OH 2 O

N

O

Bu

O Bu

Sn

OH

H NH

Sn HN O HO H H 2O Bu Bu O N

O O N

O

O Bu OH 2 H O H NH Sn

Sn HN O HO H H2 O Bu Bu O N

O

(2)

(1)

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

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

a b c d

Complex

Coordination mode

A-549

P388

HL-60

(1) (2) (3) (4) (5) (6) (7) (8) Cisplatin

seven seven six six six six six six four

72 74.7

100 100

98.9 98.6 7.8 22.4 34.0 8.6 21.5 26.9 100

15.1

48.4

BGC-823

Bel-7402

KB

16.4 16.4 88.8b 12.8 13.3 7.1 79.1d

6.7 89.4a 12.6 17.4 12.7 90.8c

10.9 8.7 39.2 24.4 19.5 69.4

IC50 = 4.9 lM. IC50 = 5.2 lM. IC50 = 6.5 lM. IC50 = 8.1 lM.

Cl

Cl

Ph O Ph Sn O

C

Cl

O O R O C O C Sn O O R

C O Cl

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

Cl

Sn O Sn

Ph C

O

O

O O O

Sn

Ph Sn

Cl C Ph Sn O

O C

O O

O C

Cl

O

O

Ph

(8)

Cl

Fig. 2. Structures of the organotin(IV) carboxylate complexes containing 4-chlorophenyl group in the ligand.

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Refs. [47] [47] [58] [58] [58] [58] [58] [58] [47,58]

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

Coordination mode

IC50 (lM) against cancer cell lines L-929

A-549

T-24

MCF-7

8505C

A253

A549

DLS1

BGC-823

Bel-7402

LMS cells

HL-60

Cisplatin (9) (10) (11) (12) (13) (5) (14) (15) (16) (17) (18) (19) (20)

four five six six five five six six five five five five seven seven

0.69 0.88 1.02 0.95

1.53 7.2 0.91 4.83

41.66 0.43 19.73 4.52

7.99 0.69 1.24 0.62

5.0

0.81

1.51

5.1

6.5

8.1

5

2.89

2.65

0.132 0.172

0.081 0.100

0.094 0.129

0.060 0.178 4.9

5.2 >20 14.83 5.13 0.049 0.21 4.23

15.9 4.96 1.94 0.01 0.13 2.88

Refs.

0.029

0.0224 >20 16.05 8.97 0.056 1.49 6.55

had the highest antitumor activity, while the diorganotin(IV) derivatives with a too short (methyl) or a too long (n-octyl) carbon chain length had very low activities. The activity of the diphenyltin(IV) complex (7) was also weak, although usually better than those of dimethyltin(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 did not result in a high cytotoxic activity. It was suggested that high coordination number and steric hindrance around tin were important factors for the weak activity of complex (8), which limit the access of tin to the target [58]. Neutral and cationic organotin(IV) complexes with pyruvic acid thiosemicarbazone (9–11) (Fig. 3) were synthesized and evaluated for the in vitro cytotoxic activity against the cells of three human cancer 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 strain L) [59]. The MCF-7, L-929 and A-549 cells were determined by the SRB assay, while T-24 cells by the MTT assay. The diorganotin(IV) complexes (9–11) were similar to cisplatin against L-929 cancer cell line and more cytotoxic than cisplatin against the MCF-7 and T-24 cancer cell lines (Table 2). The complex (9) was 11.6 and 106 times more active than is cisplatin against MCF-7 and T-24 cell lines, respectively, as shown by the IC50 values (Table 2). The complex (10) was 6.4 times more active than is cisplatin against the MCF-7 cell line and 2.7 times more active than is cisplatin 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 cisplatin against MCF-7 cell line and 9.2 times more active than is cisplatin against the T-24 cell line (Table 2). These results showed that complexes (9–11) were selectively active against the MCF-7 and T-24 cancer cell lines [59]. The complex (9) was highly active against the T-24 bladder cancer cell line at very low concentration,

N

H2 N S

CH3 O N Sn

O

H N

H2 N S

Sn

R H 2O

(9)

O

O

O

Sn

Sn

O

Cl

C

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

C

O

S

S

H 3C

O

O

H 3C

R

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

[58,59,63,65] [59] [59] [59] [63] [63] [58] [65] [73] [73] [73] [73] [73] [73]

and can be considered as a future candidate as an anticancer drug and merits further in vivo investigation. The presence of the xylylthioacetato and mesitylthioacetato ligands was observed to have a positive influence on the cytotoxicity of gallium [60] and titanium [61] complexes. In the order to know the effect of xylylthioacetato and mesitylthioacetato ligands on the cytotoxicity of triphenyltin(IV) complexes, the triphenyltin(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 cytotoxicity against the human tumor cell lines 8505C (anaplastic thyroid cancer), A253 (head and neck tumor), A549 (lung carcinoma) and DLD-1 (colon carcinoma) using the SRB micro culture colorimetric assay [62,63]. The IC50 values showed that the tin complexes (12, 13) studied were more active than is cisplatin against all 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 the complex (13) indicated a preference of complex (12) against DLD-1 cells [63]. The compounds (12) and (13) had activities up to 285 and 2520 times greater than their gallium(III) and titanocene(IV) analogues, respectively [60,61,63]. The cytotoxic activity of complexes (12, 13) was from 8 to 85 times greater than is that of cisplatin. It was suggested that greater tolerances of high tin concentrations in biological systems may be possible (in direct contrast to the large number of side-effects associated with very low concentrations of platinum). This observation makes these tin compounds ideal candidates for further studies [63]. It has been shown that triorganotin(IV) compounds show significant anticancer activity and elongation of survival time of tumor-bearing animals [64]. In view of these findings, the triphenyltin(IV) carboxylate (14) (Fig. 5), as synthesized previously, was

CH3 O N

KB

CH 3

(12)

CH 3

CH 3

(13)

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

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M.K. Amir et al. / Inorganica Chimica Acta xxx (2014) xxx–xxx

O Sn H3 C

O

C

N

O

C

S

Sn

CH 3

(14) Fig. 5. Structures of the triorganotin(IV) complex bis[triphenyltin(IV)](3-carboxypyridine2-thionato).

investigated for its anti-proliferative and antitumor activities [65]. Trypan blue dye exclusion assay was used to determine cell viability on leiomyosarcoma cells (LMS) and human breast adenocarcinoma cells (MCF-7). The LMS and MCF-7 cells, which were treated 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 lower than 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 incubation 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 of treatment, the IC50 value for cisplatin was 25 lM and the IC50 value for the complex (14) was 40.7 nM. For MCF-7 cell growth proliferation (MTT assay) after 48 h of treatment, the IC50 value for cisplatin was 28 lM and the IC50 value for the complex (14) was 45.3 nM. These findings showed that IC50 values for the complex (14) were much lower than the IC50 values for cisplatin against these two cell lines. Cell recovery data (the ability of treated cells to grow after drug withdrawal-colony efficiency) showed that LMS and MCF-7 cell cultures treated with the complex 14, lost their ability to proliferate and growth arrest seemed irreversible. In order to quantify apoptosis or necrosis, the LMS and MCF-7 cells were treated with the complex 14 and evaluated by flow cytometry assay. Treated and untreated LMS and MCF-7 cells were stained with Annexin V-FITC and PI. The untreated LMS cells showed in total about 9.26% of background cell death. The LMS cells treated with 20, 40 and 60 nM of the complex 14 for 48 h showed 16.22%, 35.29% and 70.72% apoptosis, while the necrosis remained stable at 1.31%, 3.93% and 2.21%, respectively. These results showed that the complex 14 causes a dose-dependent cytotoxic response in the LMS cells. Untreated MCF-7 cells showed in total about 11.89% of background cell death. The MCF-7 cells treated with 20, 40 and 60 nM of the complex 14 for 48 h showed 19.84%, 41.88% and 66.1% apoptosis, while the necrosis remained stable at 2.41%, 1.33% and 1.86%, respectively. These results

obtained by flow cytometry assay were confirmed by DNA fragmentation analyses. The presence of laddering of low molecular weight DNA indicated that the LMS cells treated with the complex 14 undergo apoptosis at high concentrations (greater than 20 nM). The in vivo antitumor activity was performed on twenty female Wistar rats, which were first inoculated with 4  106 LMS cells. After the appearance of a palpable tumor mass (smaller than 1.5 cm diameter), the inoculated animals were divided into two groups. The control group (CG) and the experimental group (EG), each consisting of 10 animals. All EG animals were treated with 4  5.4 mg/kg (body weight) of the complex (14) (dissolved in 1 mL of tricapryline) every three days. The CG animals were left without any treatment till death. All animals were observed for their behavior once a day. Treatment was terminated after the first animal death (from EG) occurred. For both groups, the mean survival time of the animals (MST), the mean tumor weight and mean tumor growth rate (MTGR) were calculated. The results showed that the complex 14 prolonged mean survival time of the animals by 200% and decreased mean tumor growth rate (MTGR) compared to the control group. It was observed that the 30% (3 out of 10) of the tumour-bearing animals were totally cured [65]. These results indicated that the complex 14 might be a promising new antitumor agent. It has also been shown that organotin(IV) hydroxamates possess strong antitumor activity against preneoplastic rat hepatocytes (RH), Ehrlich ascites (EA), human promyelocytic leukemic (HL-60), human hepatocellular carcinoma (Bel-7402), human gastric carcinoma (BGC-823), and human nasopharyngeal carcinoma (KB) cell lines. Di-n-butyltin(IV) hydroxamates are prominent for antitumor activity among the diorganotin(IV) hydroxamates. It was seen that the activity of dibutyltin(IV) hydroxamates was dependent on the type of molecular structure [20–22,67–72]. In order to explore further the influence of the nature, the number and the position of the halo atom and nuclearity, two types of dibutyltin(IV) arylhydroxamates, mononuclear chloride (15–18) and tetranuclear (19, 20), were prepared [73]. These dibutyltin(IV) hydroxamates (15–20) (Fig. 6) were investigated for cytotoxicity in vitro against the human promyelocytic leukemic (HL-60), human gastric carcinoma (BGC-823), and human nasopharyngeal carcinoma (KB) cell lines by MTT and SRB assay. The complexes 18 and 19 exerted strong cytotoxic effects against all tested carcinoma cell lines with much lower IC50 values even than that of cisplatin (Table 2). It was seen that almost all complexes show good selectivity against KB carcinoma cell lines and the complex 18 with two fluorine atoms at C2 and C6 positions of benzene ring was the prominent one (Table 2). Three of the complexes (17, 18 and 19) were more active than is cisplatin against KB cell lines, and complexes 18 and 19 were more active than is cisplatin against all tested cell lines (Table 2). The cytotoxicity of complex 18 was greater than the complex 19 [73]. The antitumor activity of 18

R R Bu Bu C HN C C NH O NH O Bu Bu O O O O Sn Sn Sn Sn O O O Bu O O Bu HN C NHBu C O HN C R R R Bu R

Cl Sn

O

C

R

O NH

5

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

R = 3-BrC6H4 (19)

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

R = 4-BrC6H4 (20)

Fig. 6. Structures of the mononuclear and tetranuclear di-n-butyltin(IV) arylhydroxamate complexes.

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M.K. Amir et al. / Inorganica Chimica Acta xxx (2014) xxx–xxx

Sn

Sn

O

O C N

N O

C

O N

H

N

(21)

N

H

N

(22)

O

C

N

O

N

C

O

O H H 3C

C

C

H3 C

O

Sn

Sn O

O

(23)

OH

(24)

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

was compared with a mixed-ligand complex DBDCT reported previously [74]. Comparison of the IC50 values suggested that complex 18 (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]. These studies indicated that the amount and position of X-substituents tend to affect greatly the antitumor activity. Apoptosis rate of tumor cells was determined in KB cells, which were most sensitive ones to the most cytotoxic tested complexes (18 and 19). Early stages of apoptosis are characterized by perturbations in the cellular membrane. It leads to a redistribution of PS to the external side of the cell membrane, which causes a Ca flux. The Annexin V is a Ca-dependent phospholipid binding protein with high affinity for PS. Therefore, fluorescently labeled annexin V can be used to identify early apoptosis cells. Late apoptosis and necrotic cells have lost membrane integrity and can be stained by PI. Untreated KB cells showed about 21.2% of background cell death. The KB cells treated with 2.5, 10 and 20 lM of complex 18 showed 54.8%, 84.8% and 83.9% apoptosis, respectively. These results showed that complex 18 causes a dose-dependent cytotoxic response in KB cells. For 19, the total apoptosis percentage were 17.7%, 56.2% and 36.7% at concentrations of 2.5, 10 and 20 lM, respectively. Both complexes 18 and 19 were more toxic than is cisplatin to KB cells, which even at concentration of 20 lM did not show toxicity, due to the improved lipophilicity of complexes 18 and 19 [73]. Cell cycle analysis was performed by PI single labeling using decreased concentrations of complexes, 18, 19 and cisplatin (0.25, 0.5 and 1 lM) in order to study DNA cell content changes in cell cycle. The phases of the cell cycle can be differentiated on the basis of content of genetic material which, in non-dividing cells is limited to one copy of DNA. The cell population in the S phase (DNA replication phase) is synthesizing genetic material and thus contains more DNA than do quiescent cells. The subsequent G2/M phase (interphase/mitosis) is characterized by the presence of two copies of DNA. Therefore, the alternations in these phases were used as a basis for the comparison of different treatments. It was established that exposure of cells to 18, 19 and cisplatin led to a decrease in the percentages of the S phase and an increase in the percentage of the G0/G1 phase. The complex 18 displayed higher cells arrest for the G0/G1 phases than did the complex 19 and cisplatin. These data demonstrated that complex 18 was even better than complex 19, consistent with the former apoptosis rate of tumor cells and cytotoxicity assays [73]. These results indicate that the complexes 18 and 19 can be promising antitumor agents in future. In another study, it has been shown that triphenyltin (IV) 2[(E)-2-(aryl)-1-diazenyl] benzoates have high in vitro cytotoxic potential against human tumor cell lines. Molecular docking studies on these compounds indicated that the azo group nitrogen atoms and formyl, carbonyl, ester and hydroxyl oxygen atoms in

the ligand moiety exhibit hydrogen bonding interactions with the active site of the amino acids of various enzymes, such as ribonucleotide reductase, thymidylate synthase and thymidylate phosphorylase [76,77]. A series of tributyltin(IV) complexes with 2/4-[(E)-2-(aryl)-1-diazenyl] benzoate ligands (21–24) (Fig. 7) was synthesized and tested for cytotoxicity studies on the human tumor cell lines A498 (renal cancer), EVSA-T (mammary cancer), H226 (non-small-cell lung cancer), IGROV (ovarian cancer), M19 MEL (melanoma), MCF-7 (mammary cancer) and WIDR (colon cancer) [77]. The cytotoxicity was estimated by the microculture (SRB) test [78]. Usually, complex 21 was more cytotoxic than were the other test complexes (22–24) against all the cell lines tested (Table 3). On increasing the steric bulk at the coupling site of the ligand framework by the addition of a tert-butyl group, as in compound (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) against EVSA-T cell line [77]. These results reveal the importance of substituents in the ligand skeleton in defining the cytotoxic potential of 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 these complexes (21–24) makes them prominent in the triorganotin(IV) complexes. Their activity was attributed to the tetrahedral geometry of the complexes in solution, as well as to the presence of an azo functionality in the ligand framework, as was subsequently confirmed by docking results [75,76]. The cytotoxicity data for compound 21, together with its better solubility, suggested that compound 21 might be a promising candidate for further in vitro and in vivo studies after appropriate modification. [77]. A number of triphenyltin(IV) 4-[(E)-2-(aryl)-1-diazenyl] benzoates (25–27) having triphenyltin(IV) carboxylate at para position in the diazo-forming moiety, and triphenyltin(IV) 2-[(E)-2-(aryl)-1diazenyl] benzoates (28–29) having a triphenyltin(IV) carboxylate group at the ortho position in the diazo-forming moiety were prepared (Fig. 8) [79]. These complexes were checked for their cytotoxic potential across the panel of human tumor cell lines A498, EVSA-T, H226, IGROV, M19 MEL, MCF-7 and WIDR. The results of in vitro cytotoxicity of the tested compounds (25–29) were compared with the results from other related triphenyltin(IV) complexes (30–31) having triphenyltin (IV) carboxylate at the ortho position in the diazo-forming moiety. The cytotoxicity results showed that the test complexes (25–31) were more toxic than standard drug 5FU (Table 3). The cytotoxicity data (ID50) for the test complexes (25–31) were of the same order of magnitude and the change of ligand substitution does not influence the cytotoxic activity significantly. These results indicated that structural variation of the L–R skeletons does not influence the activity. In

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M.K. Amir et al. / Inorganica Chimica Acta xxx (2014) xxx–xxx Table 3 In vitro ID50 values (ng/ml) of organotin (IV) carboxylates against different cell lines. Complex

Coordination mode

(21) (22) (23) (24) (25) (26) (27) (28) (29) (30) (31) DOX CDDP 5-FU MTX ETO TAX

four four four four four four four four four four four

ID50 (ng/ml) against cancer cell lines A498

EVSA-T

H226

IGROV

M 19 Mel

MCF-7

WIDR

162 176 177 182 103 103 101 101 162 101 103 90 1503 143 37 1314 <3.2

97 100 27 101 43 41 35 43 97 41 49 8 493 475 5 317 <3.2

148 165 167 163 102 101 102 102 148 104 101 199 645 340 2287 3934 <3.2

214 253 269 239 107 107 110 111 214 109 101 60 229 297 7 580 <3.2

118 126 127 125 100 98 101 103 118 103 104 16 711 442 23 505 <3.2

113 120 112 118 53 43 41 79 113 92 78 10 653 750 18 2594 <3.2

106 105 105 106 102 100 105 106 106 104 95 11 576 225 <3.2 150 <3.2

O O Ph3 SnO

N

OH

N

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

OSnPh 3 N

OH

N R

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

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

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

O

CH 3

O

CH 3

CH 2 C O Sn O O C H2 C

O

O

O

C

O

O

CH 3

O

O

C

(33)

H 3C

O

O

O C H 2C

Sn O

(34)

H 3C

O

C

H3 C

C

CH 2

O

Sn O

O

(35)

CH 3

O

O Sn

Sn O

[77] [77] [77] [77] [79] [79] [79] [79] [79] [79] [79] [77,79] [79] [79] [79] [79] [79]

period in both the solid-state and in solution than were triphenyltin(IV) complexes containing amino acetate skeletons [80,81]. Among organotin(IV) complexes, organotin(IV) carboxylates show significant antifungal, antibacterial and antitumor activities, which are essentially related to the number and nature of the organic groups attached to the central Sn atom. However, the role of carboxylate ligand cannot be ignored. So, a series of organotin (IV) carboxylates (32–36) (Fig. 9) were synthesized and evaluated for in vitro anticancer assay against prostate cancer cells (PC-3) [82]. The experimental conditions for the in vitro anticancer assays are 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, a behavior 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 that organo-ligand played an important role for the cytotoxic activity of these complexes. The di-n-butyltin carboxylate (32) had the strongest anticancer activity, while the diorganotin derivatives with a too short (methyl or ethyl) or a too long (n-octyl) carbon chain length had low activities [82]. The research efforts on the biological activity of new organotin(IV) complexes with different RCOOH (R = carbazole) as ligands have increased recently because the carbazole and its derivatives have shown pronounced cytotoxicity and anticancer activity [83]. Three new organotin(IV) complexes (37–39) (Figs. 10 and 11),

CH2 C

O

O

O O C H 2C

H3 C

CH 3

CH 2

Sn

(32)

Refs.

O

O C H2 C

(36) H3C

O

Fig. 9. Structures of organotin(IV) carboxylates, [Bu2SnL2] (32), [Et2SnL2] (33), [Me2SnL2] (34), [Me6Sn2L2]n (35), and [Oct2SnL2] (36), where L = O2CCH2C6H4OCH3-4.

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M.K. Amir et al. / Inorganica Chimica Acta xxx (2014) xxx–xxx

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

Coordination mode

(32) (33) (34) (35) (36) (37) (38) (39) (40) (41) (42) (43) (44) (45) (46) (47) (48) (49) (50) (51) (52) (53) (54) (55) (56) (57) (58) Doxorubicin 5-FU Cisplatin

six six six five six five, six six five five six five, six five five five five five five five five five five five six six six five six

IC50 (lg/ml) against cancer cell lines PC-3

HepG2

BEL-7402

A549

Refs. B16-F10

HeLa

HT1080

U87

MCF-7

HEK-293

HCT-15

2.53 5.30 32.92 4.21 >100 1.93 9.82 4.23 0.55 2.95 0.88

0.60 8.25 3.70 0.36 2.48 0.52

0.08 1.91 0.93 25.72 31.74 2.68 29.76 4.89 29.69 0.70 5.72

40.63 400 15.73 326 40.74 38.95 >776 >1086 0.912

19.17 5.9

C O Sn Bu

Bu Sn Bu O O C

O

O

0.87

1.46

3.50

Bu

Sn Bu

50.65 242 317 235 439 49.22 >388 >543

25.13 98.04 25.40 471 20.46 9.14 >388 >2174

8.97

6.72

3.71

O

O Bu O

O O

O C N

Bu N

N

C O

O Sn Bu C

O Sn

Sn

N

(37)

N

Bu C

Sn Bu

2.60

N

C O O

42.95 445 258 124 184 33.06 >388 >543 17.43

N

Bu

O

0.06 0.60 74.0 0.09 28.9 5.32 34.5 39.5

25.02 238 54.36 498 25.21 25.04 >776 >543

5.99

N

5.00 6.39 6.13 10.7 279 33.4 5.12 218.6

O

O O

[82] [82] [82] [82] [82] [83] [83] [83] [90] [90] [90] [92] [92] [92] [92] [92] [92] [97] [97] [104] [104] [104] [104] [104] [104] [104] [104] [82] [83] [90,92,104]

O O

Sn

Bu Sn

C Bu Sn O

O N

C O O

O O

Bu

C N

(38)

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

derived from a carbazole carboxylic acid, were prepared and investigated 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 that these complexes (37–39) were more cytotoxic than is the standard drug 5-flurouracil because the IC50 values for these complexes (37– 39) were much lower than was that for 5-flurouracil (Table 4). The results obtained indicate the order of the antitumor activity as: (37) > (39) > (38) > organotin(IV) precursors [83]. It was proposed that the di-n-butyltin(IV) derivative 37 with a weaker Sn–O bond was more active against the two human tumor cell lines than were complexes 38 and 39, because further ligand replacement with biological ligands was possible. The Sn–O bond length (2.771 Å) in complex (37) was much longer than other Sn–O bonds. Ligand replacement from the Sn–O-core cluster to Sn–DNA complex fol-

lowing the Sn–O cleavage for 37 was expected. The activity of the cytotoxic complexes (37–39) was also attributed to the ability of the ligand to form unobstructed H-bonds and/or p  p stacking that 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 ferrocenyl moiety with heterocyclic structures may increase their biological activities or create new medicinal properties [88,89]. Three organotin(IV) carboxylate derivatives (40–42) (Figs. 12 and 13) containing a novel ligand ‘‘3-trifluoromethyl-5-ferrocenyl -pyrazol-1-yl-acetic acid’’ were prepared as a strategy for obtaining new drug candidates in which the metal and the ligand could act synergistically [90]. Anti-tumor activities of complexes (40–42) were evaluated using human hepatocellular liver carcinoma cells

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M.K. Amir et al. / Inorganica Chimica Acta xxx (2014) xxx–xxx

F N N

Fe

Bu

Sn

Sn O C

N N

O O

O

Sn

Bu Bu Fe

C O

Sn

O

F F

(42)

F

F F F N N

Fe

Bu Bu

C O

O

Bu

F F

F F

O C

Bu Bu

O

N N F

Fe

Fig. 13. Structure of the tetranuclear organotin(IV) complex 3-trifluoromethyl-5-ferrocenyl-pyrazol-1-yl-acetic acid as ligand.

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

(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. The order of the anti-tumor activity of the studied complexes was as 40 > 42 > 41. The complexes (40) and (42) had greater inhibitory effect 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 cell line would make this complex a potent anti-tumor agent. The ligand alone exhibited low inhibition of cellular proliferation against 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 on 1,3-benzenedicarboxylic acid and 1,4-benzenedicarboxylic acid ligands, were synthesized and evaluated for antitumor activity against (HeLa) cervical cells, (HT1080) fibrosarcoma cells and (U87) glioma cells [92]. The (MTT) assay that differentiates dead from living cells was adapted [92,93]. It was observed from IC50 values that the complex (45) was the most efficient antitumor agent for HeLa having greater antitumor activity than cisplatin (Table 4) [94]. Complexes (43), (44) and (46) were the most efficient antitumor agents for U87 having greater antitumor activities

F N N

Fe O Ph

Sn

Ph H 3C

O O

CH 3

Ph Sn

O

F

O O

O

Sn Ph

Ph F F

(40)

Ph

Sn C

Ph O

N N F

Fe

F F

F F

F

Fe

N N Fe O O O C BuO C Bu Sn O Sn N F F C O Sn O O O F N N O Sn OO F C O Sn F F N Bu O C O Sn Bu C O O Fe O N N Bu N N F F Fe F F F Fe F N N

Ph

C

than cisplatin (Table 4) [95]. Cisplatin had no effect on HT1080 cancer cells [96], but the complexes (43–48) had an effect on HT1080 cancer cells and the complexes (43–45) stood out in this case [92]. The selectivity in antitumor activity against different cancer cells can be attributed to different structures and different substituents on the ligand of these complexes. Two organotin(IV) carboxylates (49–50) (Fig. 15) with (E)-3(2nitrophenyl) propionic acid were prepared and examined for antitumor activity against HeLa, HT1080 and U87 cell lines using MTT assay [97]. Selectivity was observed in the complexes (49–50) for antitumor activity against different cell lines. It was observed from IC50 values that the activities of complex (49) against three cancer cell 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 antitumor activity and could be future candidate as anticancer agent after in vivo study. In living organisms orotic acid is very much important in the ‘de nuovo’ biosynthesis of pyrimidine bases of nucleic acids [98]. Some metal orotates are widely used in medicine due to therapeutic properties [99,100]. Platinum orotates, palladium orotates, and zinc orotates have interesting anticancer properties [101–103]. In order 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 against five cancer cell lines of human origin, MCF-7 mammary cancer, HEK-293 kidney cancer, PC-3 prostate cancer, HCT-15 colon cancer and HepG-2 liver cancer. In vitro anti-cancer screening data

Fe

F F

containing

Bu

(41)

Fig. 12. Structures of the tetranuclear and hexanuclear organotin(IV) complexes containing 3-trifluoromethyl-5 ferrocenyl-pyrazol-1-yl-acetic acid as ligand.

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CH 3 H O

H O O

O

Sn

O

Sn

O

O O O

(43)

O O

O O

O

O H

(44)

O H

CH3 Bu

H O

Bu O

Sn

Sn

O O

O

O O

O

O O H

Bu

Bu Bu Bu

Sn O

O O C

Bu O

Bu

Bu

O H

O

O

Bu O C

H Bu O Sn

O O

O

Bu

(47)

Bu

O H

O

O

Bu O

O C

C

O O

O

Bu

Bu

Bu Bu O Sn H 3C BuSn Bu Bu CH3 O O O O Sn Sn C Bu O O O O Bu H O C O C O H Bu O Bu O O Bu O Sn Bu Sn C OBu O O Bu O H3 C (48) Sn Sn CH3 O Bu Bu Bu

Sn BuSn O O Sn

O Bu Bu C Bu Sn OBu O O Sn Sn Bu

Bu

Bu

Sn BuSn O O Sn

H Bu O Bu Bu O Sn C BuSn OBu O O O (46) S Sn n C

O

(45)

Bu O

Bu

O C

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

O2 N

NO 2

Sn O

Bu

Bu

O

O

O 2N n

(49)

O Bu

O Sn Bu C Bu C Bu O Sn O O Sn O2 N Bu O O C Bu O

C

O C

Sn

O

O2 N

(50)

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

showed that these complexes (51–58) had low to moderate cytotoxicity against these five cancer cell lines (Table 4). It was observed that the complex (56) was most active against all the cell lines, followed by the complex (51). These complexes (51–58) were less active in comparison to cisplatin, 5-fluorouracil and methotrexate, except the complex (56) and the complex (53) (Table 4). The complex (56) exhibited comparable activity against HCT-15 in 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 organotin(IV) orotates (51–58) was explained on the basis of structureactivity relationship. It was proposed that the activity of the organotin complexes mainly depends mainly on the hydrolytic stability of Sn–X bond (X = O, N, Cl, F and S), whereas the Sn–C bond is hydrolytically more stable. It was reported that either organotin(IV) compounds as whole or R3Sn+ and R2Sn2+ produced on

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H N

O

O

O

HN R R

HN

O

O

O

Sn R O

O

N H

N H

O

O

O

R

Sn O R O HO O NH O

O

N H

O

OH O

H N

O

NH O

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

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

O O O Bu Sn N NH Bu O O O O NH

HN

NH O

H N

O

O

N H

O Bu O O Sn O HN

O

O NH N Bu O

NH O

(57)

(58)

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

H3 C O

O NH O O Ph Sn

(59)

Ph

H 3C O Ph

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

O NH O O Bu Sn

(60) Bu

Bu

Acknowledgement

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

We thank the TWAS and Higher Education Commission of Pakistan for financial support.

hydrolysis/dissociation might be the final active species responsible for the anti-cancer activity of tri- and diorganotin compounds [23,105]. Since the studied organotin(IV) orotates (51–58) were very stable to air and moisture, and may had relatively strong Sn–X (O/N) bond, this may be correlated to the observed low-tomoderate activity of these organotin(IV) orotates (51–58) [104]. Triorganotin(IV) complexes (59–60) with the carboxylate ligand derived from maleic anhydride and p-aminoacetophenone have also been synthesized (Fig. 17) and screened for antitumor activity by potato disc antitumor assay [106]. The IC50 values showed that these complexes (59–60) were more active than the free ligand. The complex (60) exhibited best tumor inhibitory activity with the lowest IC50 value of 7.37 lgml1 [107].

References

3. Conclusions In this review on anticancer activity of organotin(IV) carboxylates, it is noted that most of the organotin carboxylates such as the complexes (1, 2, 5, 9–14, 17–19, 21–31, 37–46, 49) have greater antitumor activity than do the standard drugs against different cell lines, indicating that these complexes have great potential for future use as medicine. Different organotin(IV) carboxylates have selectivity for different cell lines. This selectivity in antitumor activity against different cancer cells can be attributed to the different structures and different substituents on the ligand of these complexes. Some of the organotin(IV) carboxylates are active even against cancer cells where cisplatin is inactive. These studies have shown that the cytotoxicity of organotin(IV) carboxylates depends upon the chain length of the alkyl groups. The butyltin(IV) carboxylates have greater anticancer activity, while the organotin(IV) carboxylates with a too short (methyl or ethyl) or a too long (n-octyl) carbon chain length have low activity. The polynuclear character of organotin(IV) carboxylates results in poor anticancer activity due to high coordination number and steric hindrance around tin, which limit the access of tin to the target. Some structural effects may increase the antitumor activity of organotin(IV) carboxylates.

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