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Sen Sarma, M.: Cytotoxic activity of organotin(IV) complexes …….

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Review Article

Cytotoxic activity of organotin(IV) complexes - a short review

Moumita Sen Sarma

Assistant Professor, Department of Chemistry, Fakir Chand College, Diamond Harbour –

743331, West Bengal, India.

Correspondence should be addressed to Moumita Sen Sarma; [email protected]

Abstract

Over the recent decades, investigations on organotin(IV) complexes have received

considerable attention due to the structural diversity they exhibit and their diversified non-

biological and biological applications. Organotins are also finding important place as effective

antitumour agents. This review briefly discusses the cytotoxic activity of various organotin

compounds against different cancer cell lines.

Key Words: Organotin (IV) complexes, Anti-tumour activity, Cytotoxic activity

Introduction

The relationship between metal ions and cancer are both intriguing and controversial.

Since its discovery by Furst in 19631, metal chelates continue to play an important role in the

cure and cause of malignancy. In addition to this, the discovery of the antitumour activities of

titanocene dichloride2-4 and certain diorganotin derivatives5,6 stimulated much interest in the

research of organometallic compounds as antitumour agents.

The introduction of cisplatin as the first inorganic compound approved for clinical use

in 1978 produced a great impetus in cancer treatment. Cisplatin is used to treat various types

of cancers like small cell lung cancer, ovarian cancer, lymphomas, bladder cancer, cervical

cancer and germ cell tumours7. Unfortunately, the use of cisplatin was also identified to be

associated with number of side effects such as nephrotoxicity, neurotoxicity, ototoxicity,

myelotoxicity, hemolytic anemia and several disadvantages such as the emergence of

cisplatin resistance. Hence, cisplatin combination chemotherapy (which now includes

carboplatin and oxalipatin, which are also platinum derivative drugs) was consequently being

introduced8. In addition to the organometallic complexes of Pt, other organometallic

compounds derived from Sn, Au, Ti, Cu, Pd and Ru have also emerged as potent antitumour

Prajnan O Sadhona ……., Vol. 2, 2015

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agents. Recent studies on the antitumour activities of organotins have shown that low doses

of organotins can induce cell death and have better or similar potential when compared with

other drugs which are in clinical use9.

Antitumour activity of organotin(IV) complexes

Although the first organotin(IV) compound was tested for its antitumour activity10 in

1929, no systematic study was undertaken afterwards and as a result only 1509 organotin

compounds have been tested in various tumour systems by the end of 198111. Organotin

compounds with coordination number greater than four are significant for their large spectrum

of biological activity12,13 including antifungal, antibacterial, antimicrobial, antinematicidal,

antiinsecticidal, antiherbicidal and anti-inflammatory activities and also interesting structures.

Along with this their potent antitumour activity has led many researchers to investigate them

as effective antitumour agents and a large body of literature is now available14-29.

Brown firstly reported30 the restraint effect of triphenyltin acetate for the growth of

anticancer cells. It has been demonstrated that certain triphenyltin benzoates exhibit

exceptionally high in vitro activity31 against MCF-7 and WiDr cell lines. Some novel

triphenyltin carboxylates32 also revealed interesting low ID values compared to the clinically

established antitumour drugs.

Di-n-butyltin, di-t-butyltin and diphenyltin 2, 6-pyridine carboxylates33-35 were found

to be more active than cisplatin against MCF-7, a mammary tumour, and WiDr, a colon

carcinoma. The anhydrous bis(dicylohexylammonium)bis(2,6-pyridine dicarboxy- lato)

dibutyl stannate is reported to display higher in vitro antitumour activity than those of

carboplatin and cisplatin36.

Bis{3-methoxysalicylato[di(n-butyl)]tin(IV)}oxide, obtained by the condensation of

Bu2SnO and 3-methoxysalicylic acid , exhibited higher antitumour activities in vitro against

two tumour cell lines , MCF-7 and WiDr than those of the 5-Me and 4-Meo analogues37.

Gielen et al. synthesized and screened38 a series of organotin compounds against MCF-

7 and WiDr and found that the complexes exhibited very promising antitumour activities. Di-

n-butyltin bis (2, 5-dihydroxybenzoate) was found to be as active as cisplatin in vitro against

murine Colon 26 carcinoma.

Saxena and Tandon39 screened a series of di-n-butyltin complexes of Schiff bases

derived from S-substituted dithiocarbazates and p-fluoroaniline for their activity against P-388


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Lymphoyte Leukaemia and suggested that the presence of highly electronegative groups can

greatly enhance the activity.

The dibutyltin complexes of the general formula Bu2SnL (where L= dianion of

tridentate Schiff bases derived from the condensation of 2-hydroxy-1-naphthaldehyde or acetyl

acetone with Gly, L- -Ala, DL- Val, DL- 4-aminobutyric acid, L-Met, L-Leu and PhGly) have

exhibited higher antitumour activities than those observed for cisplatin and carboplatin40.

Barbieri et al.41 reported the antitumour activity of diorganotin(IV) complexes with

adenine (R2SnAd2) and glcylglycine(R2SnGly-Gly) against the P-388 lymphocyte leukaemia

in mice. The (R2SnGly-Gly) were active against leukaemia in very small doses. They suggested

the antileukaemic activity of R2SnGly-Gly depends upon the peculiar structure and bonding of

the solids.

Ruisi et al. have tried to interpret the action of R2Sn(IV) glycylglycinates (R= Me, n-

Bu, n-Oct and Ph) on a molecular basis. Of the various tumours studied the Bu2Sn(Gly-Gly)

was only active against P-388 leukaemia. On the basis of solution studies using various

spectroscopic techniques, it is likely that solvated species in aqueous solution or a mixture of

water and organic solvent and unsolvated species (mainly organic solvent) are present in

equilibrium and contribute to passage of alkyltin complexes across the cell membrane which

in turn produces the biological activity42. A series of organotin dipeptide compounds and a

number of diorganotin halides and pseudohalides [SnR2X2L2] (L= amino ligand e.g., py, bpy,

phen, en) have displayed modest antitumour activity43.

Many di-n-butyl, tri-n-butyl and triphenyltin complexes with hydroxyaryl- carboxylic,

ketocarboxylic, fluoroarylcarboxylic acids and many other oxygen and nitrogen containing

derivatives of carboxylic acids display high antitumour activities44-48.

Cardarelli et al. investigated the antitumour activity of a number of organotin

compounds, namely, tri-butyltin fluoride, dibutyltin dichloride.2-2’-bipyridyl, 1,10-

phenanthroline.dibutyltin complex and dibutyltin histidine by administering these to cancerous

mice in drinking water and found that the tumour growth rates were significantly reduced49.

Studies on the tin content in various body organs led Cardarelli et al.50 to hypothesize that

soluble organotin compounds of various types introduced into the body are concentrated in the

thymus gland. The tin in the thymus is then processed into one or more biochemical that acts

as anti-carcinogens. The isolation and evaluation of thymic extracts reasonably pointed to the

unknown tin-bearing anti-oncogenic biochemicals of steroid nature. On the basis of their


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hypothesis, Cardarelli et al.51 patented several organotin compounds of steroids which show

marked antitumour activity.

The synthesis and in vitro screening of even more water soluble organotin compounds,

containing a polyoxaalkyl moiety linked to tin either by a carbon-tin or by a carbon-oxygen

bond is one of the latest development by Gielen and his coworkers52,53.

The compounds Ph2Sn(OH)Cl, (Et2SnO)n and ClMe2SnOSnMe2Cl as well as their

octahedral adducts R2SnX2L2 (where R is alkyl or aryl, X is halide or thiocyanate and L2 are

nitrogen atoms of the bidentate ligands 1,10-phenanthroline, 2-2’-bipyridyl and 2-

aminomethylpyridine) have been determined to be active against P-388 Lymphocytic

Leukaemia in mice54. The mechanism of antitumour action of these drugs proposed was the

preferred transportation of the complex species into the tumour cells, which would be attacked

by hydrolyzed R2Sn(IV)2+ moieties.

Casas et al. reported that [SnMe2(PyTSC)(OAc)].HOAc, [SnMe2(DAPTSC)],

[SnPh2(DAPTSC)].2DMF where H2DAPTSC= 2,6-diacetylpyridinebis(thiosemicarbazone)

all suppress proliferation of FLC . DMSO-induced differentiation of FLC was slightly

suppressed by [SnMe2(DAPTSC)] and was unaffected by [SnPh2(DAPTSC)].2DMF and

[SnMe2(PyTSC)(OAc)].HOAc55.

S. G. Teoh and coworkers reported that bis(acetonethiosemicarbazone-S) dichloro

diphenyltin(IV), SnPh2Cl2(atsc)2 exhibited significant cytotoxicity against human colon

adenocarcinoma, breast adenocarcinoma, hepatocellular carcinoma and acute lymphoblastic

leukaemia56.

In aqueous solution, most of the organotin complexes undergo dissociation, aquation

and hydrolysis reactions. For diorganotin complexes, mono-, di- and poly-nuclear

dialkyltin(IV) species co-exist in the aqueous solution, depending on pH. Moreover dialkyl

dihydroxo tin(IV) species prefer to be five- or six- coordinated by binding weakly to one or

two water molecules57. R2Sn bond seems rather stable in aqueous solution, but the triorganotins

will release one alkyl group to give active R2Sn species, the half-life of this process has been

shown to be between 3 and 6 days58. The R2Sn(IV)2+ has been suggested as the active species

for the organotin anticancer agents59.

Atassi assumed that water-soluble organotin(IV) compounds are probably more active

than complexes soluble only in organic solvents. More recent results on the antitumour activity

of the organotin complexes on the tumour cell lines seem to point to a necessary balance

between solubility and lipophilicity in order to optimize their efficacy48,60,61. Attempts to


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improve the bioavailability of the organotin(IV) cations by the formation of water soluble

complexes62 or by their inclusion into -cyclodextrin63 have also been reported.

Organotin carboxylated derivatives have shown high cytotoxic activity against various

cell lines of human origin. Three new tri-n-butyltin derivatives from 4-oxo-4-

(arylamino)butanoic acids were tested for their in vitro anti-proliferative effect on HeLa, CaSki

and ViBo cell lines. All of the compounds showed potency against all three strains and null or

low cytotoxic activity (necrotic) as well. The most potent of the derivatives as an anti-

proliferative agent against the three cell lines was tributylstannyl 4-oxo-4-[(3-trifluoromethyl-

4-nitrophen-1-yl)amino]butanoate, exhibiting an IC50 value of 0.43 μM against the HeLa cell

line64.

The biological activity of organotin(IV) complexes with pyridoxal thiosemicarbazone

(PLTSC) [SnR2(PLTSC-2H)] (R=Me, Et, Bu, Ph) were also evaluated65. With the exception

of the Me complex, the other three suppressed Friend erythroleukaemia cells (FLC)

proliferation with the lowest thresholds for the latter two compounds.

Nine diorganotin(IV) compounds of Schiff bases derived from salicylaldehyde /

substituted salicylaldehyde and thiosemicarbazide were synthesized. Their cytotoxicity was

also investigated against several human cancer cell lines66. The results obtained indicated that

amongst the different organotins selected for the study, Ph2SnL1was found to possess the

highest potency against most of the cell lines studied followed by n-Bu2SnL1 and Ph2SnL2

respectively. Me2SnL2 appeared to be the least potent.

The results further suggested that all the compounds selected for the study were not

equally effective against the various cancer cell lines. This difference in the degree of

selectivity could, presumably, be either due to differential binding potential of the compounds

or metabolic activities of the cell lines which helps in overcoming the cytotoxic effects of the

organotins. The formulae of the ligands and the abbreviations of the complexes used for this

study are presented in Scheme 1.

L1: X = H; L2: X = Br

1: Me2SnL1; 2: n-Bu2SnL1; 3: Ph2SnL1; 4: Me2SnL2.H2O; 6: Ph2SnL2

Scheme 1: The formulae of the ligands and the abbreviations of the complexes66


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Figure 1: Crystal structure of [Ph2SnL1] (3)66

Five organotin complexes of terpyridine derivatives were synthesized and

characterized. The mononuclear Sn(IV) complexes were six-coordinated adopting a distorted

octahedral geometry. A brief outline of the fluorescence spectra and the in vitro cytotoxicity

of Sn(IV) complexes were reported67.

Figure 2: Inhibitory effect of dibutyltin complex of salicylaldehyde thiosemicarbazone (n-

Bu2SnL1) on different Human cancer cell lines. Adriamycin (ADR) has been used

as positive control66

A new arenetelluronic triorganotin ester, namely (Me3Sn)4[o-Me-PhTe(μ-O)(OH)O2)]2

has been prepared by the reaction of o-tolyltelluronic acid and Me3SnCl in the presence of

potassium hydroxide. Cytotoxic assessments showed that the complex can induce apoptotic

cell death via accumulation of reactive oxygen species, ROS, collapse of the matrix

0

20

40

60

80

100

120

Colo205 Hop62 MCF7 PC3 SiHa ZR-75-1 A-2780

Human cancer cell lines

% I

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ibit

ion

10 ug/ml20 ug/ml40 ug/ml80 ug/ml


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metalloproteinase, MMP and activating caspase-3, a caspase protein (cysteine-aspartic acid

protease). The results indicated that ROS is crucial to the cytotoxicity induced by the

complex68.

Figure 3: Crystal structure of (Me3Sn)4[o-Me-PhTe(μ-O)(OH)O2)]268

Very recently a review by Hadjikakou et al focusses on the antiproliferative and anti-

tumour activity of organotin compounds69.

Three main factors which have been found to play an important role in determining the

structure-activity relationship for organotin(IV) derivatives (L)xRnSnX4-n are:

the nature of the organic group R

the nature of halide or pseudohalide X

the nature of donor ligand

Examination of the structures of Sn(IV) compounds containing a N-donor atom and

tested for antitumour activity revealed that in the active tin complexes the average Sn-N bond

lengths were greater than 239 pm, whereas inactive complexes had Sn-N bond lengths < 239

pm, which implies that predissociation of the ligand may be an important step in the mode of

action of these complexes , while the coordinated ligand may favour transport of the active

species to the site of action in the cells, where they are released by hydrolysis70.

Also, a comparison of the structures of the active and inactive compounds suggest71

that in all the active compounds there is

The availability of coordination positions at Sn

The occurrence of relatively stable ligand-Sn bonds, Sn-N and Sn-S

Low hydrophilic decomposition of these bonds


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With regard to the data published on all the Sn(IV) derivatives , it can be concluded

that R2Sn(IV)2+ compounds generally exhibit higher antitumour activity than those of the

corresponding mono-, tri- and tetra- organotin(IV) or the inorganic Sn(IV) derivatives, and

within the diorganotin series , the highest activity is exerted by the Et2Sn(IV)2+ and Ph2Sn(IV)2+

complexes. Also, it has been established that the R2Sn(IV)2+ compounds which exhibit

maximum antitumour activity combined with low mammalian toxicity are adducts of the type

R2SnX2L2 (X=halogen, pseudohalogen, L= O- or N- donor ligand)70.

Conclusion

From the foregoing description of the antitumour properties of organotin(IV)

complexes it is clear that such complexes are likely to find applications in medicine. Organotins

offer the potential of reduced cytotoxicity, non-cross resistance and a different spectrum of

activity compared to conventional chemotherapeutic agents such as platinum-containing

compounds72-74. The exact mechanism of action of organotins on controlling tumour growth is

not well known75. It has been reported that organotins induce tumour cell death in a dose

dependent manner75-78. At higher concentrations, these compounds induce degenerative

changes indicative of necrosis accompanied by random DNA breakdown. Electron microscopic

studies revealed that organotin-induced cytotoxicity to be associated with cell shrinkage,

chromatin condensation, fragmentation of DNA, and development of apoptotic bodies79. It has

been suggested that organotins, like other DNA binding drugs, induce cellular stress which

activates the tumour suppressor p53 leading to apoptotic death79. The involvement of zinc and

calcium dependent endonucleases has also been suggested in cytotoxicity induced by

organotins80.

DNA is believed to be the main cellular target for most of the metal anticancer agents.

The anticancer nature is the coordination of metal ions with DNA molecules, causing DNA

damage in cancer cells, blocking the division of the cancer cells and resulting in cell death. The

aqueous interactions of solvated di- and triorganotin (IV) species R2Sn(IV) and R3Sn(IV)

(R=Me, Et, n-Bu, n-Oct, Ph in ethanol solution) with native DNA(calf thymus) have been

investigated by 119Sn Mössbauer spectroscopy at pH between 5 and 7.481-84. The addition of

ethanolic organotins [R2SnCl2(EtOH)2 or R3SnCl(EtOH)] to DNA yielded solid products, the

119Sn Mössbauer spectra suggested that the tin was coordinated by the phosphodiester groups

of the nucleotides. While the water soluble hydrolyzed dimethyltin(IV) species did not show

any interaction with native DNA81,84.


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Yang et.al.85 studied the binding modes of (CH3)2SnCl2, (C2H5)2SnCl2,

(C2H5)2SnCl2(phen) with DNA and nucleotides in aqueous solution by using modern

techniques. The results show that all the above compounds exhibit high affinity to the

phosphate group of the nucleotides. The interactions of (CH3)2SnCl2 and (C2H5)2SnCl2 with

calf thymus DNA suggested that organotins(aqueous) binded to DNA via only the phosphate

group. In addition, the relationship between DNA binding property of metal anticancer

complex and their anticancer activity was discussed in the review and a hypothesis named

‘Two-Pole Complementary Principle’ was also put forward and some criterias were suggested

as well.

Recently, a review by Tabassum et al focusses on chemical and biotechnological

developments in organotin cancer chemotherapy [86]. This review provides a substantial

knowledge on the action mode of organotins in cancer chemotherapy. The coordinating mode

of organotin compounds towards DNA and cancer cells is discussed. Most of the organotins

tested are DNA-targeted and mitotic, the action mode occurring via a gene-mediated pathway.

These potential anti-cancer drugs are actually being studied widely, and whilst they are

efficacious and perhaps curative against a select number of neoplasias, suffer from a variety of

deficiencies, notably severe systemic toxicity and a tendency to elicit drug resistance.

Acknowledgement

The author is grateful to her research guide Prof. (Dr.) Abhijit Roy, Retired Professor,

Department of Chemistry, North Bengal University, for introducing and teaching her the facets

of organotin chemistry during her doctoral works. She is also obliged to the authority of Fakir

Chand College for providing necessary infrastructure and to all her colleagues for their constant

support and encouragement.

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