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Journal of Inorganic Biochemistry 79 (2000) 139–145

Synthesis, characterization and in vitro antitumor activity of

di- and triorganotin derivatives of polyoxa- and biologically relevant
carboxylic acids
Marcel Gielen a,*, Monique Biesemans a, Dick de Vos b, Rudolph Willem a
a
Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium
b
Medical Department, Pharmachemie B.V., NL-2003 RN Haarlem, Netherlands

Received 16 April 1999; received in revised form 20 August 1999; accepted 23 August 1999

Abstract

An overview of the development of anti-tumor organotin derivatives, sometimes as active in vitro as doxorubicin, is presented and discussed.
Solubility in water is an important issue, dominating the in vivo testing of compounds with promising in vitro properties. Several water-
soluble organotin compounds gave the best in vitro activities. Novel, useful organotin anti-tumor compounds should be designed toward
improved water solubility. q2000 Elsevier Science Inc. All rights reserved.

Keywords: Antitumor activity; Organotin derivatives; Carboxylic acids

1. Introduction
Platinum compounds such as cisplatin [1,2] and carbopla-
tin [3] are used in cancer chemotherapy to treat testicular,
ovarian and bladder cancer, often in combination with other
drugs. Also, small cell lung cancer as well as non-small cell
lung cancer has been found responsive to platinum chemo-
therapy. Likewise, other platinum compounds are under
investigation for anti-cancer treatment, such as ormaplatin
and oxaliplatin [4–16]. In addition to platinum compounds,
derivatives of other transition metals are being investigated
for their anti-tumor properties [17].
The disease-oriented primary screen of the NCI consists
of a panel of 60 different human tumor cell lines [18,19]. In
the present work, the NCI approach was followed by using
an in vitro primary screen with seven human tumor cell lines,
of which five belong to the NCI panel.
The next step consists of testing promising new derivatives
in human tumor xenografts of nude mice [20,21]. An in vivo
murine tumor model was selected, initially the mouse L1210
leukemia [22], later on, the mouse Colon 26 [23,24], being
expected to possess a higher predictive value than the L1210.
* Corresponding author. Fax: q32-2-629-3281; e-mail: mgielen@vub.
ac.be
In the present study the results of the in vitro and in vivo
testing of organotin compounds are summarized and dis-
cussed. Organotin compounds may yield new leads for the
development of anti-tumor drugs, which display another
spectrum of anti-tumor activity, may show non-cross-resis-
tance with platinum drugs and may possess less or different
toxicity as compared to platinum compounds. In vitro tests
were carried out in the Laboratory for Tumor Biology and
Pharmacology of the Academic Hospital Rotterdam, The
Netherlands. In vivo tests were carried out by the Department
of Medical Oncology of the Free University of Amsterdam,
The Netherlands, under the supervision of Dr G.J. Peters.
The following human tumor cell lines have been used in
the in vitro tests: MCF7 breast cancer, EVSA-T breast cancer,
WIDR colon cancer, IGROV ovarian cancer, M19 MEL mel-
anoma, A498 renal cancer and H226 non-small cell lung
cancer. MCF7 is estrogen receptor (ER)q/progesterone
receptor (PgR)q and EVSA-T is ERy/PgRy. The cell
lines WIDR, M19 MEL, A498, IGROV and H226 belong to
the anti-cancer screening panel of the National Cancer Insti-
tute, USA [18]. The experimental protocol has been given
elsewhere [25,26].
In Table 1, the IC50 values (in mM) of some well-known
oncology drugs are presented [27]. IC50 values may show
some variation due to the biological nature of the test. Slight

0162-0134/00/$ - see front matter q2000 Elsevier Science Inc. All rights reserved.
PII S 0 1 6 2 - 0 1 3 4 ( 9 9 ) 0 0 1 6 1 - 0

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140 M. Gielen et al. / Journal of Inorganic Biochemistry 79 (2000) 139–145

Table 1 Table 2
IC50 values (in mM) of some well-known oncology drugs IC50 values (in mM) of di-n-butyltin dihydroxybenzoates, 1–5, and of per-
fluorophenyl-containing di-n-butyltin carboxylates 6–9
DOX MTX CPT 5-FU
MCF7 EVSA-T WIDR IGROV M19 MEL A498
MCF7 1290 40 2300 5700
EVSA-T 820 11 1400 3700 1 30 100 220 158 108 240
WIDR 390 6.6 3200 1700 2 280 108 240 200 121 240
IGROV 510 15 560 2300 3 13 80 167 95 93 93
M19 MEL 760 51 1900 3400 4 240 56 930 220 350 520
A498 250 81 7500 1100 5 7 89 210 111 121 186
H226 590 5000 11000 2600 6 24 22 118 29 48 42
7 30 23 148 32 62 56
8 15 28 210 29 53 73
changes in the system during the years of testing may also 9 17 19 122 21 35 71
cause changes in the IC50 values.
this poor solubility is a problem when in vivo screenings are
performed.
2. Results and discussion The substitution of hydrogen for fluorine in the carboxylate
moiety slightly increases the water solubility. Therefore,
Many organotin compounds have been synthesized in the extensive research towards the effect of fluorine substitution
past years. The condensation reaction of carboxylic acids with has been carried out. A range of fluorine-substituted tin ben-
di-n-butyltin oxide, triphenyltin hydroxide and tri-n-butyltin zoates has been synthesized [28,39–44] and their in vitro
acetate yields the corresponding organotin carboxylates anti-tumor activity assessed. In order to explore new struc-
[28]. Depending upon the reaction conditions and the tural elements and to improve the solubility of the com-
organotin precursor used, one of the organotin structures A, pounds, novel derivatives containing the dihydroxybenzoate
B or C described in Fig. 1 can be obtained. [44] and the perfluorobenzoate [45] moieties were prepared.
From all the compounds prepared and tested, only a selec- These compounds, for which the latter displayed improved
tion will be presented. The carboxylic acids involved here are solubilities, while the former did not, were tested in vitro and
steroid carboxylic acids [29], terebic acid [30], 2,3:4,6-di- found to display promising activity, especially the latter ones.
isopropylidene-2-keto-L-gulonic acid [31], gibberellic acid The IC50 values (in mM) of selected compounds are sum-
[32] and 3S,4S-3-[(R)-1-(tertiobutyldimethylsilyloxy)- marized in Table 2.
ethyl]-4-[(R)-1-carboxyethyl]-2-azetidinone [33] as well
as 3,6-dioxaheptanoic acid [34], 3,6,9-trioxadecanoic acid 1 [2,4-(OH)2C6H3COO]2Sn(n-Bu)2
[34], 4-carboxybenzo-18-crown-6 [35] and 4-carboxy- 2 [2,6-(OH)2C6H3COO]2Sn(n-Bu)2
benzo-15-crown-5 [35]. All the compounds synthesized 3 [2,3-(OH)2C6H3COO]2Sn(n-Bu)2
were characterized by elemental analysis, 1H, 13C and 117Sn 4 [3,5-(OH)2C6H3COO]2Sn(n-Bu)2
NMR, electrospray mass spectrometry and 119mSn Mossbauer
¨ 5 [2,5-(OH)2C6H3COO]2Sn(n-Bu)2
6 {[(C6F5COO)(n-Bu)2Sn]2O}2
spectroscopy. 7 {[(C6F5CH2COO)(n-Bu)2Sn]2O}2
The first series of organotin compounds that were synthe- 8 (C6F5CH2COO)2Sn(n-Bu)2
sized were only marginally soluble in solvents such as etha- 9 {[(C6F5CH_CHCOO)(n-Bu)2Sn]2O}2
nol. Ethanol is used to dissolve the organotin compounds for
the preparation of the solution needed for the screenings, to The introduction of a polar group enhances the solubility
which a 100-fold excess of water is then added. The com- and the in vitro activity. Four of the compounds, 1, 5, 7 and
pounds were however sometimes soluble enough because the 8, were tested in vivo in the murine Co 26 model [46]. Only
concentrations needed were quite low [36–38]. However, compound 7 showed modest activity. Toxicity was mainly
gastrointestinal.
The organotin steroidcarboxylates 10–16, depicted in Fig.
2, have also been synthesized and tested in vitro [29]. As
seen in Table 3, showing their IC50 values, the compounds
13–16 display an appreciable in vitro anti-tumor activity, the
compounds 10–12 being less active.
Compounds 10 and 12 were also studied in the murine Co
26 tumor model but were so toxic to the tumor-bearing mice
that a second injection could not be given. After administra-
tion weekly at a dose of 15 mg/kg, compound 10 gave a T/
Fig. 1. Structures of tri- and diorganotin carboxylates. C (relative tumor size of the treated (T) mice divided by the

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 M. Gielen et al. / Journal of Inorganic Biochemistry 79 (2000) 139–145 141

Fig. 4. Structures of the organotin gibberellates 20–22.

Fig. 2. Structures of the organotin steroidcarboxylates 10–16.

Fig. 5. Structure of the carboxylate moiety present in the compounds

23–26.

19 could be given. Two injections of compound 18 resulted

Fig. 3. Structures of the organotin terebates 17–19.
relative tumor size of the control (C) mice expressed in %)
of 42% and an ILS (increase of median life span) of 8%,
compound 12 gave a T/C of 77% and an ILS of 30%. Com-
pound 10 thus showed a marginal activity in the Colon 26 in
mice, since the limit of activity for Co 26 is precisely 42%.
The tin steroidcarboxylates exhibit anti-tumor activity, but
solubility still remains a drawback, affecting their in vivo
properties. In order to try to make organotin compounds more
soluble, another structure, which contained a five-membered
ring moiety as well as polar substituents, was used. This led
to the synthesis of organotin terebates, 17, 18 and 19 [30],
the structures of which are given in Fig. 3. The in vitro test
results of these compounds are shown in Table 4.
Again the novel organotin compounds were found to have
high in vitro anti-tumor activity. Compounds 17–19 were
tested also in vivo in the mouse Colon 26 [47]. There was
again considerable toxicity. Only one injection of compound
Table 3
IC50 values (in mM) of the organotin steroidcarboxylates 10–16
in 3/5 toxic deaths in one week. Some in vivo activity was
detected for compound 18.
More organotin carboxylates with polar substituents were
designed, such as the gibberellates 20–22, shown in Fig. 4,
the IC50 values (in mM) of which are depicted in Table 5.
The triphenyltin derivative 21 is extremely active, the di-n-
butyltin and tri-n-butyltin compounds 20 and 22 somewhat
less but still more active than doxorubicin.
Another series of compounds of this type belonging to
category A, namely triphenyl- (23) and tri-n-butyltin (24)
carboxylates derived from the complex carboxylic acid, are
shown in Fig. 5. Analogous di-n-butyltin derivatives belong-
ing to categories B and C, respectively compounds 25 and
26, have also been synthesized and tested in vitro. Their IC50
values (in mM) are shown in Table 6. Again the triphenyltin
derivative appears most active, the other compounds being
still more active than doxorubicin.
A further series of compounds, 27–31, having again polar
substituents in the carboxylate moiety, are depicted in Fig. 6.
Compounds 27, 28 and 30 are reasonably active. The dime-

MCF7 EVSA-T WIDr IGROV M19 MEL A498 H226

10 163 61 400 160 122 220 430

11 390 160 600 144 460 930 1180
12 73 65 380 132 158 192 390
13 24 4.5 29 27 77 98 92
14 21 -4 20 -4 67 182 100
15 15 -4 30 22 30 15 80
16 24 -4 20 23 43 71 71

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142 M. Gielen et al. / Journal of Inorganic Biochemistry 79 (2000) 139–145

Table 4
IC50 values (in mM) of the organotin terebates 17–19

MCF7 EVSA-T WIDR IGROV M19 MEL A498 H226

17 49 46 240 33 112 112 190

18 6.7 6.7 25 8.9 25 34 18
19 34 5.9 34 37 83 83 77

Table 5
IC50 values (in mM) of the organotin gibberellates 20–22

MCF7 EVSA-T WIDr IGROV M19 MEL A498

20 280 260 430 270 270 350

21 4.3 -4 -4 10 7.2 29
22 161 83 117 183 175 270

Table 6
IC50 values (in mM) of the organotin carboxylates 23–26

MCF7 EVSA-T WIDr IGROV M19 MEL A498 H226

23 22 14 22 29 37 55 48
24 58 44 59 210 144 230 153
25 134 87 250 134 92 145 138
26 180 151 790 280 153 350 440

Fig. 6. Structures the organotin compounds 27–31.

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 M. Gielen et al. / Journal of Inorganic Biochemistry 79 (2000) 139–145 143

Table 7
IC50 values (in mM) of the organotin compounds 27–31

MCF7 EVSA-T WIDr IGROV M19 MEL A498 H226

27 28 16 161 58 30 58 190
28 170 154 820 270 230 370 280
29 1820 660 2900 2400 260 1200 4800
30 113 65 231 104 153 113 410
31 3900 2600 10000 2900 3200 4500 2200

Table 8
IC50 values (in mM) of the organotin polyoxaalkanecarboxylates 32–39

MCF7 EVSA-T WIDr IGROV M19 MEL A498 H226

32 27 25 70 77 64 66 68
33 74 93 190 190 200 350 141
34 120 124 760 260 230 270 320
35 -1 -1 3.9 -1 -1 -1 3.3
36 17 17 36 63 46 40 47
37 76 53 84 187 160 200 118
38 147 112 840 300 280 250 480
39 -1 -1 -1.8 -1 -1 -1 -1

Table 9
IC50 values (in mM) of the organotin benzocrowncarboxylates 40–46

MCF7 EVSA-T WIDr IGROV M19 MEL A 498 H 226

40 21 17 18 43 23 61 52
41 53 9 17 45 106 150 150
42 160 136 830 280 230 300 300
43 15 19 100 34 29 53 31
44 2.9 -2 -2 -2 -2 -2 -2
45 3.3 -2 -2 -2 -2 -2 -2
46 320 280 390 380 330 57 580

Fig. 7. Structures the organotin polyoxaalkanecarboxylates 32–39.

thyltin compound is inactive, as expected. Their IC50 values

are given in Table 7.
The last most recent IC50 values are related to the devel-
opment of water-soluble organotin carboxylates. The first
series concerns derivatives of polyoxaalkanecarboxylates, Fig. 8. Structures the organotin benzocrowncarboxylates 40–46.

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144 M. Gielen et al. / Journal of Inorganic Biochemistry 79 (2000) 139–145
compounds 32–39 (Fig. 7 and Table 8) [34], and the second
one, of benzocrowncarboxylates, compounds 40–46 (Fig. 8
and Table 9) [35]. Tables 8 and 9 show that several of these
water-soluble organotin compounds are more active than
doxorubicin.
3. Conclusions
Many organotin compounds have been synthesized in
recent years. Test results made clear that considerable in vitro
activity has been detected for several types of organotin com-
pounds, as has been demonstrated in the selection presented
in this paper. Usually, the in vitro activity was higher than
that of cisplatin and often organotin compounds possessed
activities comparable with or better than that of doxorubicin.
The development process led to compounds with definite
pharmacological activity: anti-tumor activity in vivo, but also
toxicity. Incidentally, neurotoxicity, known for cisplatin and
oxaliplatin, was detected. The lack of water solubility pre-
vented the use of aqueous solutions in the in vivo tests and
necessitated the use of arachidis oil for the preparation of a
suspension. Because of their hydrosolubility, it will be pos-
sible to test aqueous solutions of the last two series that were
indeed also quite active in vitro.
Further chemical and pharmacological studies will be nec-
essary to unravel a structure–activity relationship from which
novel organotin anti-tumor drugs with possible clinical appli-
cations can be developed.
Acknowledgements
We are grateful to Mr H.J. Kolker, Dr J. Verweij, Professor
Dr G. Stoter, Dr J.H.M. Schellens, Laboratory of Experimen-
tal Chemotherapy and Pharmacology, Department of Medical
Oncology, Rotterdam Cancer Institute, NL-3008 AE, Rotter-
dam, The Netherlands, for performing the in vitro screenings.
All students, especially Mrs M. Kemmer and Mr H. Dalil, are
sincerely acknowledged for their sound synthesis and char-
acterization work. This research was supported by the Belgian
‘Nationaal Fonds voor Wetenschappelijk Onderzoek’ (Grant
No. G.0054.96, M.G.), and the Fund for Scientific Research-
Flanders (Grant No. G.0192.98, R.W., M.B.).
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