Synthesis, structure and in vitro biological activity of new hydroxy-naphthoquinonato triorganotin compounds

Article abstract of DOI:10.1080/15533170601028298

We report herein on the synthesis, structure and in vitro antitumor activity of new triorganotin compounds of the general type (R ₃Sn)_nL, where R=Me, Bu, Ph, Bz; L¹=5-Hydroxy-1, 4-naphthoquinone; L²=2-Hydroxy-1,4-naphthoquinone; L ³=5,8-dihydroxy-1,4-naphthoquinone; n=1 for L¹ & L² n=2 for L² and L³. The compounds were synthesized by reacting the triorganotin hydroxide with the parent hydroxy-quinone and were characterized by IR, ¹H, NMR, and thermal measurements. The spectroscopic analysis provides evidence on the formation of a chelate ring that is responsible for the stabilization of the triorganotin cation with the Sn central atom in a five-coordinated environment exhibiting distorted trigonal bipyramidal geometry. The new compounds were tested for their cytotoxicity against five human tumor cell lines and one non-tumor human cell line and the results are reported.

Full text of DOI:10.1080/15533170601028298

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Synthesis, Structure and In vitro Biological Activity
of New Hydroxy‐Naphthoquinonato Triorganotin
Compounds
Vasiliki Valla a , Maria Bakola‐Christianopoulou a , Pericles Akrivos b , Vesna Kojic c
&
Gordana Bogdanovic c
a Department of Chemical Engineering , Aristotle University of Thessaloniki , Thessaloniki,
Greece
b Department of Chemistry , Aristotle University of Thessaloniki , Thessaloniki, Greece
c Experimental Oncology Department , Institute of Oncology , Serbia and Montenegro
Published online: 15 Feb 2007.
To cite this article: Vasiliki Valla , Maria Bakola‐Christianopoulou , Pericles Akrivos , Vesna Kojic & Gordana Bogdanovic (2006)
Synthesis, Structure and In vitro Biological Activity of New Hydroxy‐Naphthoquinonato Triorganotin Compounds, Synthesis and
Reactivity in Inorganic, Metal-Organic, and Nano-Metal Chemistry, 36:10, 765-775
To link to this article: http://dx.doi.org/10.1080/15533170601028298
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Synthesis and Reactivity in Inorganic, Metal-Organic and Nano-Metal Chemistry, 36:765–775, 2006
Copyright # 2006 Taylor & Francis Group, LLC
ISSN: 0094-5714 print/1532-2440 online
DOI: 10.1080/15533170601028298
Synthesis, Structure and In vitro Biological Activity of New
Hydroxy-Naphthoquinonato Triorganotin Compounds
Vasiliki Valla and Maria Bakola-Christianopoulou
Department of Chemical Engineering, Aristotle University of Thessaloniki, Thessaloniki, Greece
Pericles Akrivos
Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki, Greece
Vesna Kojic and Gordana Bogdanovic
Experimental Oncology Department, Institute of Oncology, Serbia and Montenegro
The antitumor potential of quinonoidal compounds was
We report herein on the synthesis, structure and in vitro initially brought up by the 1974 NCI report on the screening
antitumor activity of new triorganotin compounds of the
general type (R3Sn)nL, where R 5 Me, Bu, Ph, Bz; L1 5 5-
of 1500 synthetic and natural quinones for their anticancer
activities.[7] The binding ability of quinones in different oxi-
dation states is an additional factor for the extensive interaction
Hydroxy-1,4-naphthoquinone; L2 5 2-Hydroxy-1,4-naphthoqui-
none; L3 5 5,8-dihydroxy-1,4-naphthoquinone; n 5 1 for L1
&
L2 n 5 2 for L2 and L3. The compounds were synthesized by
reacting the triorganotin hydroxide with the parent hydroxy- electron transfer and redox reactions.
of naphthoquinones with biological systems mainly through
1
quinone and were characterized by IR, H-, NMR, and thermal
Three major representatives of hydroxy-naphthoquinones,
measurements. The spectroscopic analysis provides evidence on
the formation of a chelate ring that is responsible for the stabiliz-
ation of the triorganotin cation with the Sn central atom in a five-
coordinated environment exhibiting distorted trigonal bipyrami-
based on their biological activity, are juglone, lawsone and
naphthazarine (Figure 1). Juglone displays potent biological
properties including antimalarial, antibacterial, antiviral, and
dal geometry. The new compounds were tested for their cytotox- antifungal properties as well as cytotoxic properties.[8–12]
icity against five human tumor cell lines and one non-tumor
human cell line and the results are reported.
Juglone’s isomer, lawsone, is a natural p-quinone whose
hydroxyl group in position 2, upon deprotonation, presents tau-
tomeric structures which provide an o-quinone character that
Keywords hydroxy-naphthoquinones, triorganotins, SRB assay
may imitate biological systems processes. Therefore, lawsone
has been reported to exhibit antioxidant and immunomodula-
tory properties[13] as well as antimicrobial activity.[14] Due to
its tautomeric effects, lawsone has been reported to form
complexes with a wide range of metals.[15–18] Supporting the
above, our group has previously described a number of juglone
and lawsone chelates with several transition metals[19,20]
that have been found to exert noticeable antimicrobial and
anti-bacterial activity. On the other hand, literature on the
naphthazarine nucleus is always in respect to its tautomeric char-
acter behaving as a bis-alkylating molecule. We have already
reported on a cis-platin analogue naphthazarine complex with
the stoicheiometry Pt2(C10H4O4)(NH3)2Cl2 which exhibits
potent antitumor activity comparable with that of cisplatin, but
with much lower nephrotoxicity.[21] We have also noticed
antibacterial and cytogenetic effects on human lymphocytes
attributed to diplatinum complexes of naphthazarine.[23,23]
Continuing our work on quinone chemistry, we are now
expanding our research in the study of organotin naphthoquino-
nates based on the literature indicating the solid biological
INTRODUCTION
The 1,4-naphthoquinone structure is common in numerous
natural products associated with antifungal, antibacterial,
antiviral, and antitumour activities.[1] 1,4-naphthoquinone
pharmacophore is known to impart cytotoxity in a number of
drugs including among others streptonigrin,[2] actinomycins,[3]
mitomycins,[4] alkannins[5] and 2-hydroxynaphthoquinone
derivatives.[6]
Received 01 August 2006; accepted 14 September 2006.
We thank Mr. Sidiropoulos and Associate Professor Mrs. Lalia-
Kantouri for acquiring the thermal analysis data and Assistant
Professor Mrs. A. Kourounakis for providing the 1H-NMR spectra.
Address correspondence to Vasiliki Valla, Department of Chemical
Engineering, Aristotle University of Thessaloniki, University Campus,
24, Thessaloniki, GR-541.Greece. E-mail: vickyva@auth.gr
765

766
V. VALLA ET AL.
FIG. 1. (a) Structure of the hydroxy-naphthoquinones studied in this work; (b) HOMO & LUMO orbitals of the free ligands.
applications of organotin compounds. In the last 30 years, a the reaction conditions and coordination modes of benzoqui-
respectful number of organotins have been synthesized, none derivatives with diphenyl- and triphenyltin.
characterized and tested for their antitumor profile. The antic-
ancer properties of more than 200 compounds from this field
have been reviewed by M. Gielen.[24–28]
In general, triorganotin compounds exhibit biological
EXPERIMENTAL
Materials. Triorganotin chlorides and hydroxy-naphtho-
activity mainly because of their ability to bind proteins.[29]
quinones are commercially available from Sigma-Aldrich
and were used without further purification. Tribenzyltin
Both the structure and anti-cancer activity of triorganotins
chloride was prepared by a standard method reported in the
varies according to the ligand-metal interactions. The conducted
studies indicate that ligands tend bind to organotin (IV) cations
literature.[31]
All the solvents used in the reactions were of AR grade and
via monodentate, bridging, or chelating coordination modes.
Despite the detailed studies conducted for both quinones
and triorganotins, only a very limited amount of work has
were purchased from Sigma Aldrich.
Measurements. Carbon and hydrogen elemental analyses
been done to investigate the triorganotin compounds of were performed with a Perkin-Elmer 240 B analyzer. The
hydroxy-naphthoquinones. Brown et al[30] has studied the melting points were obtained from a Buchi B-540 model that
organotin (IV) –orthoquinone systems and has concluded on has a maximum of 4108C. IR spectra from 4000–200 cm21

NEW HYDROXY-NAPHTHOQUINONATO TRIORGANOTIN COMPOUNDS
767
were recorded on Perkin-Elmer Spectrum One spectropho- 200 ml of 10 mmol TRIS (pH ¼ 10.5) base was added to all
tometer with samples investigated in KBr disc in a 2:100 the wells. Optical density was measured on a microplate
1
ratio. H-NMR spectra were recorded with a Bruker AM 300 reader (Multiscan MCC340, Labsystems) at 540/690 nm.
(300 MHz) in ca. 5% solution of CDCl3 using Me4Si as The wells without cells, containing compete medium only,
internal standard. The spectra were acquired at room tempera- acted as the blank. Cytotoxicity was calculated according to
ture (298 K). Simultaneous thermogravimetric (TG) and differ- the formula:
ential thermal analysis (DTA) of the new triorganotin samples
were carried out on a Setavam SetSys-12 Model instrument and
ð1 ꢁ ODTEST=ODCONTROLÞ ꢀ 100:
spectra recording and analysis was conducted via the SetSys
2000 software. Heat was applied at the rate of 108C/min, the
temperature maximum being 6508C. The experiment was
conducted under nitrogen atmosphere. Sample weights were
approximately 10 mg.
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 (Figures 1 and 4). To depict
Figures 1b and 4, standard ab initio molecular orbital theory
and DFT was used on the GAUSSIAN-98 program suite on
an Intel CELERON 3,2 GHz PC.[45] The geometry of the
trimethyltin derivative of juglone (compound 1; Figure 4)
was fully optimized at the B3LYP level of density functional
theory, using the B3LYP/LANL2DZ basis set. DFT calcu-
lations were performed on hydroxy-naphthoquinones by the
hybrid B3LYP method, using the RB3LYP/6-31G(d) basis
set (Figure 1). The HOMO, LUMO orbitals and the MEP
surface (Figures 1 and 4) were visualized with ChemOffice
2002 (PC version).
Synthesis
Juglone derivatives (compounds 1–4). 1,2 mmol of
trimethyl (0-24 g), tributyl (0-52 ml), triphenyl (0.46 g), and
tribenzyl tin chloride (0.51 g) accordingly were dissolved in
20 ml MeOH. The stoicheiometric quantity of NaOH was
added and the resulting mixture was left stirring for about 15
minutes. Then 1 mmol (0.17 g) of the hydroxy-naphthoquinone
suspended in 30 ml MeOH was added slowly, under continu-
ous magnetic stirring, to the resulting triorganotin hydroxides.
The mixtures were stirred for 24 hours at room temperature and
were then condensed via evaporation. After cooling down to
room temperature, the mixture was filtered. The solvent of
the filtrate was gradually removed by evaporation under
vacuum until solid product was obtained. The precipitate was
washed several times with water, methanol, and diethyl
ether. The solid was then recrystallized from ethanol. The
final product was air-dried.
Cell Lines. Five human tumour cell lines and one human
non-tumour cell line were used in the study: K-562 (Chronic
myelogenous leukemia), MCF-7 (Breast adenocarcinoma,
estrogen receptor positive, ER þ ), HeLaS3 (Epitheloid carci-
noma 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 supplemented with
10% of fetal calf serum (FCS, NIVNS) and antibiotics:
100 IU/ml of penicillin and 100 mg/ml of streptomycin
(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.
SRB assay. Cytotoxicity was evaluated by colorimetric
(1) SnMe3L1: dark-brown colour, Yield: 79% Anal Cal for
C13H14O3Sn (MW ¼ 337); C, 46,29; H,4,15%. Found:
C, 46,59; H, 3,95H%.
IR(cm21): 3015–3065 m(C-Har); 2870–2945w(-C-
Haliph); 1615vs(C55O); 1588s (C55C-C-O); 1259s(C-O);
587s, 560s(Sn-C); 471 m, 457s(Sn-O).
1H-NMR(d): 0.56(s) (9H: Sn-CH3); 6,7(s) (2H: H2,
H3); 7,2-7,8(m) (3H; H6, H7, H8).
SRB assay after Skehan et al.[32] Single cell suspension was (2) SnBu3L1: dark-brown colour, Yield: 76%. Anal Cal for
plated into 96-well microtitar plates (Costar, flat bottom):
1 ꢀ 104 of K562 and 5 ꢀ 103 of MCF-7, PC3, HeLa,
Hs294T and MRC5 cells, per 180 ml of medium. Plates were
preincubated 24 h at 378C, 5% CO2. Tested substances were
added to all wells except the control wells. The microplates
were incubated for 48 hours. After the incubation period,
SRB assay was carried out: 50 ml of 80% trichloroacetic acid
(TCA) was added to all the wells. An hour later, plates were
washed with distillate water and 75 ml of 0.4% SRB was
C22H32O3Sn (MW ¼ 463); C, 57,02; H, 6,90%. Found:
IR(cm21): 3015–3065 m(C-Har); 2920-2980 m(-C-
Haliph); 1617vs(C55O); 1590s(C55C-C-O); 1264s(C-O);
507 m, 610 m(Sn-C); 220 m, 420 m(Sn-O).
1H-NMR(d): 0,9–1,65(m) (27H:Sn-Bu): 0,9(m):Hd,
1,25(m):Hc, 1,35(m):Hb, 1,65(m):Ha; 6,7(s) (2H: H2, H3);
7,2–7,5 (m) (3H:H6, H7, H8). Numbering for the t-Bu
group: dCH3cCH2bCHa2CH2-Sn
C, 57,45; H, 6,49%.
added to all the wells. Half an hour later, plates were washed (3) SnPh3L1: dark-brown colour, Yield: 72%. Anal. Calcd.
with citric acid (1%) and dried at room temperature. Finally,
for C28H20O3Sn (MW ¼ 523); C, 64,24; H, 3,82%.

768
V. VALLA ET AL.
Found: C, 63,97; H, 3,79%.
(9) (SnMe3)2L3: Blue-purple colour, Yield: 82%. Anal.
Calcd. for C16H22O4Sn2 (MW ¼ 516); C, 37,21;
H, 4,20%. Found: C, 36,95; H, 3,96%.
IR(cm21): 3015–3065 m(C-Har); 1634vs (C55O);
1595s(C55C-C-O); 1266s(C-O); 230 m, 270 m, 450vs(Sn-
C); 450vs, 403 m(Sn-O).
IR(cm21): 3020–3062 m(C-Har); 2870–2950w(-C-
Haliph); 1605vs(C55O); 1530s(C55C-C-O); 1175s(C-O);
570 m, 545 w(Sn-C); 440 m, 370 w(Sn-O).
1H-NMR(d): 0,65(s) (18H; Sn-CH3); 6,8–6,9(s) (2H:
H2, H3); 7,6(d) (2H: H6,H7)
1H-NMR(d): 6,8(s) (2H: H2, H3); 7.2–7.8(m) (18H:
ligand and Sn-Ph protons undistinguishable)
(4) SnBz3L1: dark-brown colour, Yield: 71%. Anal Cal for
C31H26O3Sn (MW ¼ 565); C, 65,84; H, 4.60%. Found:
C, 65,50; H, 4,89%.
(10) (SnBu3)2L3: Blue-purple colour, Yield: 79%. Anal. Calcd.
for C34H58O4Sn2 (MW ¼ 768); C, 53.12; H, 7.55%.
Found: C, 52.88; H, 7.25%.
IR(cm21):
3000-3173 m(C-Har);
2910-3000(-C-
Haliph); 1643vs(C55O); 1594s(C55C-C-O); 1265 s(C-O);
239 w, 340 m, 459s (Sn-C); 440 m(Sn-O).
1H-NMR(d): 2,36(s) (6H: –CH2 of the benzyl group);
6,7–6.9(s) (2H; H2, H3); 7,0–8,0(m) (18H: ligand and Sn-
Ph protons undistinguishable)
IR(cm21): 3020–3060 m(C-Har); 2870–2960 m(-C-
Haliph); 1610vs(C55O); 1547s(C55C-C-O); 1182s(C-O);
510 m, 605s (Sn-C); 410 m, 419 m(Sn-O).
1H-NMR(d): 0.8–1.8(m): (54H; Sn-Bu): 0.8(t):Hd,
1,27(m):Hc, 1,45(m):Hb, 1,8(m):Ha; 6.85 (2H:H2, H3);
7,45(s) (2H: H6, H7)
Lawsone derivatives (compounds 5–8): The same
method and quantities were applied as described here.
(5) SnMe3L2: dark red colour, Yield: 74%. C13H14O3Sn (11) (SnPh3)2L3: Blue-purple colour, Yield: 87%. Anal. Calcd.
(MW ¼ 337); C, 46,29; H, 4,15%. Found: C, 46,58; H,
for C46H34O4Sn2 (MW ¼ 888); C, 62,16; H, 3,82%.
3,95%.
Found: C, 62,49; H, 3,53%.
IR(cm21): 3015–3075 m(C-Har); 2870–2945w(-C-
Haliph); 1625vs(C55O); 1520s(C55C-C-O); 1261s(C-O);
558, 550s(Sn-C); 476s 419w (Sn-O).
IR(cm21): 3013 m-3100 m(C-Har); 1608vs(C55O);
1548s(C55C-C-O); 1182s(C-O); 234 m 275 m, 457vs(Sn-
C); 385 m, 470s(Sn-O).
1H-NMR(d): 0,60(s) (9H: Sn-CH3); 6,35(s) (1H: H3)
7,0–7,7(m) (4H: H5, H6, H7, H8)
1H-NMR(d): 6,8(s) (2H: H2, H3); 7,2-7,8(m)- 32H
(ligand and Sn-Ph protons, undistinguishable).
(6) SnBu3L2: dark red colour, Yield: 71%. Anal. Calcd. for (12) (SnBz3)2L3: Blue-purple colour, Yield: 83%. Anal. Calcd.
C22H32O3Sn (MW ¼ 463); C, 57,02; H, 6,90%. Found:
for C52H46O4Sn2 (MW ¼ 972); C, 64.19; H, 4.73%.
C, 57,15; H, 6,48%.
Found: C, 63.90; H, 4.56%.
IR(cm21): 3015-3070 m(C-Har); 2890-2970 m(-C-
Haliph); 1620vs(C55O); 1540s(C55C-C-O); 1255s(C-O);
510s, 617s(Sn-C); 225 m, 457 m(Sn-O).
1H-NMR(d): 0,9–2(m) (27H; Sn-Bu): 0,90(t):Hd,
0,95(t):Hc, 1,4(m):Hb, 2,0(m):Ha, 6,5(s): (1H; H3); 7,26–
8(m) (4H: H5, H6, H7, H8).
IR(cm21): 3020-3070 m(C-Har); 2890–3000 m(-C-
Haliph); 1597vs (C55O); 1490s (C55C-C-O); 1179s
(C-O); 342s, 448s (Sn-C); 464 m, 310 m (Sn-O).
1H-NMR(d): 3,20(s) (12H: –CH2 of the benzyl
group); 6.7–6.9(s) (2H: H2, H3); 7.0–8.9(m) (32H:
ligand and Sn-Ph protons, undistinguishable).
(7) SnPh3L2: dark-red colour, Yield: 78%. Anal. Calcd. for
C28H20O3Sn (MW ¼ 523); C, 64,24; H, 3,82%. Found:
C, 63,98; H, 4,01%.
IR(cm21): 3064–3150 m(C-Har); 1613vs(C55O);
1553s(C55C-C-O); 1279s(C-O); 238 m, 277 m 451s(Sn-
C); 461vs 421 m(Sn-O).
RESULTS AND DISCUSSION
All the new triorganotin hydroxy-naphthoquinonates are
remarkably stable in light, air, or heat exposure. They are inso-
luble in water and moderately soluble in CHCl3, DMSO, and
DMF. They are dark-colored and mostly amorphous. Ligands
L1 and L3 react readily exhibiting instant color and texture
alterations while the reaction with L2 evolves slowly with a
gradual color change. This is probably due to a different
kinetic phenomenon and can be attributed to the structure of
the ligand (see Figure 1).
1H-NMR(d): 6,65(s):(1H:H3); 7–8,2(m) (19H-ligand
and Sn-Ph-protons, undistinguishable).
(8) SnBz3L2: dark red colour, Yield: 70%. Anal. Calcd. for
C31H26O3Sn (MW ¼ 565); C, 65,84; H, 4,60%. Found:
C, 66,05; H, 4,31%.
IR(cm21): 3000–3116 m(C-Har); 2900-3000 m(-C-
Haliph); 1596vs(C55O); 1509s(C55C-C-O); 1247s(C-O);
239 w, 410 w, 561 s(Sn-C); 340 m, 310 m(Sn-O).
1H-NMR(d): 2,40(s) (6H: -CH2 of the benzyl group);
6,7(s): (1H:H3); 7,2–7,9(m): (19H: ligand and Sn-Ph
protons, undistinguishable).
The compounds are generally synthesized by the follow-
ing two routes. The first involves the metathesis reaction
between the alkalimetal salt of the quinone and the corre-
sponding organotin halide, while the second involves the
interaction of the organotin hydroxide with the parent
quinone. Both synthetic pathways lead to the same final
products.
Naphthazarine derivatives (compounds 9-12): The
above method was applied using a 1:2,2 ratio (5,8-dihy-
droxy-1,4-naphthoquinone to triorganotin chloride).

NEW HYDROXY-NAPHTHOQUINONATO TRIORGANOTIN COMPOUNDS
769
The triorganotin derivatives formulated as R3Sn(m-L)
or R3Sn(m-L)SnR3 (R ¼Me, Bu, Ph, Bz; L ¼ hydroxy-
naphthoquinonato ligand) may be described as the corres-
ponding hydroxy-naphthoquinonate, in accordance with the
reaction stoicheiometry, the elemental analysis and spectro-
scopic results. The general reaction scheme is outlined in
Figure 2.
Hydroxy-naphthoquinones tend to coordinate to metal ions
by different modes according to Figure 3a. Our main goal has
been to determine whether the formation of a chelate ring will
occur or if the final product will exhibit a monodentate Sn-O
bonding. Spectroscopic data provide evidence on the formation
of a chelate ring responsible for the stabilization of the
triorgano-tin cation with the Sn central atom in a 5-coordinated
environment exhibiting distorted trigonal bipyramidal
geometry. Juglone and naphthazarine are coordinated to
central Sn (IV) via a phenolic and a quinoidal oxygen
FIG. 3. (a) The two probable coordination modes of the compounds studied.
The carbonyl oxygen lone pair is drawn in the tetrahedral species to account for
the bond in the trigonal bipyramidal one; (b) Proposed structures of the new
triorganotin naphthoquinonates.
forming 6-membered rings, while lawsone forms
a
5-membered chelate with the participation of its phenolic
oxygen and its neighboring quinoidal one (Figure 3b). The
R-substituents of the tin cation complete the trigonal bipyrami-
dal coordination environment.
IR Spectra
Several indications were obtained from a close comparison
between the spectra of the free ligands and those of related
complexes. The sharp bands in the region 3500–3000 cm21
obtained in the spectra of the free hydroxy-naphthoquinones
are assigned to the -OH stretching vibrations and disappear
in the spectra of the new compounds. The new broad weak
bands in the 3500–3300 cm21 region in complexes 2, 7 and
10 were attributed to the presence of some non-coordinated
water molecules in the samples.
Figure 4a depicts the optimized structure of trimethyltin
juglonato (compound 1). It is interesting to notice that, in
spite of the R-substituents attached to Sn and the steric
demands of the naphthoquinonic ring, the juglonato ligand
prefers to function as a chelating moiety giving out a five-
membered coordinated structure.
As expected for a R3SnO2 structural motif, the tin(IV) atom
bears a five-coordinate geometry with two of the R-substituents
occupying the equatorial positions of a trigonal bipyramide.
The third R-group is found on the apical site.
The strong broad band, centered in the donors at
ꢀ2600 cm21 due to the intramolecular hydrogen bond
(O-H. . .-O), disappears in the triorganotin derivatives. The
n(55C-H)stretching vibrations of the free ligands appear in
the region 3010–3060 cm21 and show no major spectral
changes upon complex formation. In the spectra of trimethyltin
complexes, the medium stretching vibrations of the methyl
groups were found in the region 2870–2990 cm21. In the
spectra of all tributyltin complexes, we assign the very strong
stretching vibrations of the n-Bu skeleton at 2956 cm21 for
the naCH3 and at 2925 cm21for the (naCH2) group respect-
ively. In the spectra of the tribenzyltin derivatives, the incor-
poration of the tribenzyl- group is indicated by the typical
pattern present in the region 2915–3100 cm21, accounting
for n(C-C-H) and n(C55C-H) stretching vibrations.
In a second step, the observation of the HOMO and LUMO
of L1 and its trimethyltin derivative (Figure 4b) suggest that the
trimethyltin fragment is not involved in the description of the
frontier orbitals and that the charge transfer remains located
on the conjugated ligand as anticipated in the case of molecular
chromophores (Figure 4c).
In the new complexes, both carbonyl vibrations are shifted
to lower wavenumbers. The n(C55O) stretching vibration of
the free ligands (C455O for L1, C155O for L2; C155O and
C455O for L3) appears as a strong intensity band at
FIG. 2. General reaction scheme: Presentation of the two alternative path- 1664 cm21 for juglone, 1675 cm21 for lawsone, and
1621 cm21 for naphthazarine, respectively. Upon complexa-
tion, the hydrogen-bonded carbony1 band of the free ligands
is bathochromically shifted to lower frequencies by 10–
80 cm21, depending on the complex corroborating the partici-
pation of the quinonic carbonyl (C55O) group in coordination
ways for the general preparation of triorganotin hydroxy-quinonates. The reac-
tion scheme applies to a mono-hydroxy-naphthoquinonate (HL); in the case of
bis-hydroxy-naphthoquinonates (H2L) the triorganotin to hydroxy-quinone
ratio is set to 2:1 and the compound should be referred to as (R3Sn)2(m-L).
The above synthetic route has been applied to trimethyl, tributyl, triphenyl
and tribenzyl derivatives.

770
V. VALLA ET AL.
FIG. 4. (a) Optimized structure of trimethyltin juglonato (compound1) computed at the B3LYP/LANL2DZ level of theory; (b) HOMO and LUMO orbitals
of trimethyltin juglonato (compound 1) at the B3LYP/LANL2DZ level of theory; (c) Molecular electrostatic potential (MEP) (isopotential surfaces of 1.00
a.u.) of juglonato trimethyltin (compound 1) at the B3LYP/LANL2DZ level of theory (white colour represents positive; black colour represents negative).
with tin. The shift in the positions of these bands is extensively spectra of tributyltin derivatives the Sn-Bu vibrations were
used as a diagnostic tool of the hydroxy-naphthoquinonate observed at ca. 610 and 510 cm21. New peaks in the region
anions’ coordination mode.
610–220 cm21 are assigned to v(Sn-O) and v(Sn-C)
The shifted carbonyl band activates the adjacent C55C stretching vibrations and also confirm the coordination. The
skeletal in-plane vibration of the conjugated aromatic ring n(Sn-Cl) band that appears in the range 270–290 cm–1 of the
and these activated C55C vibrations can be seen in the region spectra of the triorganotin chlorides, is absent in all complexes.
1509–l597 cm21, at lowered wavenumbers by 10–85 cm21
The above indicate the coordination of hydroxy-naphtho-
when compared with those of the free ligands. In the free quinones to tin via quinoidal and phenolic oxygen forming a
ligands spectra, the n(C-O) band appears in 1216 cm21 for 6-membered chelate ring in the case of L1 and L3 and a
the juglonato moiety, 1226 cm21 and 1142 cm21 for the 5-membered chelate for L2.
lawsonato and naphthazarinato moieties. Upon derivatization,
due to the electronic density delocalization of the system,
1H-NMR Spectra
a shift in higher frequencies by 30–65 cm21, is noticed. This
is consistent and indicative of the coordination of the expected integration and peak multiplicities but aromatic
The 1H NMR spectra of the new complexes show the
phenolic or quinonic oxygen with tin.
In the complexes spectra, we assign the strong or medium
signals undergo a more complex pattern upon chelation.
In compounds 3,4,7,8,11 and 12 a typical singlet at 1,5 d is
absorptions in the range 470–340 cm21 to symmetric and observed that is assigned to the water of CHCl3.
asymmetric v(Sn-O) modes, based on the literature available
on b-diketonato derivatives.[33,34] The n(-OH) band of
Ph3SnOH (3615 cm21) is not found in the spectra of the
In all the studied triorganotin (IV) hydroxy-naphthoquino-
nates the signal due to the hydrogen of phenolic or quinoidal
protons of the free ligands disappears suggesting coordination
products, indicating complex formation together with the with tin.
appearance of intense -C-H out-of-plane deformation bands
The chemical shifts of the signals for the methyl, butyl,
at ꢀ730 and ꢀ690 cm21. Moreover, in the spectra of the phenyl and tribenzyl group appear at the same position as in
triphenyltin derivatives, the symmetric and asymmetric the free organotins and have been assigned in the spectra of
stretching vibrations of the SnPh3 moiety, already described the complexes. More particularly, the Sn-CH3 moiety is
by Whiffen,[35] appear at ca. 450, 270 and 230 cm21
.
The triphenyltin compounds show the usual benzene ring
found at 0.56 d for L1, 0.60 d for L2 and 0.65 d for L3 as a
single signal in all three cases. The tributyltin (IV) derivatives
show at least two different sets of signals for the alkyl groups
absorptions. In particular, a band at ꢀ1077 cm21, which is
assigned to a C-H in plane deformation vibration, has been bonded to tin, which are typical for five-coordinate species.
shown to be characteristic of the phenyltin group. In the Another set of multiplets due to C-H protons is observed

NEW HYDROXY-NAPHTHOQUINONATO TRIORGANOTIN COMPOUNDS
771
between 0.80 and 2.0 d for these derivatives. In L1, the band is Thermal Studies
seen at 0.9–1.65 d. In L2 the same band is located in the region
The observations made during the acquirement of the
melting points have dictated the need to further investigate
the thermal profile of the new compounds. In any of the
cases, we did not notice a clear melting point. On the
contrary, multiple dissociations (even in temperatures around
1208C) are apparent, followed by texture and color alterations,
indicating that the new complexes undergo phase alterations
during their exposure to heat. The coordination course of
hydroxy-naphthoquinones used in this study further support
the above remarks, given their ability to exist in different oxi-
dation states, which lead to variable final structures. The tri-
phenyl tin naphthoquinonates were studied in a range up to
6508C, but up to this temperature, the total mass loss does
not exceed the 50% of the initial mass (Table 1). This
implies either that breakdown is not complete until this temp-
erature or that SnO2 formation occurs but organic residues
remain.
0.9–2 d(m). Similarly, we assign the multiplet in the area 0.8–
1.8 d for the tributyl derivative of naphthazarine. In the spectra
of the triphenyltin (IV) complexes, it is not possible to dis-
tinguish between signals due to aromatic protons of the
ligand and those linked to tin, but integration took their
presence into account. A complicated set of multiplets due to
the ligand aromatic and phenyl ring protons of the Sn-Ph3
moiety is observed in the range 7.2–7.8 d for compounds 3
and 11 and in the range 7–8.2 d for compound 7.
The -CH2 group of the tribenzyl tin moiety is present at
2.36 d as a singlet in compound 4, at 2.40 d also a singlet for
compound 8 and at 3.20 d corresponding to 12H for the
tribenzyltin derivative of naphthazarine.
The downfield shift of the signals for H3 and H6 for juglone,
H6 and H8 for lawsone and H2, H3, H6 and H7 for naphthazarine
are attributed to the involvement of the corresponding
quinoidal carbonyls and phenolic hydroxyls in complexation.
This trend is correlated with the formation of Sn-O bonds,
which generate a decrease of electron density on the
hydroxy-naphthoquinone ring.
Contrary to the belief that the Sn-C bond is stable at
temperatures up to 2008C, evidence for decomposition is seen
in forms of exothermic processes at much lower temperatures.
In the compounds studied herein, several bonds could cleave
at elevated temperatures e.g., Sn-C, Sn-0, C-C, C-0 and C-H.
However, the Sn-C bond must be considered to be the least ther-
mally stable. To support this, the IR spectrum of the residues, all
the typical bands of the hydroxy-naphthoquinones used are still
present, indicating the thermal stability of the ligands used. The
thermogravimetric (TG) analysis reveals that the decomposition
occurs as the temperature increases. The degradation patterns
are not differentiated according to the ligand but only according
to the R- substituent of the organotin moiety. The weight losses
observed due to thermal decomposition are quite close to the
calculated values. The slight differences in the values indicate
the error, which in any case remains within the acceptable
range of +3%.
In compound 2, a singlet at 6,7 d corresponding to two
protons provides evidence on the coordination and is similar
to the singlet at 6.7–6.9 d of compound 4. H3 and H6 of
L1 undergo the higher shifts because of the coordination
taking place in their neighbourhood. In the lawsone compounds
(5–8), we have been able to distinguish the H3 proton in the
trimethyl [6,35 d(s)], tributyl [6,5 d(s)], triphenyl [6,65 d(s)],
and finally to the tribenzyl [6,7 d(s)] derivative. As far as the
naphthazarine triorganotins are concerned, it is noteworthy
that the two protons of the quinonic ring (H2, H3) undergo a
noticeable shift and are located at the range 6,8–6,9 d(s) as
a singlet. The poor solubility of the compounds prevented
observation of the expected tin satellites.
TABLE 1
Thermal data of Ph3SnL1 and (Ph3Sn)2L3
TG/DTG
DTA( 8C)
Compound
Ph3SnL1
Step
1
Temp range ( 8C)
Mass loss % Found (Theor)
Moiety evolved
—
endo (2)
exo (þ)
90–125
—
100
125
230
—
—
2
200–250
275–360
.650 8C
12,80%(14,72%)
415% (39,38%)
—
Phenyl group
SnPh moiety
—
215
350
—
3
Residue
—
—
(Ph3Sn)2L3
1
75–135
1,5%(8,67%)
Phenyl group
100
—
—
135
240
2
220–250
275–340
.650 8C
12,5%
38%(39,41%)
—
—
SnPh3 moiety
—
215
325
—
3
Residue
—
—

772
V. VALLA ET AL.
The degradation pattern of the triphenyl tin derivative of the tributyltin derivatives, against five human tumour cell
juglone and lawsone (Ph3SnL1, Ph3SnL2) are similar and lines K562, MCF-7, HeLaS3, PC3, Hs 294T and one non-tumour
show a slight weight loss of ꢀ12% up to 2508C. In the human cell line MRC5. The compounds have been tested using
juglone derivative, two enotherms are observed at 1008C and the colorimetric SRB assay. The results are summarized in
1258C, followed by an exotherm at 2158C and an endotherm Table 2. Most of the compounds were found to be toxic not
at 2308C. None of these phenomena can be attributed to the only against tumour cells but, unfortunately, against normal
compounds’ melting and have therefore been assigned to the MRC5 cells as well. The new compounds were tested in the
typical for organotins, phase alteration processes. From the range of concentrations from 1028 to 1024 M and they were
temperature of 2508C and up, a rapid weight loss begins. At continuously present in the culture for 48 h.
3508C, an exotherm is noticed, corresponding to 40% weight
Regarding the profile of cytotoxicity, dose dependent
loss, which may be accounting for the SnPh moiety. The response was found for all cell lines except PC3 (prostate
gradual weight loss continues up to 6508C without any carcinoma cell line), i.e., cytotoxicity of compound increased
evidence of the juglone or lawsone degradation. The triphenyl with concentration, whereas in PC3 cell line the highest
derivative of naphthazarine (Ph3Sn)2L3, follows a three-step response was obtained with the smallest concentration of
decomposition pattern. Initially, we notice two distinct compounds. This is quite unusual but the same response was
endothermic phenomena at 1008C, and 1358C, respectively, obtained during the second experimentation with PC3 cells
with a weight loss around 7.5%, corresponding to the loss of and therefore we have concluded that this is a true response
one phenyl group. This is followed by an exotherm at 2158C and not an experimental mistake. Due to absence of dose-
and an endotherm at 2408C with no noticeable weight loss. response in PC3 cells, IC50 values were not calculated for the
This may indicate that within this temperature range, oxidative majority of the compounds. Additionally, we have noticed a
or thermal degradating processes are occurring. Between dose-dependent response for all cell lines. Most of the com-
2258C–3508C, a gradual but rapid weight loss occurs. The pounds at concentrations of 1025 and 1024M gave cytotoxicity
last step of the decomposition is characterized by an exother- above 80% regardless of the cell type. Another observation
mic phenomenon at 3258C, which shows a 38% weight loss is that there is no tissue specific cell response, thus cells of
and probably corresponds to the evolution of one SnPh3 different origin (leukemia cells, breast and cervix cancer
moiety. Up to 6508C, no evidence of naphthazarine degra- cells, normal lung fibroblasts) are sensitive to the tested
dation is present.
compounds.
HeLa cells appeared slightly more sensitive to all
compounds when compared to other cell lines. The triphenyl
and tributyl derivatives of naphthazarine are approximately
100 fold more potent than doxorubicin against HeLa cells.
Simultaneously, we notice that HeLa cells are almost twice
as sensitive as doxorubicin to triphenyltin lawsonato, while
they show response that is analogue to the reference
compound when treated with tributyltin juglonato. The
melanoma cells (Hs 294T) are known to be non-sensitive to
doxorubicin and we have acquired the same result for our
Cytotoxicity Studies
A useful organotin anti-tumor agent ought to possess alkyls
of low toxicity and high activity that will induce a subsequent
dealkylation in vivo and will therefore promote biological
activity. Such equilibria are found among the butyl and
phenyl derivatives and this is why they are popularly used in
the synthesis of experimental anti-tumor tin drugs.
Based on the preceding, we have measured the percent (%)
of cytotoxicity of the new triphenytin compounds and two of
TABLE 2
IC50 (mM) values (SRB assay) of some of the new hydroxy naphthoquinonato triorganotin derivatives
IC50, mM, 48 h, SRB
K562
MCF 7
HeLa
Hs 294T
MRC 5
Doxorubicina
Ph3SnL1
0.82
0.09
0.55
0.29
0.38
.100
1.19
2.28
5.08
0.06
4.67
9.87
0.04
0.05
29.85
0.58
0.32
0.0012
0.0004
0.0082
0.06
Bu3SnL1
19.97
0.12
1.46
23.33
0.28
0.59
Ph3SnL2
(Ph3Sn)2L3
(Bu3Sn)2-L3
.100
24.58
9.76
aDoxorubicin (Mol. Formula: C27H29NO11) is an antibiotic belonging to the anthracycline group, widely used in human cancer chemotherapy
in breast and pulmonary cancers. Its activity has been mainly attributed to its intercalation between the base pairs of DNA.

NEW HYDROXY-NAPHTHOQUINONATO TRIORGANOTIN COMPOUNDS
773
tributyltin derivatives, while at the same time a remarkable while at the same time, the binding affinity of tin to proteins or
sensitivity is expressed towards the triphenyltins. enzymes will change their interaction process with DNA,
High cytotoxicity against MRC5 cells is surely undesirable thereby affecting cell proliferation. Although the details of
and as a result, these compounds are not available candidates the mechanism of DNA-organotin interaction have not yet
for antitumor testing on tumor bearing animals. The presenting been clearly defined, there is solid evidence that the majority
data indicate that in most cases, the tributyltin derivatives are of organotins are toxic because they combine with an
less cytotoxic than the triphenyl derivatives.
enzyme inactivating it. Tin forms a bond with the active site
In our effort to justify the toxic profile of the tested that is too strong to be readily broken, thus preventing the
compounds, we have attributed a key influence to the enzyme from reacting with its substrates.
compounds’ limited solubility, which does not allow cellular
Organotins are known to interact in vitro with several
penetration of any kind. A successful anticancer agent ought to enzymes e.g., human aromatase and acetyltransferase,[40]
be soluble in non-toxic solvents to facilitate administration while there is evidence that they enhance human CG secretion
either to the bloodstream or to the alimentary tract. Triorganotins as well.[41] Given that naphthoquinones are also involved in the
are reported to transport organic anions across the phospholipid in-vivo biosynthesis of estrogens,[42] a proposed toxicity mech-
bilayer through an exchange diffusion mechanism with anism may involve the combinatorial effect of the inhibitory
chloride but their membrane permeability potential is in strict action of an enzyme like cytochrome P-450 by the tin moiety
line with the ligand they carry.[36] In our case, the ligands are acting as an endocrine-disrupting agent along with the simul-
bulky enough to prevent the new compounds from entering a cell. taneous activity of the naphthoquinone metabolites—semiqui-
A definite correlation also exists between cytotoxicity and none radicals—that will produce hydroxyl radicals, powerful
lipophilicity, with highly hydrophilic or lipophilic agents oxidizing agents that are responsible for damaging among
being far less toxic when compared to the intermediate others, the estrogen biosynthesis. This synergistic effect
species. We presume therefore, that since the toxicity of the might be able to explain the higher sensitivity of HeLa cells
parent R3SnX analogues are higher than that of R2SnX2 or given that the cervix is one of the organs where steroids are
R2SnX L2 (where L ¼ bidentate ligands) compounds,[37] this synthesized. This might also interpret the peculiar response
results in a highly toxic profile for their deriving compounds of PC3 cells if we take into consideration the ability of
as well.
organotins to interact with 5-a-reductase (the enzyme that
The other factor decisively affecting the toxicity in this case catalyses the testosterone biosynthesis) as well as the
is the nature of the ligands. Early enough, d’ Arcy-Doherty,[38] inhibitory effect that semiquinone radicals may have in its
has shown that juglone is more toxic than lawsone to rat hep- intermediate stages.
atocytes by an order of magnitude which has been attributed
Nevertheless, both the stability and solubility of the new
to the potential of these compounds to induce conditions of oxi- triorganotins should be accounted when proposing this mech-
dative stress and depletion of reduced GSH. The cytotoxicity of anism. Additionally to the above, we believe that the nature
these quinones is enhanced upon metal complexation. For of the ligand environment in combination to the character of
example, the iron complexes of juglone are more toxic than tin in the coordination process also influences the cytotoxicity
the ones of lawsone indicating that the toxicity mechanisms pattern. Based on previous studies on structure-/activity corre-
differ. It has been suggested that the depletion of intracellular lation of organotins (IV),[43,44] we have attributed a role on the
glutathione by lawsone is enzyme mediated whereas in the availability of coordination positions at tin. The cytotoxic
case of juglone, the direct chemical reaction with glutathione activity of triorganotins (IV) is dependent on their geometric
is responsible for the depletion. The mechanism of toxicity behavior when in solution. The more active tetrahedral struc-
of juglone involves the formation of its corresponding naphtho- tures are bound to increase their coordination number
semiquinone, active oxygen species and redox cycling. No through O, S, or N donors while the five coordinated species,
such evidence is available for lawsone, due to its very low which is the case herein, cannot undergo further coordination
one-electron reduction potential (E1/7-415 mV), which offers and are expected to exhibit their activity as they stand. The
a very poor substrate for reduction to a semiquinone by preceding remarks combined with the proposed structure of
cellular reductases. As far as the effect of hydroxyl substitution the new compounds, should justify their toxic profile.
on the toxicity of 1,4-naphthoquinones is concerned, the
sequence of potency is 5,8-dihydroxy-1,4-naphthoquinone .5-
hydroxy-1,4-naphthoquinone ,2-hydroxy-1,4-naphthoquinone
REFERENCES
as Babich[39] showed in his experiments with HepG2, and
1. O’Brien, P. J. Molecular mechanisms of quinone cytotoxicity.
BALB/cell lines.
Chem. Biol. Interact. 1991, 80, 1–41.
Based on the above, the toxic profile in the case herein
2. Yee, S. B.; Pritsos, C. A. Comparison of oxygen radical gener-
might in part result from the dissociation of the complexes in
ation from the reductive activation of doxorubicin, streptonigrin,
the cell culture media, resulting in the production of semiqui-
nones or free radicals that will interfere with DNA replication
and menadione by xanthine oxidase and xanthine dehydrogenase.
Arch. Biochem. Biophys. 1997, 347 (2), 235–241.

774
V. VALLA ET AL.
3. Martin, R. B. 2-amino-1,4-naphthoquinone as a model compound 20. Christianopoulou, M.; Ecateriniadou, L.; Sarris, E. Evaluation of
for actinomycins. Acta Biochim. Biophys. 1964, 91, 642–644.
4. Moore, H. W.; Czerniak, R. Naturally occurring quinones as
potential bioreductive alkylating agents. Med. Res. Rev. 1981,
1 (3), 249–280.
the antimicrobial activity of a new series of hydroquinone
chelates of some transition metals. Eur. J. Med. Chem. 1986,
21 (5), 385–390.
21. Papageorgiou, V. P.; Christianopoulou, M.; Boutis, L.;
Papageorgiou, A.; Tsipis, C. Synthesis and antitumor activity of
a novel diplatinum complex of the binucleating naphthazarinato
ligand. Inorg. Chim. Acta 1986, 124 (4), 203–206.
22. Bakola-Christianopoulou, M.; krivos, P. D.; Ecateriniadou, L. B.;
Sarris, K. On the anti-bacterial activity of non-charged
m-naphthazarinato compounds. Eur. J. Med. Chem. 1988,
23 (1), 87–90.
5. Papageorgiou, V. P.; Assimopoulou, A. N.; Couladouros, E. A.;
Hepworth, D.; Nicolaou, K. C. The chemistry and biology of
alkannin, shikonin, and related naphthazarin natural products.
Angew Chem. Int. Ed. 1999, 38 (3), 270–301.
6. Hatzigrigoriou, E.; Papadopoulou, M. V; Shields, D. 2-Alkylsulfo-
nyloxy-3-hydroxy-1,4-naphthoquinones: A novel class of radio-
and chemosensitizers of V79 cells. Oncol. Res. 1993, 5, 29–36.
7. Asche, C. Antitumour quinones. Mini Rev. Med. Chem. 2005, 23. Lialiaris, T.; Mourelatos, D.; Boutis, L.; Papageorgiou, A.;
5 (5), 449–467.
Christianopoulou, M.; Papageorgiou, V.; Dozi-Vassiliades, J.
Comparative study on cytogenetic effects by diplatinum com-
plexes of the ligands of naphthazarine and squaric acid in
human lymphocytes. J. Pharmacol. Exp. Therap. 1989, 251 (1),
368–371.
8. Inbaraj, J. J.; Chignell, C. F. Cytotoxic action of juglone and
plumbagin: a mechanistic study using HaCaT keratinocytes.
Chem. Res. Toxicol. 2004, 17, 55–62.
9. Paulsen, M. T; Ljungman, M. The natural toxin juglone causes
degradation of p53 and induces rapid H2AX phosphorylation 24. Gielen, M.; Willem, R.; Biesemans, R.; Boulam, M.; Khloufi, A.;
and cell death in human fibroblasts. Toxicol. Appl. Pharmacol.
2005, 209 (1), 1–9.
Elde Vos, D. Exceptionally high in vitro antitumor activity of sub-
stituted triphenyltin benzoates including salicylates against a
human mammary tumor, MCF-7, and a colon carcinoma, WiDr.
Appl. Organometal. Chem. 1992, 6 (3), 287–291.
10. Wang, H.; Mao, Y.; Chen, A. Y. Stimulation of topoisomerase II-
mediated DNA damage via a mechanism involving protein thiola-
tion. Biochemistry 2001, 40 (11), 3316–3323.
25. Gielen, M. Tin-based antitumour drugs. Coord Chem. Rev. 1996,
151, 41–51.
11. Chao, S. H.; Greenleaf, A. L.; Price, D. H. Juglone, an inhibitor of
the peptidyl-prolyl isomerase Pin1, also directly blocks transcrip- 26. Gielen, M.; Biesemans, M.; de Vos, D.; Willem, R. Synthesis,
tion. Nucleic Acids Res. 2001, 29, 767–773.
12. Varga, Z.; Bene, L.; Pieri, C.; Damjanovich, S.; Gaspar, R. Jr. The
effect of juglone on the membrane potential and whole-cell Kþ
characterization and in vitro antitumor activity of di- and triorga-
notin derivatives of polyoxa- and biologically relevant carboxylic
acids. Inorg. Biochem. 2000, 79, 139–145.
currents of human lymphocytes. Biochem. Biophys. Res. 27. Gielen, M. Organotin compounds and their therapeutic potential:
Commun. 1996, 218 (3), 828–832.
13. Habbal, O. A.; Al-Jabri, A. A.; El-Hag, A. H.; Al-Mahrooqi, Z. H.;
Al-Hashmi, N. A. In-vitro antimicrobial activity of Lawsonia
A report from the organometallic chemistry department of the free
university of Brussels. Appl. Organometal. Chem. 2002, 16,
481–494.
inermis Linn (henna). A pilot study on the Omani henna. Saudi 28. Gielen, M.; Biesemans, M.; Willem, R. Organotin compounds:
Med. J. 2005, 26 (1), 69–72.
14. Mikhaeil, B. R.; Badria, F. A.; Maatooq, G. T. Antioxidant and
from kinetics to stereochemistry and antitumour activities. Appl.
Organometal. Chem. 2005, 19, 440–450.
immunomodulatory constituents of henna leaves. Z Naturforsch 29. Pellerito, L.; Nagy, L. Organotin(IV)nþ complexes formed with
[C]. 2004, 59 (7–8), 468–476.
15. Salunke-Gawali, S.; Rane, S. Y.; Puranik, V. G; Gugand-
Duhayon, C.; Varret, f. Three dimensional hydrogen-bonding
biologically active ligands: equilibrium and structural studies,
and some biological aspects. Coord. Chem. Rev. 2002, 224,
111–150.
network in a copper complex of 2-hydroxy-1,4-naphthoquinone: 30. Brown, M.A.; McGarvey, B. R.; Ozarowski, A.; Tuck, D. G.
Structural, spectroscopic and magnetic properties. Polyhedron Studies of organotin(IV)-orthoquinone systems. J. Organometal.
2004, 23 (16), 2541–2547. Chem. 1998, 550 (1–2), 165–172.
16. Bodini, M. E.; Bravo, P. E.; Aranciba, V. Voltammetric and spec- 31. Sisido, K.; Takeda, Y.; Kinugawa, Z. Direct synthesis of organto-
troscopic study of the iron(II) complexes with the semiquinone of
2-hydroxy-1,4-naphthoquinone (lawsone) in aprotic medium.
Polyhedron 1994, 13 (3), 497–503.
tin compounds. I. Di and tri-benzyltin chlorides. J. Am. Chem.
Soc. 1960, 83, 538–541.
32. Skehan, P.; Storeng, R.; Scudiero, D.; Monks, A.; McMahon, J.;
Vistica, D.; Warren, J. T.; Bokesch, H.; Kenney, S.; Boyd, M. R.
New colorimetric cytotoxicity assay for anticancer-drug screening.
J. Natl. Cancer Inst. 1990, 82 (13), 1107–1112.
17. El-Hendawy, A. M. Complexes of lawsone with uranium, molyb-
denum, ruthenium and osmium, and their use as organic oxidants.
Polyhedron 1991, 10 (20–21), 2511–2518.
18. Garge, P.; Padhye, S.; Tuchagues, J. Iron(II) complexes of ortho- 33. Marchetti, F.; Pettinari, C.; Cingolani, A.; Pettinari, R.; Rossi, M.;
functionalized para-naphthoquinones 1. Synthesis, characterization,
electronic structure and magnetic properties. Inorg. Chim. Acta.
1989, 157 (2), 239–249.
Caruso, F. Organotin(IV) derivatives of novel b-diketones: Part
V. Synthesis and characterization of di- and triorganotin(IV)
derivatives of 4-acyl-5-pyrazolones modified in position 3
of the pyrazole. Crystal structure of (1,3-diphenyl-4-benzoyl-
pyrazolon-5-ato)triphenyltin(IV). J. Organomet. Chem. 2002,
645 (1–2), 134–145.
19. Christianopoulou, M. Synthesis and studies of some bivalent
metal chelates of 1,2-dihydroxy-9,10-anthracenedione and
5-hydroxy-1,4-naphthalenedione. Polyhedron 1984, 3 (6), 7–29.

NEW HYDROXY-NAPHTHOQUINONATO TRIORGANOTIN COMPOUNDS
775
34. Mahon, M. F.; Molloy, K. C.; Omotowa, B. A.; Mesubi, M. A. 42. Bolton, J. L.; Pisha, E.; Zhang, F.; Qiu, S. Role of quinoids in
estrogen carcinogenesis. Chem. Res. Toxicol. 1998, 11 (10),
1113–1127.
Organotin(IV) derivatives of acylpyrazol-5-ones. J. Organometal.
Chem. 1996, 511, 227–237.
43. Szorcsik, A.; Nagy, L.; Gajda-Schrantz, K. Structural studies on
organotin (IV) complexes formed with ligands containing fS, N,
Og donor atoms. J. Radioanal. Nucl. Chem. 2002, 252 (3), 523–530.
44. Nath, L. M.; Pokharia, S.; Yadav, R. Organotin(IV) complexes of
amino acids and peptides. Coord. Chem. Rev. 2001, 215 (1),
99–149.
35. Whiffen, D. H. Vibrational frequencies and thermodynamic prop-
erties of fluoro-, chloro-, bromo-, and iodo-benzene. J. Chem. Soc.
1956, 1350–1355.
36. Ortiz, A.; Teruel, J. A.; Aranda, F. J. Effect of triorganotin com-
pounds on membrane permeability. Biochim. Biophys. Acta.
2005, 1720 (1–2), 137–142.
45. Gaussian 98; Revision, A.11. Frisch, M. J.; Trucks, G. W.;
Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A.;
Stratmann, R. E., Jr.; Burant, J. C.; Dapprich, S.; Millam, J. M.;
Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.;
Tomasi, J.; Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.;
Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J.;
Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.;
Salvador, P.; Dannenberg, J. J.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Cioslowski, J.; Ortiz, J. V.;
Baboul, A. G.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.;
Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.;
Nanayakkara, A.; Challacombe, M.; Gill, P. M.W.; Johnson, B.;
Chen, W.; Wong, M. W.; Andres, J. L.; Gonzalez, C.;
Gordon, M.; Replogle, E. S.; Pople, J. A.; Gaussian, Inc.;
Pittsburgh, PA, 2001, Gaussian 98 program.
37. Sherman, L. Relationship of cytotoxic groups in organotin
molecules and the effectiveness of the compounds against
leukaemia. Appl. Organometal. Chem. 1988, 2 (1), 65–72.
38. d’Arcy Doherty, M.; Rodgers, A.; Cohen, G. M. Mechanisms of
toxicity of 2- and 5-hydroxy-1,4-naphthoquinone; absence of a
role for redox cycling in the toxicity of 2-hydroxy-1,4-
naphthoquinone to isolated hepatocytes. J. Appl. Toxicol. 1987,
7 (2), 123–129.
39. Babich, A.; Stern, A. In vitro cytotoxicities of 1,4-naphthoqui-
none and hydroxylated 1,4-naphthoquinones to replicating cells.
J. Appl. Toxicol. 1993, 13(5), 353–358.
40. Cooke, G. M. Effect of organotins on human aromatase activity in
vitro. Toxicol Lett. 2002, 126 (2), 121–130.
41. Osada, S.; Nishikawa, J.; Nakanishi, T.; Tanaka, K.; Nishihara, T.
Some organotin compounds enhance histone acetyltransferase
activity. Toxicol. Lett. 2005, 155 (2), 329–335.