Synthesis, spectroscopy and in vitro cytotoxicity of new hydroxyanthraquinonato triorganotin compounds

Article abstract of DOI:10.1080/15533170601172450

We will present herein data on the synthesis, structural investigation and in vitro antitumor activity of new triorganotin compounds of the general type (R3Sn)2Q, where R=Bu, Ph, Bz, Q1=1,4-dihydroxy-9,10-anthracenedione (quinizarin), Q2=1,5-dihydroxy-9,10-anthracenedione (anthrarufin), Q3=2,3-dihydro-9,10-dihydroxy-1,4-anthracenedione (leucoquinizarin) and R3SnQ4 where Q4=1,2-dihydroxy-9,10-anthracenedione (alizarin). The compounds were synthesized by refluxing the organotin hydroxide with the parent quinone and were characterized by IR, 1H- NMR and thermal measurements. The spectroscopic analysis of the new triorganotins, provides evidence on the formation of a monodentate Sn-O bond for quinizarin, anthrarufin and leucoquinizarin, which are coordinated to Sn(IV) central atom via the phenolic oxygen donor atoms, with the R-substituents of the organotin moiety completing the tetrahedral coordination environment. On the contrary, organotin alizarinates form a six-membered chelate ring, which stabilizes the Sn central atom in a five-coordinated environment exhibiting distorted trigonal bipyramidal geometry. The ligand is coordinated to Sn (IV) via the quinoidal oxygen and its neighbouring phenolic one. The new compounds were tested for their cytotoxicity against human tumor and normal cell lines and the results are reported. Copyright

Full text of DOI:10.1080/15533170601172450

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Synthesis, Spectroscopy and in vitro Cytotoxicity of
New Hydroxyanthraquinonato Triorganotin Compounds
Vasiliki Valla a , Maria Bakola‐Christianopoulou a , Vesna Kojic b & Gordana Bogdanovic b
a Department of Chemical Engineering, Aristotle University of Thessaloniki , Thessaloniki,
Greece
b Institute of Oncology, Experimental Oncology Department , Sremska Kamenica, Serbia and
Montenegro
Published online: 30 Mar 2007.
To cite this article: Vasiliki Valla , Maria Bakola‐Christianopoulou , Vesna Kojic & Gordana Bogdanovic (2007) Synthesis,
Spectroscopy and in vitro Cytotoxicity of New Hydroxyanthraquinonato Triorganotin Compounds , Synthesis and Reactivity in
Inorganic, Metal-Organic, and Nano-Metal Chemistry, 37:1, 41-51
To link to this article: http://dx.doi.org/10.1080/15533170601172450
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Synthesis and Reactivity in Inorganic, Metal-Organic and Nano-Metal Chemistry, 37:41–51, 2007
Copyright # 2007 Taylor & Francis Group, LLC
ISSN: 1553-3174 print/1553-3182 online
DOI: 10.1080/15533170601172450
Synthesis, Spectroscopy and in vitro Cytotoxicity of New
Hydroxyanthraquinonato Triorganotin Compounds
Vasiliki Valla and Maria Bakola-Christianopoulou
Department of Chemical Engineering, Aristotle University of Thessaloniki, Thessaloniki, Greece
Vesna Kojic and Gordana Bogdanovic
Institute of Oncology, Experimental Oncology Department, Sremska Kamenica, Serbia and Montenegro
exhibit higher biological activity than their di-and mono-ana-
We will present herein data on the synthesis, structural logues,[1] probably due to their ability to bind proteins[2] and
investigation and in vitro antitumor activity of new triorganotin
compounds of the general type (R3Sn)2Q, where R 5 Bu,
although the exact mechanisms of action remain unknown,
researchers tend to attribute their biological applications to
Ph, Bz, Q1 5 1,4-dihydroxy-9,10-anthracenedione (quinizarin),
Q2 5 1,5-dihydroxy-9,10-anthracenedione (anthrarufin), Q3 5
2,3-dihydro-9,10-dihydroxy-1,4-anthracenedione (leucoquinizarin)
interactions of the organotin moieties with cellular mem-
branes.[3,4] Organotins are known to interact in-vitro with the
and R3SnQ4 where Q4 5 1,2-dihydroxy-9,10-anthracenedione activity of several enzymes, e.g., human aromatase[5] and acet-
yltransferase,[6] while there is evidence that they enhance
human CG secretion.[7]
During the last 30 years a respectful number of organotin
(alizarin). The compounds were synthesized by refluxing the orga-
notin hydroxide with the parent quinone and were characterized
1
by IR, H- NMR and thermal measurements. The spectroscopic
analysis of the new triorganotins, provides evidence on the for-
mation of a monodentate Sn-O bond for quinizarin, anthrarufin
complexes has been synthesized and tested for their antitumor
and leucoquinizarin, which are coordinated to Sn(IV) central profile[8,9] but both the structure and anti-cancer activity
atom via the phenolic oxygen donor atoms, with the R-substituents
of the organotin moiety completing the tetrahedral coordination
varies according to the ligand- metal interactions. Subse-
quently, we find reports on carboxylates[10,11] and carboxylate-
environment. On the contrary, organotin alizarinates form a six-
membered chelate ring, which stabilizes the Sn central atom
in a five-coordinated environment exhibiting distorted trigonal
derivatives,[12–14] peptides and amino acids,[15] diketones
and di-ketone-derivatives,[16–22] steroids,[23] NSAIDs,[24]
bipyramidal geometry. The ligand is coordinated to Sn (IV) via other drugs[25,26] as well as on a wide range of N, S, O donor
ligands.[27] In each case, the binding mode to organotin cations
depends on the ligand’s properties chelation encountered may
the quinoidal oxygen and its neighbouring phenolic one. The new
compounds were tested for their cytotoxicity against human
tumor and normal cell lines and the results are reported.
be monodentate, bridging or is some cases polymeric.
Despite the thorough tin-chemistry study, only a very
Keywords hydroxyanthraquinones, triorganotins, SRB assay
limited amount of work has been done to investigate the poten-
tial triorganotin quinonoids. Brown et al.[28] have studied some
organotin (IV)–orthoquinone systems concluding on the
reaction conditions and coordination modes of benzoquinone
derivatives with diphenyl- and triphenyltin but no further
work leading to safe conclusions on the coordination mode
of organotin quinonates has been conducted.
INTRODUCTION
The last two decades’ organotin compounds have found a
solid application field within pharmaceuticals since most of
them show potent antitumor activity. In general, triorganotins
Among quinonoids, anthraquinones with hydroxy groups
directly attached to the quinonic ring constitute an intriguing
class of compounds with unique biological activity.[29] For
example, hydroxyquinones constitute the functional core of
anti-tumor agents daunorubicin and adriamycin (also known
as doxorubicin), which are considered highly active agents in
metastatic breast cancer (MBC).[30] The deriving semiquinone
radicals have been implicated in their anti-tumor action and
their associated toxic effects.[31] Recently, it has been shown
Received 8 October 2006; accepted 24 November 2006.
We thank Mr. Sidiropoulos and Associate Professor Mrs. Lalia-
Kantouri for acquiring the thermal analysis data and Assistant Pro-
fessor Mrs. A. Kourounakis for providing the 1H-NMR spectra.
Address correspondence to Vasiliki Valla, Department of
Chemical Engineering, Aristotle University of Thessaloniki, Univer-
sity Campus, GR-541 24, Thessaloniki, Greece. E-mail: vickyva@
auth.gr
41

42
V. VALLA ET AL.
that the chelated forms of these drugs achieve intercalation formation of a wide variety of metal complexes has been
with DNA, and, more importantly, in the free radical chemistry reported for quinizarin and anthrarufin,[39] while alizarin exhi-
of the drug.[32]
biting linkage isomerism, acts as a chelate via the 1,2- or the
Our group has previously contributed to the study of hydroxy- 1,9-oxygen atoms and forms complexes with Ru, Cu, Ni, Hg,
anthraquinone chelation with reports on the mononuclear and and a variety of transition metals.[40,41]
homobinuclear chelates of 1,5-dihydroxy-9,10-anthracenedione,
1,8-dihydroxy-anthracenedione, 1-amino-4-hydroxy-9,10-anthra-
cenedione and 1,2-dihydroxy-9,10-anthracenedione.[33–35]
EXPERIMENTAL
Herein, we continue our research on quinone chelates by
Materials
presenting the profile of new triorganotins: anthrarufin,
Triorganotin chlorides were purchased from Sigma-Aldrich
alizarin and leucoquinizarin, typical examples of hydroxyan-
and hydroxy-anthraquinones from FLUKA. All reagents were
thraquinones with established biological activity (Figure 1).
used without further purification. Tribenzyltin chloride was
The first three have been tested for genotoxicity with the hep-
atocyte/ DNA repair test and for effects on oxidative phos-
prepared by a standard method reported in the literature.[42]
All the solvents used in the reactions were of AR grade and
phorylation in isolated rat liver mitochondria. Among them,
were purchased from Sigma Aldrich.
only alizarin has exerted an uncoupling and inhibitory effect
on mitochondrial respiration.[36]
Measurements
On the other hand, leucoquinizarin’s peptides have been
recently reported to afford topoisomerase I inhibition.[37] The
chelation process of these hydroxyanthraquinones usually
evolves via their tautomeric anthraquinoid structures.[38] The
Carbon and hydrogen elemental analysis was performed
with a Perkin-Elmer 240 B analyzer. Attempts to define the
melting points using a Buchi B-540 model (maximum
FIG. 1. (a) Structure and nomenclature of the hydroxyanthraquinones studied, (b) Computer-simulated structures of quinizarin, anthrarufin, leucoquinizarin and
alizarin using B3LYP/6-31G(d) calculations for energy minimization; (c) HOMO & LUMO orbitals of the free ligands.

NEW TRIORGANOTIN COMPOUNDS
43
4108C), in most cases gave out no clear values. Infrared spectra 200 ml of 10 mmol TRIS (pH ¼ 10.5) basis was added to all
in the range 4000–200 cm21 were recorded as KBr discs wells. Optical density was measured on a microplate reader
(2:100 ratio) on a Perkin-Elmer Spectrum One spectrometer. (Multiscan MCC340, Labsystems) at 540/690 nm. The wells
1H-NMR spectra were recorded with a Bruker AM 300 without cells, containing compete medium only, acted as
(300 MHz) in ca. 5% solution of CDCl3 using Me4Si as blank. Cytotoxicity was calculated according to the formula:
internal standard, at room temperature. Simultaneous thermo-
gravimetric (TG) and differential thermal analysis (DTA)
were carried out on samples weighing 10 mg, with a Setavam
SetSys-12 Model. Spectra recording and analysis was con-
ducted with the SetSys 2000 software. A heating rate of
108C/min from ambient temperature to a maximum of
6508C was applied, under nitrogen atmosphere.
ð1 ꢁ ODTEST=ODCONTROLÞ ꢀ 100
and was expressed as a percent of cytotoxicity (CI%). Data
presented herein, represent the mean of the quadruplicate
wells obtained from two independent experiments. IC50
values define the dose of compound’s dose that inhibits cell
growth by 50%. The IC50 of compounds was determined by
median effect analysis and were calculated using the
CalcuSyn program.
Computational Details (Figure 1)
To depict Figure 1 standard ab initio molecular orbital
theory and DFT was used on the GAUSSIAN-98 program
suite on a Intel CELERON 3,2 GHz PC. DFT calculations
were performed on hydroxy-anthraquinones by the hybrid
B3LYP method, using the RB3LYP/6-31G(d) basis set. The
HOMO and LUMO orbitals were visualized with ChemOffice
2002 (PC version).
Synthesis
Quinizarin and Anthrarufin Derivatives (Compounds 1–6)
2,2 mmol of tributyl (0.95 ml), triphenyl (0.84 g), and tri-
benzyl tin chloride (0.94 g) accordingly were dissolved in
40 ml propanol. The stoicheiometric quantity of NaOH was
added and the resulting mixture was left stirring for about 15
minutes. Then, 1 mmol (0.24 g) of quinizarin (or anthrarufin)
suspended in 30 ml propanol was added slowly and under con-
tinuous magnetic stirring to the resulting triorganotin hydrox-
ides. The mixture was refluxed for 12 hours and was then
condensed via evaporation. The resulting compound was
filtered and the precipitate was washed several times with
water, propanol, acetone and diethyl ether. The solid was
recrystallized from propanol.
Cell Lines
Five human tumor cell lines and one human non-tumour
cell line were used: K-562 (Chronic myelogenous leukemia),
MCF-7 (Breast adenocarcinoma, estrogen receptor positive,
ER þ ), HeLaS3 (Epitheloid carcinoma of cervix), PC-3
(Prostate cancer), Hs 294T (Melanoma, metastatic to lymph
node) and MRC-5 (Lung foetal fibroblasts). The cells were
grown in RPMI 1640 (K562 and Hs294T cells) or Dulbecco’s
modified Eagle’s medium (DMEM) with 4.5% of glucose
(MCF-7, PC3, HeLaS3, and MRC5 cells). Media were sup-
plemented with 10% of fetal calf serum (FCS, NIVNS) and
antibiotics: 100 IU/ml of penicillin and 100 mg/ml of strepto-
mycin (ICN Galenika). All cell lines were cultured in flasks
(Costar, 25 cm2) at 378C in the 100% humidity atmosphere
and 5% of CO2. Only viable cells were used in the assays.
Viability was determined using Trypan blue in a due exclusion
assay.
Leucoquinizarin Derivatives (Compounds 7–9)
The same method and quantities were applied as described
previously.
Alizarin Derivatives (Compounds 10–12)
The same method was applied as described above, but the
ratio of triorganotin hydroxide to hydroxy-anthraquinone was
altered to 1.2:1 (therefore 0.52 ml tributyl, 0.46 g triphenyl,
0.51 g tribenzyl tin chloride and 0.24 g alizarin were used).
SRB Assay
Cytotoxicity was evaluated by the colorimetric SRB assay
reported from Skehan et al.[43] Single cell suspension was
plated into 96-well microtitar plates (Costar, flat bottom):
RESULTS AND DISCUSSION
The new triorganotin hydroxyanthraquinonates are mostly
1 ꢀ 104 of K562 and 5 ꢀ 103 of MCF-7, PC3, HeLa, amorphous but vividly coloured. They exhibit stability to
Hs294T and MRC5 cells, per 180 ml of medium. Plates were light, air and heat exposure. They are insoluble in water and
preincubated 24 h at 378C, 5% CO2. Tested substances were most inorganic and organic solvents and only slightly soluble
added to all wells except the control wells and microplates in CHCl3 and DMSO, a property that has obstructed their
were incubated for 48 h. After incubation period (48 h) SRB thorough study. Analytical data of the new compounds are pre-
assay was carried out: 50 ml of 80% trichloroacetic acid sented in Table 1. Their synthesis occurred via the interaction
(TCA), was added to all wells. An hour later, plates were of the organotin hydroxide with the parent quinone. The trior-
washed with distillate water and 75 ml of 0.4% SRB was ganotin derivatives formulated as R3Sn(m-Q)SnR3 (R ¼ Bu,
added to all wells. Half an hour later, plates were washed Ph, Bz; Q ¼ hydroxyanthraquinonato ligand) may be
with citric acid (1%) and dried at room temperature. Finally, described as the corresponding hydroxyanthraquinonates, in

44
V. VALLA ET AL.
TABLE 1
Physical properties of the new triorganotin hydroxyanthraquinonates
Elemental analysis
theoretical (found) (%)
Compound
Molecular type
M.W.
Yield (%)
Color
Quinizarin derivatives
1. (Bu3Sn)2Q1
C38H60O4Sn2
C50H36O4Sn2
C56H48O4Sn2
818
938
62
74
60
Dark purple red
55.75 (55.90) C
7.33 (7.52) H
63.96 (64.03) C
3.83 (3.70) H
65.75 (65.24) C
4.69 (4.57) H
2. (Ph3Sn)2Q1
3. (Bz3Sn)2Q1
1022
Anthrarufin derivatives
4. (Bu3Sn)2Q2
C38H60O4Sn2
C50H36O4Sn2
C56H48O4Sn2
818
54
69
57
Deep brown red
Dark brown
Deep red
55.75 (55.20) C
7.33 (7.02) H
5. (Ph3Sn)2Q2
6. (Bz3Sn)2Q2
938
63.96 (63.50) C
3.83 (40.10) H
65.75 (65.30) C
4.69 (4.42) H
1022
Leucoquinizarin derivatives
7. (Bu3Sn)2Q3
C38H62O4Sn2
C50H38O4Sn2
C56H50O4Sn2
820
940
53
68
57
55.61 (55.13) C
7.56 (7.82) H
63.83 (63.35) C
4.04 (4.21) H
65.63 (64.00) C
4.88 (4.54) H
8. (Ph3Sn)2Q3
9. (Bz3Sn)2Q3
1024
Alizarin derivatives
10. Bu3SnQ4
C26H34O4Sn
C32H22O4Sn
C35H28O4Sn
529
589
631
68
76
64
58.97 (58.54) C
6.42 (6.70) H
65.19 (65.20) C
3.74 (3.81) H
66.56 (66.22) C
4.44 (4.55) H
11. Ph3SnQ4
12. Bz3SnQ4
accordance with the reaction stoicheiometry and spectroscopic which one of the anthraquinoid tautomeric structures will
results. The general reaction scheme is outlined in Figure 2. prevail to the chelation with Sn and whether monodentate or
The anthraquinones used herein, may coordinate to metal bidentate Sn-O bonding will be preferred. Experimental obser-
ions by different modes. Our main goal has been to determine vation indicates that quinizarin (Q1) and anthrarufin (Q2) react
FIG. 2. General reaction scheme, applied to tributyl, triphenyl and tribenzyl-tin derivatives.

NEW TRIORGANOTIN COMPOUNDS
45
ionization degree but also in the contribution of the tautomeric
9,10-, 1,10-, and 1,5-anthraquinoid structures while affording
complexation.
On the other hand, alizarin as a 1,2-chelate displays ligand-
based redox chemistry and its ionization follows the equilibria:
AQðOHÞ2
O
AQðOHÞOꢁOAQO2ꢁ
where AQ(OH)2 is alizarin, and AQ(OH)O22 and AQO2 22 are
the corresponding mono- and dianions. The main tautomers
of alizarin are depicted in Figure 4a. The 2,9-, 1,10-, and
1,2-tautomers are more probable to participate in chelation pro-
cesses than the 9,10-anthraquinoid structure. Furthermore,[46]
complexation energies of these tautomers reveal that chelation
has a negligible influence on the structure of the anthraquinone
backbone and in most cases the ligand tends to keep a planar
conformation. The metal–oxygen bonds involve p or d metal
orbitals depending on whether the d shell is full or empty.
Bimetallic alizarinates with 9,10-anthraquinoid structures are
not formed because of the adjacent negatively charged
oxygen atoms; therefore the complexation of red metal alizar-
inates is expected to occur at the peri- or ortho-hydroxycarbo-
nyl group (Figure 4b).
FIG. 3. (a) Tautomeric forms of quinizarin; (b) Potential coordination modes
for quinizarin.
instantly while leucoquinizarin (Q3) and alizarin (Q4) deriva-
tives precipitate gradually with texture and color alterations.
According to the literature,[44] quinizarin may exist in
solution as an equilibrium mixture of 3 main tautomers
depicted in Figure 3: 1,4-dihydroxy-9,10-anthraquinone (A),
4,9-dihydroxy-1,10-anthraquinone (B), and 9,10-dihydroxy-
1,4-anthraquinone (C) (For numbering, see Figure 1). For-
mation of the majority of monometal complexes proceeds
through the 1,10-anthraquinoid structure, while the 9,10-
anthraquinoid structure is typical of bimetal complexes.
Similar studies for anthrarufin[45] show that the ligand may
occur in seven excited states that differ not only in the
Combining the above with the spectroscopic analysis of our
newly synthesized triorganotins, we have concluded on the for-
mation of monodentate Sn-O bonding for quinizarin, anthraru-
fin and leucoquinizarin, which are coordinated to Sn(IV)
central atom via the phenolic oxygen donor atoms, with the
R-substituents of the organotin moiety completing the tetrahe-
dral coordination environment. On the contrary, organotin
FIG. 4. (a) Tautomeric forms of alizarin; (b) Potential coordination modes for alizarin.

46
V. VALLA ET AL.
FIG. 5. Proposed structures of the new triorganotin hydroxyanthraquinonates, where R55Bu, Ph and Bz.
alizarinates form a six-membered chelate ring, which stabilizes shift in higher frequencies by 10–60 cm21 is noticed, which
the Sn central atom in a five-coordinated environment exhibit- is consistent and indicative of the coordination of the
ing distorted trigonal bipyramidal geometry. The ligand is phenolic oxygens with tin. We should notice that free quini-
coordinated to Sn (IV) via the quinonic oxygen of C9 and its zarin has a strong broad band ꢀ800 cm21, which is shifted
neighbouring phenolic oxygen of C1. The R-substituents of to ꢀ850 cm21 in all its triorganotin derivatives.
the tin cation complete the trigonal bipyramidal coordination
environment (Figure 5).
In free alizarin, the n(22OH) stretching vibrations appear in
the area 3385–3480 cm21. In the corresponding complexes, a
slight shift to higher frequencies by 15–30 cm21 in the form of
broader bands may be attributed to the breaking down of exten-
IR Studies
Selected IR data for the free ligands and their complexes are sive hydrogen bonding of the free ligand. These bands are
reported in Table 2. Assignments of the infrared bands were related to the stretching vibrations of the phenolic hydroxyls
made by comparing the spectra of the complexes with the and their maintenance strengthens the notion that at least one
ones of the free ligands. The sharp bands in the region of the two phenolic hydroxyls (C2-O) does not participate to
ꢀ3400 cm21 in the spectra of the free hydroxyanthraquinones coordination. The carbonyl n(C955O) stretching vibration of
are assigned to the n(22OH) stretching vibrations and disappear alizarin is found at 1664 cm21
.
in the triorganotin derivatives of quinizarin, anthrarufin and
In the corresponding complexes, a bathichromical shift to
leucoquinizarin, providing evidence that the hydroxyl groups lower frequencies by 15–35 cm21, depending on the deriva-
participate to the coordination. The n(55C22H) stretching tive (see Table 2), highlights the participation of the C955O
vibrations of the free ligands appear in the region 3015– group to coordination. Respectively, the n(C1-O) band, at
3080 cm21
.
1198 cm21 for alizarin, is shifted in higher frequencies, sup-
Upon complex formation no major spectral changes are porting the bidentate coordination of alizarin, which forms a
noticed for the tributyltin derivatives, but in the case of the tri- six-membered ring, energetically favored when compared to
phenyl and tribenzyltins both the range and tension of these the five-membered that would form with the participation of
bands increase (3015–3190 cm21), probably due to the incor- the two phenolic oxygens.
poration of the Ph and Bz substituents. The same applies to the
In the spectra of tributyltin complexes, we assign the pattern
medium n(-C-H) stretching vibrations of leucoquinizarin’ s of medium bands in the area ꢀ2850–2990 cm21 at the stretch-
saturated ring present (2855–2930 cm21).
ing vibrations of the n-Bu skeleton. Some strong to medium
The carbonyl n(C55O) stretching vibration is a sharp band intensity bands also appear in the tributyltin complexes
(only one because of the ligands’ symmetric nature) at spectra in the region 1180–1220 cm21 and are assigned to
1629 cm21 for quinizarin, 1634 cm21 for anthrarufin and n(Sn–CH3) stretching vibrations. The strong band at 510–
1633 cm21 for leucoquinizarin. Upon complexation, the band 585 cm21 is also due to the Sn22C stretching vibration and
is not influenced, providing strong evidence that the carbonyl has been previously reported by Singh[47] to be characteristic
moiety does not interact with tin. The non-involvement of of tributyltins. The triphenyltin hydroxyanthraquinonates
the carbonyls is further substantiated by the fact that no show the expected symmetric and asymmetric stretching
major changes occur in the region 1570–1590 cm21, where vibrations of the SnPh3 moiety at ca. 460, 270 and 240 cm21
.
the n(C55C) skeletal in-plane vibrations of the conjugated
aromatic ring appear.
The usual benzene ring absorptions appear in the complexes
spectra together with the typical band of the phenyltin group at
In the free ligands, the n(C22O) band appears in 1225 cm21 ꢀ1070 cm21. The n(OH) band of Ph3SnOH (ꢀ3610 cm21) is
for the quinizarinato moiety, in 1214 cm21 for anthrarufin and not found in the spectra of the products, indicating complex
1197 cm21 for leucoquinizarin. Upon derivatization, a minor formation of the triphenyltin moiety. The incorporation of

TABLE 2
Characteristic IR frequencies (cm21) of the free ligands and their triorganotin derivatives
-OH
C-Har
C-Haliph
C55O
C55C-C-O
C-O
Sn-C
—
Sn-O
Quinizarin derivatives
Free ligand
1. (SnBu3)2Q1
3436br
—
3020–3070 m
3020–3070 m
—
2890–2955 m
1629vs
1630vs
1590s
1586s
1225 s
1274 s
—
460–530 m
510 m;
580 m
460 m;
270 m;
240 m
240 m;
460 m
2. (SnPh3)2Q1
3. (SnBz3)2Q1
—
—
3020–3090 m
3020–3110 m
—
1628vs
1629 vs
1585s
1256 s
1257 s
2910–2970 m
1590 s
Anthrarufin derivatives
Free ligand
4. (SnBu3)2Q2
3417br
3015–3080 m
3015–3080 m
—
2890–2945 m
1634vs
1636vs
1571s
1570s
1214s
1270s
—
515 m;
570 w
455 m;
260 m;
240 m
555 m;
240 w
—
470–510 m
—
5. (SnPh3)2Q2
—
3015–3140 m
3015–3090 m
—
1635vs
1629vs
1570s
1577s
1241s
1261s
6. (SnBz3)2Q2
—
2930–2985 m
Leucoquinizarin derivatives
Free ligand
7. (SnBu3)2Q3
3426br
3025–3060 m
3025–3060 m
2855–2930 m
2860–2975 m
1633vs
1630vs
1581s
1590s
1197s
1226s
—
530 m;
570 m
470 m;
280 m
540 m;
260 m
—
490–545 m
—
—
—
8. (SnPh3)2Q3
9. (SnBz3)2Q3
3020–3190 m
3030–3075 m
2850–2930 m
2915–2980 m
1637vs
1630vs
1589s
1585s
1209s
1215s
Alizarin derivatives
-OH
3385–3480br
3390–3500br
C-Har
3020–3075 m
3020–3075 m
C-Haliph
—
2910–2990 m
C955O
1664vs
1645vs
C55C-C-O
1588s
1526s
C1-O
1198s
1217s
Sn-C
Sn-O
—
490–520 m
Free ligand
10. SnBu3Q4
—
570 m;
545 w
460 m;
260 m
540 m;
260 m
11. SnPh3Q4
12. SnBz3Q4
3400–3490br
3395–3505br
3015–3120 m
3020–3085 m
—
1629vs
1648vs
1479s
1531s
1226s
1219s
2940–2990 m
vs ¼ very strong; s ¼ strong; m ¼ medium; w ¼ weak; br ¼ broad.

48
V. VALLA ET AL.
the tribenzyl- group is indicated by the typical pattern present coordination with tin. The downfield shifts of the aromatic
in the region 2920–3080 cm21, accounting for n(55C-H) and and quinoid ring protons are attributed to the complexation,
n(C-C-H) stretching vibrations. The occurrence of new which generates a delocalization of electron density on the
vibrational modes in the region 545–460 cm21, which is anthraquinone ring.
absent in both the spectra of the ligands and parent organotins,
In alizarin complexes, only the H1 signal disappears, sub-
may be assigned to the n(Sn22O) stretching vibrations and stantiating our thoughts for its non-participation to the coordi-
support the linkage between the oxygen atoms and tin. The nation with tin. The other phenolic proton (H2) resonance is
bands observed at ꢀ280 and 240 cm21 in the far-IR spectra still present in a form of a weaker signal. An experiment
of the complexes have been tentatively assigned to vasym and with D2O exchange has verified the existence of a phenolic
v
sym (Sn22C) modes.
proton in alizarin derivatives (obviously H2). The 13C NMR
spectra that we managed to acquire show a significant down-
field shift of all carbon resonances compared with the free
hydroxy-anthraquinones due to electron density transfer from
the ligand to the acceptor.
1H-NMR Studies
The 1H-NMR spectra of the new complexes show the
expected integration and peak multiplicities with aromatic
signals undergoing a more complex pattern upon chelation.
1
Thermal Analysis
While trying to define the melting points of the new triorga-
Selected H-NMR data are presented in Table 3. A typical
singlet at 1.5d, when observed, has been assigned to the
water of CHCl3. The chemical shifts of the signals for the notins we have observed a complicated, multi-step process of
R-substituents appear at the same position as in the free orga- color and texture alterations, which in most cases ends with
notins and have been assigned in the spectra of the complexes. an apparent decomposition above 3508C. This behavior
The tributyltin (IV) derivatives show the typical butyl prompted us to a more detailed thermal study, which
skeleton pattern between 0.70–2.0d. In the spectra of the tri- revealed that up to 4008C several phenomena occur in associ-
phenyltin (IV) complexes it is not possible to distinguish ation with respective weight loss. The most striking one is the
between signals due to aromatic protons of the ligands and abrupt transition from a highly endothermic to a considerable
those linked to tin, but integration has taken their presence exothermic phenomenon in the region 250–3508C, where the
into account. A complicated set of multiplets due to the greatest mass loss occurs. This phenomenon may be correlated
ligand aromatic and phenyl ring protons of the Sn-Ph3, to the ligands’ coordination mode. Temperature accounts for
moiety is observed in the range 6.90–8.50d for all the com- the tautomerisation process of hydroxyanthraquinones, which
plexes. The compounds’ poor solubility has prevented obser- is respectively associated with the way the ligand approaches
vation of any tin satellites.
the metal. At least some endothermic phenomena seen herein
In the Q1, Q2, Q3 triorganotins, the signal due to the may be attributed to such an alteration in the coordination
phenolic protons of the free ligands disappears suggesting scheme especially if one takes into consideration the possibility
TABLE 3
Selected H-NMR data of the new triorganotin hydroxyanthraquinonates
1
1. (SnBu3)2Q1: 0,7–1,8 d(m): 54H, Sn-Bu; 6,9–7,2 d(m): 2H, H2,H3; 7,4–7,5 d(m): 2H, H6,H7; 7,8–8,32 d(m): 2H, H5,H8
2. (SnPh3)2Q1: 1,5 d(s) H2O in CHCl3; 6,8–7 d(m): 2H, H2,H3; 7–8,2 d(m): 34H (ligand and Sn-Ph protons, undistinguishable)
3. (SnBz3)2Q1: 3,25 d(s): 12H, -CH2 of the benzyl group; 6,9–7 d(m):2H, H2,H3; 7–8 d(m): 34H (ligand and Sn-Ph protons,
undistinguishable)
4. (SnBu3)2Q2: 0,8–1,6 d(m): 54H, Sn-Bu; 6,9–7,1 d(m): 2H, H2, H6; 7,5–7,7 d(m): 2H, H3, H7; 7,8–8 d(m): 2H, H4, H8
5. (SnPh3)2Q2: 1,5 d(s) H2O in CHCl3; 6,9–7 d(s): 2H, H2, H7; 7–8,1 d(m): 34H, (ligand and Sn-Ph protons, undistinguishable)
6. (SnBz3)2Q2: 3,5 d(s): 12H, -CH2 of the benzyl group; 6,8–6,9 d(s): 2H, H2, H6; 7–8,2 d(m): 34H, (ligand and Sn-Ph protons
undistinguishable)
7. (SnBu3)2Q3: 0,9–1,5 d(m): 54H, Sn-Bu; 3,1 d(s): 4H, H2, H3; 7,4–7,8 d(m): 2H, H6, H7; 8,3 d(s): 2H, H5, H8
8. (SnPh3)2Q3: 3,1 d(s): 4H, H2, H3; 7–8,4 d(m): 34H, (ligand and Sn-Ph protons, undistinguishable
9. (SnBz3)2Q3: 1,5 d(s) H2O in CHCl3; 3,3 d(s): 4H, H2,H3; 3,5 d(s): 12H, -CH2 of the benzyl group; 6,9–7,8 d(m): 32H, H6,H7
and Sn-Ph protons; 8,3 d(s): 2H, H5, H8
10. SnBu3Q4: 0,8–1,6 d(m): 27H, Sn-Bu; 6,9–8,0 d(m): 6H,H3, H4, H5, H6, H7, H8; 10,4 d(s):1H, H2
11.SnPh3Q4: 1,5 d(s) H2O in CHCl3; 6,9–8,6 d(m):21H, (ligand and Sn-Ph protons, undistinguishable; 10,6 d(s): 1H, H2
12. SnBz3Q4: 2,9–3,5 d(m): 12H, -CH2 of the benzyl group; 6,8–7,0 d(s): 1H, H3; 7–8,2 d(m):14H, (ligand and Sn-Ph
protons, undistinguishable); 10,2 d(s):1H, H2

NEW TRIORGANOTIN COMPOUNDS
49
of forming a five-coordinate tin center by means of the a-N
pair lone coordination.
TABLE 4
IC50 values of some of the new triorganotin
hydroxyanthraquinonates
The triphenyl derivatives of Q1, Q2 and Q3 were studied in a
range up to 650oC. Up to this temperature, the total mass loss
does not exceed the 60% of the initial mass. This implies either
that breakdown is not complete or that tin oxides may co-exist
with residue. Given the high percentage of residues, we have
acquired their IR spectra, where it is evident that part of the
hydroxyanthraquinonic ring is still present at 6008C. The ther-
mogravimetric (TG) data show that decomposition is tempera-
ture- related and differentiates according to the R- substituent
of the organotin moiety. The weight losses observed due to
thermal decomposition are in respect with the calculated
values and within the margins of experimental mistakes
(+3%.). The degradation patterns of quinizarin (Q1) and
anthrarufin (Q2) derivatives are remarkably similar and there-
fore we only present data for the triphenyl and tributyl
quinizarinate.
K562 MCF 7 HeLa Hs 294T MRC 5
Doxoru
bicin
(Ph3Sn)2Q1
0.82
0.83
1.19
5.08
29.85
0.32
0.08
3.02
0.02
0.17
1.09
0.29
0.21
2.06
1.42
0.36
1.41
0.92
0.4
0.03
12.29
0.039
0.098
1.96
(Bu3Sn)2Q1 .100
(Ph3Sn)2Q2
(Ph3Sn)2Q3
2.24
0.45
0.44
0.29
0.62
5.66
0.45
(Bu3Sn)2Q3 18.77
Ph3Sn Q4 0.82
0.02
The results are summarized in Table 4. Most of the compounds
were found to be toxic in both tumor and normal cells and were
continuously present in the culture for 48 h in the range of con-
centrations from 1028 to 1024 M.
Compound 2 (triphenyltin quinizarinate), shows a slight
weight loss of ꢀ 10% up to 2308C. Two endotherms are
observed at 1008C and 1258C, followed by an exotherm at
2008C and a weak endotherm at ꢀ3008C. None of these
phenomena may be attributed to the compounds’ melting and
have been assigned to phase alteration processes of organotins.
From the temperature of 2508C and up, a rapid weight loss
begins. At 3258C, an exotherm is noticed, corresponding to
approximately 35% weight loss, which may be accounting
for the SnPh moiety. A gradual weight loss continues up to
6008C without any evidence of quinizarin degradation. A last
weak exotherm is present at ꢀ 4258C.
Regarding the cytotoxicity profile, dose-dependent response
was found for all cell lines except PC3 (prostate carcinoma cell
line). By a second, independent experimentation, we have
verified this as a true response, which has obstructed us from
calculating the IC50 values for all compounds except tributyl
quinizarinate, for which the IC50 value was found to be
0.55 mM. Most of the compounds at concentrations of 1025
and 1024M gave cytotoxicity above 80% regardless of the
cell type, while in most cases no tissue specific cell response
was observed. All tested compounds are more active against
HeLa and Hs294T than against K562 and MCF7. The
melanoma cells (Hs 294T) are known to be non-sensitive to
doxorubicin but in our case, a remarkable sensitivity is
expressed towards these new compounds. The triphenyltin
derivatives of quinizarin and alizarin were found as active as
doxorubicin, while the tributyl leucoquinizarinate is remark-
ably less active. This same compound shows an analogous
response to doxorubicin when tested to MCF7 cells. The unde-
sirable effect of high cytotoxicity against MRC5 cells is
depicted in almost all compounds.
An equivalent degradation pattern -although a bit more
complicated- accounts for the triphenyltin derivative of leuco-
quinizarin (compound 8). A slight weight loss, not more than
5% occurs up to 2308C. Up to this temperature, we notice
two endotherms at 1008C and ꢀ 1708C, followed by an
exotherm at 2008C and finally another endotherm at ꢀ2308C.
Within the range of 2008C and 2308C, there is a 15% weight
loss, which corresponds to phenyl groups of the triorganotin
moiety. At 3508C, the rapid weight loss stabilizes, after
approximately 37% of the initial mass has been lost. A
strong exotherm is noticed in this area.
The justification of this highly toxic profile lies predomi-
nantly on the limited solubility, which allows no margin for
cellular penetration or interactions with proteins. Although it
has been repeatedly stated that triorganotins bearing tetrahedral
geometry possess a better biological activity,[8–10] in our case
this is not confirmed. Actually, we have associated the toxicity
to the non-involvement of the lone pair on the oxygen atom of
carbonyl group in coordination. This has been reported to play
a key role in the escalation of toxicity.[2,3] Moreover, toxicity is
affected by the R substituents of tin (IV) and the function of the
ligands bound to it. In the R3SnQ unit, the function of Q is to
transport the active organotin (IV) moiety to the action site
and release it there on hydrolysis. We therefore assume that
the complicated structure of hydroxyanthraquinones may not
be desirable for this process.
The degradation patterns of the tributyltin derivatives show
a higher degree of mass loss exceeding 60% of the initial mass
for compound 1 and 65% for compound 7. In both cases, the
rapid weight loss begins at ꢀ2508C and ends at ꢀ3508C.
Compound 1 shows three endotherms at ꢀ1808C, 2008C and
3508C, while compound 7 displays only two endotherms one
at 2008C and another at ꢀ3408C.
Cytotoxicity Studies
We have measured the cytotoxicity of some of the new trior-
ganotin hydroxyanthraquinonates against five human tumour
K562, MCF-7, HeLaS3, PC3, Hs 294T and one non-tumor
human cell line MRC5, using the colorimetric SRB assay.

50
V. VALLA ET AL.
characterization and behavior in solution. Crystal structure of aquo-
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