# Synthesis, Characterization, and Biological Studies of Organotin(IV) Derivatives with o- or p-hydroxybenzoic Acids

Authors: Mohamed A. Abdellah; Sotiris K. Hadjikakou; Nick Hadjiliadis; Maciej Kubicki; Thomas Bakas; Nikolaos Kourkoumelis; Yannis V. Simos; Spyros  Karkabounas; Mirela M. Barsan; Ian S. Butler
Journal: Bioinorganic Chemistry and Applications
 (2009)

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## Abstract

Organotin(IV) complexes with o- or p-hydroxybenzoic acids (o-H2BZA or p-H2BZA) of formulae [R2Sn(HL)2] (where H2L = o-H2BZA and R = Me- (1), n-Bu- (2)); [R3Sn(HL)] (where H2L = o-H2BZA and R = n-Bu- (3), Ph- (4) or H2L = p-H2BZA and R = n-Bu- (5), Ph- (6)) were synthesized by reacting a methanolic solution of di- and triorganotin(IV) compounds with an aqueous solution of the ligand (o-H2BZA or p-H2BZA) containing equimolar amounts of potassium hydroxide. The complexes were characterized by elemental analysis, FT-IR, Far-IR, TGA-DTA, FT-Raman, Mössbauer spectroscopy, H1, S119n-NMR, UV/Vis spectroscopy, and Mass spectroscopy. The X-ray crystal structures of complexes 1 and 2 have also been determined. Finally, the influence of these complexes 1–6 upon the catalytic peroxidation of linoleic acid to hydroperoxylinoleic acid by the enzyme lipoxygenase (LOX) was kinetically studied and the results showed that triorganotin(IV) complex 6 has the lowest IC50 value. Also complexes 1–6 were studied for their in vitro cytotoxicity against sarcoma cancer cells (mesenchymal tissue) from the Wistar rat, and the results showed that the complexes have high activity against these cell lines with triphenyltin((IV) complex 4 to be the most active one.


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## Body

## 1. Introduction

Organotin
compounds have many important applications and uses [1, 2]. Commercially, organotin
compounds are used as industrial and agricultural biocides because they have
high antifungal properties [3, 4]. The in
vitro fungicidal or antibacterial properties of organotins have been found
to exhibit the general order of activity: RSnX3<R2SnX2<R4Sn≪R3SnX, with the anionic X group to exert
little influence on activity [5, 6]. The combination of two biologically active
entities, however, in the same molecule could enhance their activity [7]. For
example, triphenyltin(IV) derivatives of phthalic acid and salicaldehyde have
significant activity toward a range of fungi [8, 9]. Recently, interests in organotin(IV)
carboxylates are increasing due to their possible medical uses as antitumor agents
[10]. For example, the fluoro-substituted carboxylate ligands with di- and
triorganotins produced several antitumor active compounds [11]. Hubert et al.
concluded that antitumor active tin compounds possess available coordination positions around
tin atom and also have relatively stable ligand-tin bonds with low hydrolytic
decomposition [12]. Thioamides-organotin complexes, on the other hand, have
shown high antitumor activity, which is rather related to the ligand type and
not to the geometry
of the compounds [13–17]. Given
that the antitumor action of Sn(IV) compounds may not be due to their direct
interaction with DNA constituents [18–22], their
reaction with enzymes like lipoxygenase
is always of interest in the attempt to elucidate their mechanism of
action [13–17]. This antitumor activity of the organotin complexes follows the same order of
lipoxygenase inhibition,
an enzyme taking part in the inflammation mechanism and tumor genesis [13–17].With the aim to prepare new organotin(IV-)-based antitumor
compounds of o- or p-hydroxybenzoic acid (Schemes1 (I) and (II), resp.), the synthesis of six
organotin complexes of formulae [R2Sn(HL)2] (where H2L = o-H2BZA and R = Me- (1), n-Bu- (2)) and [R3Sn(HL)], (where H2L = o-H2BZA
and R = n-Bu- (3), Ph- (4) or H2L = p-H2BZA, and R = n-Bu- (5), Ph- (6)) and their characterization by spectroscopic techniques (IR,
Raman,H1-NMR, mass Spectra, S119mn Mössbauer, UV/Vis), elemental
analysis and X-ray diffraction have been carried out. The inhibition caused by these
complexes toward the oxidation of linoleic acid to hyperoxolinoleic acid by the
enzyme lipoxygenase (LOX) follow the order 6>4>5>2>1>3 and compared with their
in vitro antitumor activity against sarcoma cells, where the order is 4>6>5≫3=2≫1. Therefore, triorganotin compounds inhibit
stronger lipoxygenase and show higher activity against sarcoma cells than
diorganotins.Scheme 1


## 2. Results and Discussion

### 2.1. General Aspects

Organotin(IV) complexes1–6 have been synthesized by reacting a
methanolic solution of organotin chloride with an aqueous solution of the
appropriate amounts of 2- or 4-hydroxybenzoic acid containing an equimolar
amount of potassium hydroxide as shown in (1) and (2):(1)R2SnCl2+2H2L+2KOH→MeOH/H2OR2Sn(HL2)+2KCl+2H2OH2L=o-H2BZAandR=Me-(1),n-Bu-(2)(2)R3SnCl+H2L+KOH→MeOH/H2OR3Sn(HL)+KCl+H2OH2L=o-H2BZAandR=n-Bu-(3),Ph-(4)orH2L=p-H2BZAandR=n-Bu-(5),Ph-(6).Complexes1-2 were
prepared with an alternative method of the one used previously for the
synthesis of these complexes [23, 24].
Complexes 1–6 are air-stable powders soluble in methanol,
ethanol, and DMSO solvents. Crystals
suitable for X-ray analysis were obtained by slow evaporation of
methanol/acetonitril solutions for compounds 1 and 2.


### 2.2. Thermal Analysis

The TGA/DTA data curves for
complexes1-2 show that they decompose generally in one stage. Thus, thermal analysis in
flowing nitrogen shows that complex 1 decomposes between 125 and 315°C with 72% mass loss which corresponds to the methyl
groups of the metal and the ligand molecules (the calculated mass loss is 72%),
compound 2 decomposes between 35 and
490°C with 74% mass loss due to the butyl groups of the metal and the ligand
molecules (the calculated mass loss is 76.50%) (Scheme 2).Scheme 2The TGA/DTA data in flowing nitrogen data
curves for complexes3–6 show that they
decompose generally in two stages. The first stage of decomposition of compound 3 lies between 20 and 255°C that
corresponds to 13% mass loss of one of the metal butyl groups (the calculated
mass loss is 13%), compound 4 decomposes between 35 and 215°C with 16% mass loss of one of the metal phenyl
groups (the calculated mass loss is 16%), compound 5 decomposes between 25 and 255°C that corresponds to 13% mass loss
of one of the metal butyl groups (the calculated mass loss is 13%), and compound 6 decomposes between 25 and 177°C with
15% mass loss of one of the metal phenyl groups (the calculated mass loss is 16%).
The second stage of decomposition is between 255 and 400°C in case of 3 which
corresponds to 44% mass loss of the ligand (o-hydroxybenzoic acid) and another
metal butyl group (the calculated mass loss is 45%), between 215 and 500°C (4)
corresponding to 43% mass loss of the ligand (o-hydroxybenzoic acid) and
another metal phenyl group (the calculated mass loss is 42%), compound 5 decomposes between 255 and 412°C which
corresponds to 45.60% mass loss of the ligand (p-hydroxybenzoic acid) and
another metal butyl group (the calculated mass loss is 45%), and compound 6 decomposes between 177 and 435°C with
42% mass loss which corresponds to the ligand (p-hydroxybenzoic acid) and another
metal phenyl group (the calculated mass loss is 42%) (Scheme 2).


### 2.3. Spectroscopy

Vibrational spectroscopy: characteristic
infrared bands of the complexes 1–6 and the
ligands are listed in Table 1.Table 1
Characteristic vibration bands (cm−1) of the o- or p-HBZA ligands
and their complexes 1–6.
CompoundInfraredRamanRef.v(OH)v(CH)vas, vsy(COO)v(Sn-C)v(Sn-C)v(Sn-O)v(Sn-C)o-H2BZA32821656, 1324[25]o-NaHBZA1577, 1373[26]134672817-27051631, 1388580, 536446——234502928-28691628, 1419562, 530435——334502957-23641633, 1352564, 538445——4344730631636, 1356600, 533420——p-H2BZA3382—1687, 1360————[27]p-NaHBZA33821547, 1416[27]534392958-29221613, 1351606, 5094574105206343330681615, 1431569, 511438450618The IR spectra of the
complexes1–6 show vibrational
bands at 3467 1, 3450 2, 3450 3, 3447 4, 3439 5, and 3433 6 cm−1, which are assigned to v(phenolic OH) [28, 29]. The corresponding vibrational bands v(O-H) of the free ligands appear at
3282 and 3382 cm−1 for o-H2BZA or p-H2BZA,
respectively [25, 27].Thevas(COO−) vibration of the free
ligand appears at 1656 cm−1 while the vs(COO−)
at 1324 cm−1 for o-H2BZA [25], and the vas(COO−)
vibration of p-H2BZA ligand appears at 1687 cm−1 while
the vs(COO−) at 1360 cm−1 [27]. The
corresponding vas(COO−) vibrations are observed at 1631 1, 1628 2, 1633 3, 1636 4, 1636 5, and 1617 6 cm−1,
respectively. The bands at 1388 1,
1419 2, 1352 3, 1356 4, 1419 5, and 1347 6 cm−1 are assigned to vs(COO−).
The Δv [vas(COO−)-vs(COO−)] difference
values of the free ligands are (332 cm−1 for o-H2BZA and 327 cm−1 for p-H2BZA) versus the corresponding values Δv for
complexes 1–6 (243 1,
209 2, 281 3, 280 4, 217 5, and 270 6 cm−1,
resp.) support the coordination of the ligand to the metal center through the
carboxylic acid group. Monodentate coordination of the –COO− group of the ligand to metal ions results in significantly higher Δv [vas(COO−)-vs(COO−)] difference values
than those observed for the ionic compounds of the ligand [30], while when the
ligand chelates, the Δv [vas(COO−)-vs(COO−)]
is considerably smaller than that observed for its ionic
compounds. For asymmetric bidentate coordination, the values are in the range of
monodentate coordination [30]. When
the –COO− group bridges metal ions, the Δv [vas(COO−)-vs(COO−)]
value is higher than that of the chelated ions and nearly the
same as that observed for ionic compounds [30]. In our case, the Δv
[vas(COO−)-vs(COO−)] values of the
ionic compounds of the o-NaHBZA and p-NaHBZA ligands (sodium salts) are 205 cm−1 and 131 cm−1, respectively [26]. Therefore, in the diorganotin
complexes 1 and 2, where higher Δv values were observed (243 1 and 209 2 cm−1), an asymmetric bidentate coordination
of the ligand to the metal ion is expected (see crystal structure, Mössbauer
spectra).The same is true in the case of triorganotin complexes 3–6 with significantly
higher Δv values
than the corresponding ones of the sodium salts of the ligands (281 3,
280 4, 217 5, and 270 6 cm−1), indicating
clearly an asymmetric bidentate coordination mode of the ligands and suggesting trigonal bipyramidal
geometry for complexes 3–6 in the
solid state in agreement with the results of Mössbauer and S119n-NMR
spectra.Bands at 425–455 cm−1 have been assigned to the stretching vibration of Sn-O bonds. The
corresponding ones for complexes 1–6 are at 446 1, 435 2, 445 3, 420 4, 458 5, and 450 cm−16 [25]. Bands at 600–500 cm−1 have been assigned to the antisymmetric and symmetric vibrations of Sn-C bond.
The corresponding ones for complexes 1–6 are at 580,
536 1, 562, 530 2, 564, 538 3, 600, 533 4, 610, 509 5, and 569, 511 6 [13–17]. No ν(Sn-Cl) vibration bands at 282
and 221 cm−1 are observed in the far FT-IR of the complexes [13].S119mn
Mössbauer spectroscopy: solid state, S119mn Mössbauer
spectroscopic data of complexes 1-2 and 4–6 are
given in Table 2.Table 2
S119n Mössbauer spectroscopic data for complexes 1–6 at 80 K.
Moleculeδ   (mm s−1)Δ   (mm s−1)C-Sn-C(°) angles*Area
(%)δ   (mm s−1)Δ   (mm s−1)C-Sn-C(°) angles*Area
(%)11.223.09130561.333.651484421.313.53143291.563.681497141.342.93100———51.242.48100———61.443.18100———T*he
C-Sn-C angles (θ) are calculated from the equation following Δ=4{R}[1−3cos2θ⋅sin2θ]1/2, where the
partial quadrupole splitting (p.q.s.),
mm⋅s−1, used
in the calculations was
([R]-[Cl])oct=−1.03  (R = Me, Bu) [31].The isomer shifts values of complexes1–6 are in
the range of δ 1.22 to 1.56 mm s−1 (Table 2), indicating that tin is in
the (4+) oxidation state in all cases [2, 32, 33]. The spectra of diorganotin(IV)
complexes 1–2 consist of
two symmetrical Lorentzian doublets which indicate the presence of two tin
atoms in different chemical environments
with the same ratio 1:1 (56: 44% 1 and 29: 71% 2, resp.). This may be due to the
presence of two different isomers in the unit cells with variable bond
distances. The quadrupole splitting values (Δ) of complexes 1-2 are 3.09 mm s−1 and 3.65 mm s−1 for 1 and 3.53 mm s−1 and 3.68 mm s−1 for 2, suggesting distorted trans-R2 octahedral geometry (2.4–5.5 mm s−1)
[2, 32, 33] in the solid state in agreement with X-ray structures. The calculated
C-Sn-C angles (°) from Mössbauer spectra [31] for the compounds 1 and 2 (Table 2) are 130° for the highest occurring isomer (56%)
and 143° for the lowest occurring isomer (44%) in case of 1 and 148 (29%), 149° (71%) in case of 2. The values of C-Sn-C
angles found from X-ray analysis at 293 K are 138.4(4)° (1)
and 144.0(3)° (2), respectively (see crystal structures).The spectra of the triorganotin(IV) complexes4–6 consist of
one symmetrical Lorentzian doublet which indicates the presence of one tin
atom. The quadrupole splitting values in case of complexes 4–6 (Δ) are 2.93 mm s−14, 2.48 mm s−1 for 5, and 3.18 mm s−16 suggesting eq-R3 trigonal bipyramidal geometry around tin
atom (2.5–4.0 mm s−1)
[2, 32, 33] in solid state in agreement with the geometry concluded from S119n-NMR
spectra.


### 2.4. NMR Spectra

H1-NMR
spectra of complexes 1–6 showed a
single resonance signal at 10.18 1, 10.16 2, 9.91 3, 9.95 4,
9.87 5, and 9.89 6 ppm, respectively, due to the hydroxyl proton
of the ligands (o-H2BZA or p-H2BZA) [34], suggesting that
the OH groups are not involved in bonding with the tin atom. The two doublet signals
at 7.83-7.79 and 6.82-6.791, 7.69-7.65 and 6.75-6.722, 7.72-7.69
and 6.73-6.703, 7.81-7.78 and 6.69-6.654, and 7.75-7.71 and
6.76-6.736 ppm are assigned to the protons of the phenyl group of the
ligands a and b, respectively (Scheme 1) [34]. In case of complex 1, the single signal at 0.83 ppm is assigned to the protons of the methyl
group of the metal.In case of complexes6 and 7,
S119n-NMR spectra were
also recorded. S119n-NMR spectra showed resonance signals at −20.0 (6)
and −212.0 (7) ppm, respectively. Although the shift ranges are somewhat
dependent on the nature of the substituents at the tin atom the δ(S119n)
values (in ppm) for R3Sn(IV) complexes with five-coordinated Sn vary
from +25 to −329 ppm [33]. Thus, the tin(IV) atoms are five coordinated in case
of complexes 5 and 6, and therefore the expected geometry
arrangement around triorganotin(IV), in solution, is suggested as trigonal
bipyramidal.Crystal and Molecular Structures of [(CH3)2sn(OOCC6H4OH)2] (1) and [(n-C4H9)2sn(OOCC6H4OH)2] (2)
The crystal
structures of complexes1 and 2 had been determined previously, at
193 and 295 K with R% values of 6.4 and 3.8, respectively [23, 24]. However, we
redetermined the structures here of both 1 or 2 complexes at room temperature
(293 K), with R% 2.18 and 4.83, respectively, for comparison and in order to
investigate the influence of the temperature on their structures [33]. ORTEP
diagrams of complexes 1 and 2 are shown in Figures 1 and 2.
Compounds1 and 2 are covalent
monomers in the solid state with a distorted octahedral geometry around the
metal ion. Table 3 summarizes Sn-O and other selected bond distances and angles
found for organotin complexes reported here and elsewhere [23, 24]. They differ
only slightly.
The Sn-O bond
distances are 2.1060(18), 2.5147(15), 2.1079(15), and 2.577Å in 1; 2.104(4), 2.564, 2.121(4), and 2.632 Å in 2 showing an asymmetric bidentate coordination of the ligand to the Sn
atom, as concluded in the
IR Section 2.3. The Sn-O bond distances found in 1 and 2 are in agreement with the corresponding bond lengths found in (CH3)2Sn(2,4,5-TF-3-MBA)2 (2,4,5-TF-3-MBA = 2,4,5-trifluoro-3-methoxybenzoic
acid) 2.115(6)–2.656(6) Å [11],
in (n-C4H9)2Sn(2,4,5-TF-3-MBA)2, 2.128(3)–2.562(3) Å [11],
and in (n-C4H9)2Sn(2,4-DHB)2 (2,4-DHB = dihydroxybenzoato) 2.110(4)–2.559(4) Å [35].
The O-Sn-O-C torsion angles found in complexes1 and 2 were O271-Sn1-O171-C17 = 178.46(14)° for 1 and (O272-Sn1-O172-C17 =
177.6(4)° for 2. This indicates the almost coplanar arrangement of the
two ligands with the tin atom. Thus, the conformation around the tin atom is trans-C2, cis-O2, cisO2. The value of the C-Sn-C angle (C31-Sn1-C41 =
138.44(11)° in 1 and C31-Sn1-C41 = 143.8(2)°in 2) implies
distortion of the octahedral structure.
In both complexes1 and 2 there are
intramolecular hydrogen bonding interactions (O12⋯O172 = 2.620(2) Å and O22⋯O272 =
2.605(2) Å for 1, O11⋯O171 = 2.621(7) Å and O21⋯O271 =
2.622(5) Å in case of 2)
stabilizing the structures. Interesting strong Sn⋯O bonding interaction
(Sn1⋯O12 = 3.463 Å in case of 1 and
Sn1⋯O21 = 3.620 Å in case of 2) leads to the formation of
dimers in both cases (Figures 1 and 2) which may
affect the distortion of the octahedron observed. The sum of van der Walls radii
of Sn and O varied between 3.80 and 4.17 Å [36]. No such interaction was observed earlier [23, 24].Table 3
Selected bond distances (Å) and
angles (deg) for the known diorganotin
compounds with carboxylate ligands.
ComplexTemperature (K)Sn-O  (Å)Sn-C  (Å)C-O (Å)C-Sn-C(°)O-Sn-O(°)Ref.12932.1060(18)2.089(3)1.350(3)138.4(4)83.4(5)[*]2.5147(15)2.093(3)1.347(3)139.1(5)2.1079(15)1.293(2)55.7(5)2.5771.252(3)22932.104(4)2.124(7)1.288(6)144.0(3)81.68(15)[*]2.5642.110(7)1.237(7)2.121(4)1.245(8)2.6321.284(8)(CH3)2Sn(o-HBZA)21932.112(3)2.092(5)1.301(5)138.2(2)56.0(1)[24]2.503(3)2.092(5)1.256(5)82.9(1)2.111(3)1.292(5)137.9(1)2.577(3)1.254(5)138.9(1)166.1(1)55.0(1)(n-C4H9)2Sn(o-HBZA)22982.117(5)2.122(9)1.28(1)143.9(3)54.5(2)[23]2.570(6)2.105(9)1.233(8)81.6(2)2.095(5)1.294(9)135.7(2)2.630(6)1.246(8)136.1(2)169.7(1)54.1(2)(n-C4H9)2Sn(2,4-DHB)22982.559(4)2.114(6)1.267(6)139.0(3)54.9(1)[35]2.110(4)2.107(7)1.281(6)138.0(1)2.508(4)1.246(6)82.8(1)2.124(4)1.294(7)167.0(1)137.7(1)55.3(1)(CH3)2Sn(2,4,5-TF-3-MBA)22982.115(6)2.091(8)1.262(9)142.2(4)135.8(2)[11]2.656(6)2.090(9)1.234(10)53.0(2)2.118(5)1.288(10)171.17(18)2.506(6)1.229(10)80.3(2)55.6(2)133.3(2)(n-C4H9)2Sn(2,4,5-TF-3-MBA)22982.128(3)2.109(5)1.287(6)147.5(2)137.80(12)[11]2.141(3)2.107(5)1.226(6)54.58(12)2.531(4)1.281(6)167.61(12)2.562(3)1.245(6)82.60(13)55.31(12)137.08(12)[*]: This work; 2HB-O,O:
2-hydroxybenzoato-O,O′; 2,4-DHB: Dihydroxybenzoato;
2,4,5-TF-3-MBA: 2,4,5-Trifluoro-3-methoxybenzoic acid.(a) Anisotropic ellipsoid representation of complex1. The ellipsoids are drawn at 50% probability level. Selected bond distances (Å) and bond angles (deg.): Sn1-O171 = 2.1069(18),
Sn1-O172 = 2.5145(15),
Sn1-O271 = 2.1086(15), Sn1-O272 = 2.577, Sn1-C31 = 2.086(3), Sn1-C41 = 2.091(3), O171-Sn1-O172 =
55.56(5), O172-Sn1-O272 = 83.39(6), and O271-Sn1-O171-C17 =
178.46(14). (b) Strong
Sn⋯O bonding interaction leads to the formation of a dimer.
(a)(b)(a) Anisotropic ellipsoid
representation of complex2. The
ellipsoids are drawn at 50% probability level. Selected
bond distances (Å) and bond angles (deg.): Sn1-O172 = 2.121(3), Sn1-O171 = 2.565, Sn1-O272 =
2.105(4), Sn1-O271 =
2.632, Sn1-C31 = 2.120(6), Sn1-C41 = 2.111(5), O172-Sn1-O272 = 81.66(13),
O171-Sn1-O271 = 170.01, and O272-Sn1-O172-C17 = 177.6(4)°. (b) Strong Sn⋯O bonding interaction leads to the formation of a dimer.
(a)(b)Study of the Peroxidation of Linoleic Acid by the Enzyme Lipoxygenase in the Presence of Complexes1–6
The
influence of complexes1–6 on the
oxidation of linoleic acid by the enzyme (LOX) was studied in a wide
concentration range. The degree of (LOX) activity (A, %) in the presence of
these complexes was calculated according to the method described previously [13]. The IC50 values found for
complexes 1–7 are 76 (1), 48 (2), 82 (3), 19 (4), 24 (5), and 11 (6) μm, respectively. Thus, five
coordinated (see Sn-NMR data) triphenyl organotin compounds 6 and 4 are the most active among this type of complexes showing the
order of activity: 6>4>5>2>1>3. Moreover, triorganotin
complexes with p-H2BZA are found to be more active than the
corresponding compounds with p-H2BZA. These values are also comparable
to the ones found for other organotin(IV) complexes [13–17] and significantly higher
than the corresponding cisplatin. For example, the IC50 values found
for the organotin compounds tested toward (LOX) were 25 μm [(n-Bu)3Sn(TBA)⋅H2O]
(HTBA = 2-thiobarbituric acid) [14], 26 and 14 μm for [(C6H5)2SnCl(HMNA)]
and [(C6H5)3Sn(MNA)Sn(C6H5)3(acetone)]
(H2MNA = 2-mercapto-nicotinic acid) [13, 14], 19, 16, and 21 μm for
[(C6H5)3Sn(MBZT)], [(C6H5)3Sn(MBZO)],
[(C6H5)3Sn(CMBZT)] [15] (MBZT =
2-mercapto-benzothiazole, MBZO = 2-mercapto-benzoxazole and CMBZT =
5-chloro-2-mercapto-benzothiazole), 10, 13, and 14 μm for [(C6H5)2Sn(CMBZT)2],
[(n-C4H9)2Sn(CMBZT)2], and
[(CH3)2Sn(CMBZT)2] [15], and 61.3, 26.2,
20.5, and 16.9 μm for [(CH3)2Sn(PMT)2], [(n-C4H9)2Sn(PMT)2],
[(C6H5)2Sn(PMT)2], and [(C6H5)3Sn(PMT)]
(PMT = 2mercapto-pyrimidine) [16]. Taking into account that higher LOX
inhibition activity is found to be related to the high cytotoxic activity
against sarcoma cells, compound 4, 5, and 6 are expected to show such high activity (see below).


### 2.5. Biological Tests

The high inhibitory activities
of complexes1–10 against
LOX activity found prompted us to study the antiproliferative activity of them
against sarcoma cells and compare these data with their structural features. Complexes 1–6 were tested for cytotoxic activity
against leiomyosarcoma cells from the Wistar rat, polycyclic aromatic
hydrocarbons (PAH, benzo[a]pyrene) carcinogenesis. Cytotoxic activities for
complexes 1–6 were
evaluated as % percentage of the cell survived in variable concentrations of the complexes after 48 hours. The
IC50 values found were >2000 (1),
150 (2), 150 (3), 5–10 (4),30–40 (5), and 25–35 (6) nm, respectively, indicating very
strong cytotoxic activity against leiomyosarcoma cells. In accordance with the LOX
inhibition activity, the five-coordinated triorganotin complexes 5, 3, and 6 showed stronger antiproliferative activity against sarcoma cell lines
(see LOX inhibition activity). The order of activity of complexes 1–6 is found to be 4>6>5≫3=2≫1. It is noteworthy to mention that triorganotin(IV)
compounds 4–6 were found to
inhibit LOX activity and anti-proliferate sarcoma cells stronger than
di-organotins. Between diorganotin(IV) derivatives of o-H2BZA 1 and 2, the dibutyltin complex exhibits significant stronger
cytotoxic activity than the corresponding one of dimethyltin complex. This is
also observed in the case of substituted salicylic
acids reported previously [34], where diethyl derivatives were found to show
approximately 10 times lower activity than the corresponding
dibutyltin complexes against human mammary tumor
cell lines (MCF-7) and human colon carcinoma cell line (WiDr) [34]. The
corresponding IC50 values of other organotin(IV) complexes found
against leiomyosarcoma cells were 5 and 125 nm for [(C6H5)3Sn(MNA)Sn(C6H5)3(acetone)]
(H2MNA = 2-mercapto-nicotinic acid) [14], and [(n-Bu)3Sn(TBA)⋅H2O]
(HTBA = 2-thiobarbituric acid) [14],
1500–3000, 1300–3000, and 500–800 nm for [(C6H5)3Sn(MBZT)],
[(C6H5)3Sn(MBZO)], [(C6H5)3Sn(CMBZT)]
(MBZT = 2-mercapto-benzothiazole, MBZO = 2-mercapto-benzoxazole and CMBZT =
5-chloro-2-mercapto-benzothiazole) [15], 300–500, 600–800, and 5000–7500 nm for [(C6H5)2Sn(CMBZT)2],
[(n-C4H9)2Sn(CMBZT)2], and
[(CH3)2Sn(CMBZT)2], [15] and 20000–60000, 700, 1000–2000,
and 100 nm for [(CH3)2Sn(PMT)2],
[(n-C4H9)2Sn(PMT)2], [(C6H5)2Sn(PMT)2],
and [(C6H5)3Sn(PMT)] (PMT = 2-mercapto-pyrimidine), [16]. From all of these values for the different
compounds, it is clear that complexes 1–6 have high
cytotoxic activity against
leiomyosarcoma cells.
Triphenylorganotin(IV)
complexes 4 and 6 are the most active compounds of this series of
compounds (where the IC50 are 5–10 nm for 4 and 25–35 nm for 6) and they are classified among the most
active organotin(IV) compounds tested.Table4 summarizes the IC50 (μm) values for LOX inhibition in comparison with cell
activity of
organotin(IV) complexes 1–6 against sarcoma cells.Table 4
IC50 values
for LOX inhibition activity and
cell cytotoxic activity of
organotin(IV) complexes 1–6.
CompoundIC50   for LOX inhibitionIC50  cell
activityRef[(CH3)2Sn(o-HBZA)2] (1)76μm>2000 nm[*][(n-C4H9)2Sn(o-HBZA)2]
(2)48μm150 nm[*][(n-C4H9)3Sn(o-HBZA)] (3)82μm150 nm[*][(C6H5)3Sn(o-HBZA)] (4)19μm5-10 nm[*][(n-C4H9)3Sn(p-HBZA)] (5)24μm30-40 nm[*][(C6H5)3Sn(p-HBZA)] (6)11μm25-35 nm[*](n-Bu)3Sn(TBA)⋅H2O]25μm125 nM[14][(C6H5)3Sn(MNA)Sn(C6H5)3(acetone)]14μm5 nm[14][(C6H5)3Sn(MBZT)]19μm1500–3000 nm[15][(C6H5)3Sn(MBZO)]16μm1300–3000 nm[15][(C6H5)3Sn(CMBZT)]21μm500–800 nM[15][(C6H5)2Sn(CMBZT)2]10μm300–500 nm[15][(n-C4H9)2Sn(CMBZT)2]13μm600–800 nm[15][(CH3)2Sn(CMBZT)2]14μm5000–7500 nm[15][(CH3)2Sn(PMT)2]61μm20000–60000 nm[16][(n-C4H9)2Sn(PMT)2]26μm700 nm[16][(C6H5)2Sn(PMT)2]21μm1000–2000 nm[16][(C6H5)3Sn(PMT)]17μm100 nm[16][*]: This work; HTBA: 2-thiobarbituric
acid; H2MNA:
2-mercapto-nicotinic acid;
MBZT: 2-mercapto-benzothiazole; MBZO: 2-mercapto-benzoxazole; CMBZT:
5-chloro-2-mercapto-benzothiazole; HPMT: 2-mercapto-pyrimidine.


### 2.6. Computational Methods–Docking Study

In
order to investigate further the complex-LOX interactions, we performed
computational molecular docking studies for the complexes1 and 2 were X-ray data
are available. The binding energy (E) of the
substrate (S: linoleic acid) to its binding site in the enzyme LOX (E)
when ES is the complex formed was E:−7.89 kcal/mole [13]. The corresponding binding energies of inhibitors 1 and 2 (I), in ESI, are calculated to −8.48 (1) and −8.23 (2) kcal/mol, respectively, while the binding energies of EI are estimated to −9.7 Kcal/mol (1) and −11.4 (2) kcal/mol. According to the binding
energy (E) values
of ES in contrast to those of EI or ESI, it is found that both ESI and EI
complexes could be formed.Figures3 and 4 show the
binding site of compound 1 toward LOX in ESI and EI, respectively.
Compounds 1 and 2 bind to both ESI and EI complexes at the same pocket where the strong inhibitors of LOX
bind [15], supporting its strong inhibition activity, found experimentally. Since high inhibition activity
of LOX has been detected
for all cytotoxic organotin(IV)-thione compounds tested previously, [13–17] strong activity would also be expected for compounds 1 and 2, although weaker
than the others, tested in this study.Binding sites of inhibitor1 toward LOX in ESI and EI, respectively.
(a)(b)Figure 4


## 2.1. General Aspects

Organotin(IV) complexes1–6 have been synthesized by reacting a
methanolic solution of organotin chloride with an aqueous solution of the
appropriate amounts of 2- or 4-hydroxybenzoic acid containing an equimolar
amount of potassium hydroxide as shown in (1) and (2):(1)R2SnCl2+2H2L+2KOH→MeOH/H2OR2Sn(HL2)+2KCl+2H2OH2L=o-H2BZAandR=Me-(1),n-Bu-(2)(2)R3SnCl+H2L+KOH→MeOH/H2OR3Sn(HL)+KCl+H2OH2L=o-H2BZAandR=n-Bu-(3),Ph-(4)orH2L=p-H2BZAandR=n-Bu-(5),Ph-(6).Complexes1-2 were
prepared with an alternative method of the one used previously for the
synthesis of these complexes [23, 24].
Complexes 1–6 are air-stable powders soluble in methanol,
ethanol, and DMSO solvents. Crystals
suitable for X-ray analysis were obtained by slow evaporation of
methanol/acetonitril solutions for compounds 1 and 2.


## 2.2. Thermal Analysis

The TGA/DTA data curves for
complexes1-2 show that they decompose generally in one stage. Thus, thermal analysis in
flowing nitrogen shows that complex 1 decomposes between 125 and 315°C with 72% mass loss which corresponds to the methyl
groups of the metal and the ligand molecules (the calculated mass loss is 72%),
compound 2 decomposes between 35 and
490°C with 74% mass loss due to the butyl groups of the metal and the ligand
molecules (the calculated mass loss is 76.50%) (Scheme 2).Scheme 2The TGA/DTA data in flowing nitrogen data
curves for complexes3–6 show that they
decompose generally in two stages. The first stage of decomposition of compound 3 lies between 20 and 255°C that
corresponds to 13% mass loss of one of the metal butyl groups (the calculated
mass loss is 13%), compound 4 decomposes between 35 and 215°C with 16% mass loss of one of the metal phenyl
groups (the calculated mass loss is 16%), compound 5 decomposes between 25 and 255°C that corresponds to 13% mass loss
of one of the metal butyl groups (the calculated mass loss is 13%), and compound 6 decomposes between 25 and 177°C with
15% mass loss of one of the metal phenyl groups (the calculated mass loss is 16%).
The second stage of decomposition is between 255 and 400°C in case of 3 which
corresponds to 44% mass loss of the ligand (o-hydroxybenzoic acid) and another
metal butyl group (the calculated mass loss is 45%), between 215 and 500°C (4)
corresponding to 43% mass loss of the ligand (o-hydroxybenzoic acid) and
another metal phenyl group (the calculated mass loss is 42%), compound 5 decomposes between 255 and 412°C which
corresponds to 45.60% mass loss of the ligand (p-hydroxybenzoic acid) and
another metal butyl group (the calculated mass loss is 45%), and compound 6 decomposes between 177 and 435°C with
42% mass loss which corresponds to the ligand (p-hydroxybenzoic acid) and another
metal phenyl group (the calculated mass loss is 42%) (Scheme 2).


## 2.3. Spectroscopy

Vibrational spectroscopy: characteristic
infrared bands of the complexes 1–6 and the
ligands are listed in Table 1.Table 1
Characteristic vibration bands (cm−1) of the o- or p-HBZA ligands
and their complexes 1–6.
CompoundInfraredRamanRef.v(OH)v(CH)vas, vsy(COO)v(Sn-C)v(Sn-C)v(Sn-O)v(Sn-C)o-H2BZA32821656, 1324[25]o-NaHBZA1577, 1373[26]134672817-27051631, 1388580, 536446——234502928-28691628, 1419562, 530435——334502957-23641633, 1352564, 538445——4344730631636, 1356600, 533420——p-H2BZA3382—1687, 1360————[27]p-NaHBZA33821547, 1416[27]534392958-29221613, 1351606, 5094574105206343330681615, 1431569, 511438450618The IR spectra of the
complexes1–6 show vibrational
bands at 3467 1, 3450 2, 3450 3, 3447 4, 3439 5, and 3433 6 cm−1, which are assigned to v(phenolic OH) [28, 29]. The corresponding vibrational bands v(O-H) of the free ligands appear at
3282 and 3382 cm−1 for o-H2BZA or p-H2BZA,
respectively [25, 27].Thevas(COO−) vibration of the free
ligand appears at 1656 cm−1 while the vs(COO−)
at 1324 cm−1 for o-H2BZA [25], and the vas(COO−)
vibration of p-H2BZA ligand appears at 1687 cm−1 while
the vs(COO−) at 1360 cm−1 [27]. The
corresponding vas(COO−) vibrations are observed at 1631 1, 1628 2, 1633 3, 1636 4, 1636 5, and 1617 6 cm−1,
respectively. The bands at 1388 1,
1419 2, 1352 3, 1356 4, 1419 5, and 1347 6 cm−1 are assigned to vs(COO−).
The Δv [vas(COO−)-vs(COO−)] difference
values of the free ligands are (332 cm−1 for o-H2BZA and 327 cm−1 for p-H2BZA) versus the corresponding values Δv for
complexes 1–6 (243 1,
209 2, 281 3, 280 4, 217 5, and 270 6 cm−1,
resp.) support the coordination of the ligand to the metal center through the
carboxylic acid group. Monodentate coordination of the –COO− group of the ligand to metal ions results in significantly higher Δv [vas(COO−)-vs(COO−)] difference values
than those observed for the ionic compounds of the ligand [30], while when the
ligand chelates, the Δv [vas(COO−)-vs(COO−)]
is considerably smaller than that observed for its ionic
compounds. For asymmetric bidentate coordination, the values are in the range of
monodentate coordination [30]. When
the –COO− group bridges metal ions, the Δv [vas(COO−)-vs(COO−)]
value is higher than that of the chelated ions and nearly the
same as that observed for ionic compounds [30]. In our case, the Δv
[vas(COO−)-vs(COO−)] values of the
ionic compounds of the o-NaHBZA and p-NaHBZA ligands (sodium salts) are 205 cm−1 and 131 cm−1, respectively [26]. Therefore, in the diorganotin
complexes 1 and 2, where higher Δv values were observed (243 1 and 209 2 cm−1), an asymmetric bidentate coordination
of the ligand to the metal ion is expected (see crystal structure, Mössbauer
spectra).The same is true in the case of triorganotin complexes 3–6 with significantly
higher Δv values
than the corresponding ones of the sodium salts of the ligands (281 3,
280 4, 217 5, and 270 6 cm−1), indicating
clearly an asymmetric bidentate coordination mode of the ligands and suggesting trigonal bipyramidal
geometry for complexes 3–6 in the
solid state in agreement with the results of Mössbauer and S119n-NMR
spectra.Bands at 425–455 cm−1 have been assigned to the stretching vibration of Sn-O bonds. The
corresponding ones for complexes 1–6 are at 446 1, 435 2, 445 3, 420 4, 458 5, and 450 cm−16 [25]. Bands at 600–500 cm−1 have been assigned to the antisymmetric and symmetric vibrations of Sn-C bond.
The corresponding ones for complexes 1–6 are at 580,
536 1, 562, 530 2, 564, 538 3, 600, 533 4, 610, 509 5, and 569, 511 6 [13–17]. No ν(Sn-Cl) vibration bands at 282
and 221 cm−1 are observed in the far FT-IR of the complexes [13].S119mn
Mössbauer spectroscopy: solid state, S119mn Mössbauer
spectroscopic data of complexes 1-2 and 4–6 are
given in Table 2.Table 2
S119n Mössbauer spectroscopic data for complexes 1–6 at 80 K.
Moleculeδ   (mm s−1)Δ   (mm s−1)C-Sn-C(°) angles*Area
(%)δ   (mm s−1)Δ   (mm s−1)C-Sn-C(°) angles*Area
(%)11.223.09130561.333.651484421.313.53143291.563.681497141.342.93100———51.242.48100———61.443.18100———T*he
C-Sn-C angles (θ) are calculated from the equation following Δ=4{R}[1−3cos2θ⋅sin2θ]1/2, where the
partial quadrupole splitting (p.q.s.),
mm⋅s−1, used
in the calculations was
([R]-[Cl])oct=−1.03  (R = Me, Bu) [31].The isomer shifts values of complexes1–6 are in
the range of δ 1.22 to 1.56 mm s−1 (Table 2), indicating that tin is in
the (4+) oxidation state in all cases [2, 32, 33]. The spectra of diorganotin(IV)
complexes 1–2 consist of
two symmetrical Lorentzian doublets which indicate the presence of two tin
atoms in different chemical environments
with the same ratio 1:1 (56: 44% 1 and 29: 71% 2, resp.). This may be due to the
presence of two different isomers in the unit cells with variable bond
distances. The quadrupole splitting values (Δ) of complexes 1-2 are 3.09 mm s−1 and 3.65 mm s−1 for 1 and 3.53 mm s−1 and 3.68 mm s−1 for 2, suggesting distorted trans-R2 octahedral geometry (2.4–5.5 mm s−1)
[2, 32, 33] in the solid state in agreement with X-ray structures. The calculated
C-Sn-C angles (°) from Mössbauer spectra [31] for the compounds 1 and 2 (Table 2) are 130° for the highest occurring isomer (56%)
and 143° for the lowest occurring isomer (44%) in case of 1 and 148 (29%), 149° (71%) in case of 2. The values of C-Sn-C
angles found from X-ray analysis at 293 K are 138.4(4)° (1)
and 144.0(3)° (2), respectively (see crystal structures).The spectra of the triorganotin(IV) complexes4–6 consist of
one symmetrical Lorentzian doublet which indicates the presence of one tin
atom. The quadrupole splitting values in case of complexes 4–6 (Δ) are 2.93 mm s−14, 2.48 mm s−1 for 5, and 3.18 mm s−16 suggesting eq-R3 trigonal bipyramidal geometry around tin
atom (2.5–4.0 mm s−1)
[2, 32, 33] in solid state in agreement with the geometry concluded from S119n-NMR
spectra.


## 2.4. NMR Spectra

H1-NMR
spectra of complexes 1–6 showed a
single resonance signal at 10.18 1, 10.16 2, 9.91 3, 9.95 4,
9.87 5, and 9.89 6 ppm, respectively, due to the hydroxyl proton
of the ligands (o-H2BZA or p-H2BZA) [34], suggesting that
the OH groups are not involved in bonding with the tin atom. The two doublet signals
at 7.83-7.79 and 6.82-6.791, 7.69-7.65 and 6.75-6.722, 7.72-7.69
and 6.73-6.703, 7.81-7.78 and 6.69-6.654, and 7.75-7.71 and
6.76-6.736 ppm are assigned to the protons of the phenyl group of the
ligands a and b, respectively (Scheme 1) [34]. In case of complex 1, the single signal at 0.83 ppm is assigned to the protons of the methyl
group of the metal.In case of complexes6 and 7,
S119n-NMR spectra were
also recorded. S119n-NMR spectra showed resonance signals at −20.0 (6)
and −212.0 (7) ppm, respectively. Although the shift ranges are somewhat
dependent on the nature of the substituents at the tin atom the δ(S119n)
values (in ppm) for R3Sn(IV) complexes with five-coordinated Sn vary
from +25 to −329 ppm [33]. Thus, the tin(IV) atoms are five coordinated in case
of complexes 5 and 6, and therefore the expected geometry
arrangement around triorganotin(IV), in solution, is suggested as trigonal
bipyramidal.Crystal and Molecular Structures of [(CH3)2sn(OOCC6H4OH)2] (1) and [(n-C4H9)2sn(OOCC6H4OH)2] (2)
The crystal
structures of complexes1 and 2 had been determined previously, at
193 and 295 K with R% values of 6.4 and 3.8, respectively [23, 24]. However, we
redetermined the structures here of both 1 or 2 complexes at room temperature
(293 K), with R% 2.18 and 4.83, respectively, for comparison and in order to
investigate the influence of the temperature on their structures [33]. ORTEP
diagrams of complexes 1 and 2 are shown in Figures 1 and 2.
Compounds1 and 2 are covalent
monomers in the solid state with a distorted octahedral geometry around the
metal ion. Table 3 summarizes Sn-O and other selected bond distances and angles
found for organotin complexes reported here and elsewhere [23, 24]. They differ
only slightly.
The Sn-O bond
distances are 2.1060(18), 2.5147(15), 2.1079(15), and 2.577Å in 1; 2.104(4), 2.564, 2.121(4), and 2.632 Å in 2 showing an asymmetric bidentate coordination of the ligand to the Sn
atom, as concluded in the
IR Section 2.3. The Sn-O bond distances found in 1 and 2 are in agreement with the corresponding bond lengths found in (CH3)2Sn(2,4,5-TF-3-MBA)2 (2,4,5-TF-3-MBA = 2,4,5-trifluoro-3-methoxybenzoic
acid) 2.115(6)–2.656(6) Å [11],
in (n-C4H9)2Sn(2,4,5-TF-3-MBA)2, 2.128(3)–2.562(3) Å [11],
and in (n-C4H9)2Sn(2,4-DHB)2 (2,4-DHB = dihydroxybenzoato) 2.110(4)–2.559(4) Å [35].
The O-Sn-O-C torsion angles found in complexes1 and 2 were O271-Sn1-O171-C17 = 178.46(14)° for 1 and (O272-Sn1-O172-C17 =
177.6(4)° for 2. This indicates the almost coplanar arrangement of the
two ligands with the tin atom. Thus, the conformation around the tin atom is trans-C2, cis-O2, cisO2. The value of the C-Sn-C angle (C31-Sn1-C41 =
138.44(11)° in 1 and C31-Sn1-C41 = 143.8(2)°in 2) implies
distortion of the octahedral structure.
In both complexes1 and 2 there are
intramolecular hydrogen bonding interactions (O12⋯O172 = 2.620(2) Å and O22⋯O272 =
2.605(2) Å for 1, O11⋯O171 = 2.621(7) Å and O21⋯O271 =
2.622(5) Å in case of 2)
stabilizing the structures. Interesting strong Sn⋯O bonding interaction
(Sn1⋯O12 = 3.463 Å in case of 1 and
Sn1⋯O21 = 3.620 Å in case of 2) leads to the formation of
dimers in both cases (Figures 1 and 2) which may
affect the distortion of the octahedron observed. The sum of van der Walls radii
of Sn and O varied between 3.80 and 4.17 Å [36]. No such interaction was observed earlier [23, 24].Table 3
Selected bond distances (Å) and
angles (deg) for the known diorganotin
compounds with carboxylate ligands.
ComplexTemperature (K)Sn-O  (Å)Sn-C  (Å)C-O (Å)C-Sn-C(°)O-Sn-O(°)Ref.12932.1060(18)2.089(3)1.350(3)138.4(4)83.4(5)[*]2.5147(15)2.093(3)1.347(3)139.1(5)2.1079(15)1.293(2)55.7(5)2.5771.252(3)22932.104(4)2.124(7)1.288(6)144.0(3)81.68(15)[*]2.5642.110(7)1.237(7)2.121(4)1.245(8)2.6321.284(8)(CH3)2Sn(o-HBZA)21932.112(3)2.092(5)1.301(5)138.2(2)56.0(1)[24]2.503(3)2.092(5)1.256(5)82.9(1)2.111(3)1.292(5)137.9(1)2.577(3)1.254(5)138.9(1)166.1(1)55.0(1)(n-C4H9)2Sn(o-HBZA)22982.117(5)2.122(9)1.28(1)143.9(3)54.5(2)[23]2.570(6)2.105(9)1.233(8)81.6(2)2.095(5)1.294(9)135.7(2)2.630(6)1.246(8)136.1(2)169.7(1)54.1(2)(n-C4H9)2Sn(2,4-DHB)22982.559(4)2.114(6)1.267(6)139.0(3)54.9(1)[35]2.110(4)2.107(7)1.281(6)138.0(1)2.508(4)1.246(6)82.8(1)2.124(4)1.294(7)167.0(1)137.7(1)55.3(1)(CH3)2Sn(2,4,5-TF-3-MBA)22982.115(6)2.091(8)1.262(9)142.2(4)135.8(2)[11]2.656(6)2.090(9)1.234(10)53.0(2)2.118(5)1.288(10)171.17(18)2.506(6)1.229(10)80.3(2)55.6(2)133.3(2)(n-C4H9)2Sn(2,4,5-TF-3-MBA)22982.128(3)2.109(5)1.287(6)147.5(2)137.80(12)[11]2.141(3)2.107(5)1.226(6)54.58(12)2.531(4)1.281(6)167.61(12)2.562(3)1.245(6)82.60(13)55.31(12)137.08(12)[*]: This work; 2HB-O,O:
2-hydroxybenzoato-O,O′; 2,4-DHB: Dihydroxybenzoato;
2,4,5-TF-3-MBA: 2,4,5-Trifluoro-3-methoxybenzoic acid.(a) Anisotropic ellipsoid representation of complex1. The ellipsoids are drawn at 50% probability level. Selected bond distances (Å) and bond angles (deg.): Sn1-O171 = 2.1069(18),
Sn1-O172 = 2.5145(15),
Sn1-O271 = 2.1086(15), Sn1-O272 = 2.577, Sn1-C31 = 2.086(3), Sn1-C41 = 2.091(3), O171-Sn1-O172 =
55.56(5), O172-Sn1-O272 = 83.39(6), and O271-Sn1-O171-C17 =
178.46(14). (b) Strong
Sn⋯O bonding interaction leads to the formation of a dimer.
(a)(b)(a) Anisotropic ellipsoid
representation of complex2. The
ellipsoids are drawn at 50% probability level. Selected
bond distances (Å) and bond angles (deg.): Sn1-O172 = 2.121(3), Sn1-O171 = 2.565, Sn1-O272 =
2.105(4), Sn1-O271 =
2.632, Sn1-C31 = 2.120(6), Sn1-C41 = 2.111(5), O172-Sn1-O272 = 81.66(13),
O171-Sn1-O271 = 170.01, and O272-Sn1-O172-C17 = 177.6(4)°. (b) Strong Sn⋯O bonding interaction leads to the formation of a dimer.
(a)(b)Study of the Peroxidation of Linoleic Acid by the Enzyme Lipoxygenase in the Presence of Complexes1–6
The
influence of complexes1–6 on the
oxidation of linoleic acid by the enzyme (LOX) was studied in a wide
concentration range. The degree of (LOX) activity (A, %) in the presence of
these complexes was calculated according to the method described previously [13]. The IC50 values found for
complexes 1–7 are 76 (1), 48 (2), 82 (3), 19 (4), 24 (5), and 11 (6) μm, respectively. Thus, five
coordinated (see Sn-NMR data) triphenyl organotin compounds 6 and 4 are the most active among this type of complexes showing the
order of activity: 6>4>5>2>1>3. Moreover, triorganotin
complexes with p-H2BZA are found to be more active than the
corresponding compounds with p-H2BZA. These values are also comparable
to the ones found for other organotin(IV) complexes [13–17] and significantly higher
than the corresponding cisplatin. For example, the IC50 values found
for the organotin compounds tested toward (LOX) were 25 μm [(n-Bu)3Sn(TBA)⋅H2O]
(HTBA = 2-thiobarbituric acid) [14], 26 and 14 μm for [(C6H5)2SnCl(HMNA)]
and [(C6H5)3Sn(MNA)Sn(C6H5)3(acetone)]
(H2MNA = 2-mercapto-nicotinic acid) [13, 14], 19, 16, and 21 μm for
[(C6H5)3Sn(MBZT)], [(C6H5)3Sn(MBZO)],
[(C6H5)3Sn(CMBZT)] [15] (MBZT =
2-mercapto-benzothiazole, MBZO = 2-mercapto-benzoxazole and CMBZT =
5-chloro-2-mercapto-benzothiazole), 10, 13, and 14 μm for [(C6H5)2Sn(CMBZT)2],
[(n-C4H9)2Sn(CMBZT)2], and
[(CH3)2Sn(CMBZT)2] [15], and 61.3, 26.2,
20.5, and 16.9 μm for [(CH3)2Sn(PMT)2], [(n-C4H9)2Sn(PMT)2],
[(C6H5)2Sn(PMT)2], and [(C6H5)3Sn(PMT)]
(PMT = 2mercapto-pyrimidine) [16]. Taking into account that higher LOX
inhibition activity is found to be related to the high cytotoxic activity
against sarcoma cells, compound 4, 5, and 6 are expected to show such high activity (see below).


## 2.5. Biological Tests

The high inhibitory activities
of complexes1–10 against
LOX activity found prompted us to study the antiproliferative activity of them
against sarcoma cells and compare these data with their structural features. Complexes 1–6 were tested for cytotoxic activity
against leiomyosarcoma cells from the Wistar rat, polycyclic aromatic
hydrocarbons (PAH, benzo[a]pyrene) carcinogenesis. Cytotoxic activities for
complexes 1–6 were
evaluated as % percentage of the cell survived in variable concentrations of the complexes after 48 hours. The
IC50 values found were >2000 (1),
150 (2), 150 (3), 5–10 (4),30–40 (5), and 25–35 (6) nm, respectively, indicating very
strong cytotoxic activity against leiomyosarcoma cells. In accordance with the LOX
inhibition activity, the five-coordinated triorganotin complexes 5, 3, and 6 showed stronger antiproliferative activity against sarcoma cell lines
(see LOX inhibition activity). The order of activity of complexes 1–6 is found to be 4>6>5≫3=2≫1. It is noteworthy to mention that triorganotin(IV)
compounds 4–6 were found to
inhibit LOX activity and anti-proliferate sarcoma cells stronger than
di-organotins. Between diorganotin(IV) derivatives of o-H2BZA 1 and 2, the dibutyltin complex exhibits significant stronger
cytotoxic activity than the corresponding one of dimethyltin complex. This is
also observed in the case of substituted salicylic
acids reported previously [34], where diethyl derivatives were found to show
approximately 10 times lower activity than the corresponding
dibutyltin complexes against human mammary tumor
cell lines (MCF-7) and human colon carcinoma cell line (WiDr) [34]. The
corresponding IC50 values of other organotin(IV) complexes found
against leiomyosarcoma cells were 5 and 125 nm for [(C6H5)3Sn(MNA)Sn(C6H5)3(acetone)]
(H2MNA = 2-mercapto-nicotinic acid) [14], and [(n-Bu)3Sn(TBA)⋅H2O]
(HTBA = 2-thiobarbituric acid) [14],
1500–3000, 1300–3000, and 500–800 nm for [(C6H5)3Sn(MBZT)],
[(C6H5)3Sn(MBZO)], [(C6H5)3Sn(CMBZT)]
(MBZT = 2-mercapto-benzothiazole, MBZO = 2-mercapto-benzoxazole and CMBZT =
5-chloro-2-mercapto-benzothiazole) [15], 300–500, 600–800, and 5000–7500 nm for [(C6H5)2Sn(CMBZT)2],
[(n-C4H9)2Sn(CMBZT)2], and
[(CH3)2Sn(CMBZT)2], [15] and 20000–60000, 700, 1000–2000,
and 100 nm for [(CH3)2Sn(PMT)2],
[(n-C4H9)2Sn(PMT)2], [(C6H5)2Sn(PMT)2],
and [(C6H5)3Sn(PMT)] (PMT = 2-mercapto-pyrimidine), [16]. From all of these values for the different
compounds, it is clear that complexes 1–6 have high
cytotoxic activity against
leiomyosarcoma cells.
Triphenylorganotin(IV)
complexes 4 and 6 are the most active compounds of this series of
compounds (where the IC50 are 5–10 nm for 4 and 25–35 nm for 6) and they are classified among the most
active organotin(IV) compounds tested.Table4 summarizes the IC50 (μm) values for LOX inhibition in comparison with cell
activity of
organotin(IV) complexes 1–6 against sarcoma cells.Table 4
IC50 values
for LOX inhibition activity and
cell cytotoxic activity of
organotin(IV) complexes 1–6.
CompoundIC50   for LOX inhibitionIC50  cell
activityRef[(CH3)2Sn(o-HBZA)2] (1)76μm>2000 nm[*][(n-C4H9)2Sn(o-HBZA)2]
(2)48μm150 nm[*][(n-C4H9)3Sn(o-HBZA)] (3)82μm150 nm[*][(C6H5)3Sn(o-HBZA)] (4)19μm5-10 nm[*][(n-C4H9)3Sn(p-HBZA)] (5)24μm30-40 nm[*][(C6H5)3Sn(p-HBZA)] (6)11μm25-35 nm[*](n-Bu)3Sn(TBA)⋅H2O]25μm125 nM[14][(C6H5)3Sn(MNA)Sn(C6H5)3(acetone)]14μm5 nm[14][(C6H5)3Sn(MBZT)]19μm1500–3000 nm[15][(C6H5)3Sn(MBZO)]16μm1300–3000 nm[15][(C6H5)3Sn(CMBZT)]21μm500–800 nM[15][(C6H5)2Sn(CMBZT)2]10μm300–500 nm[15][(n-C4H9)2Sn(CMBZT)2]13μm600–800 nm[15][(CH3)2Sn(CMBZT)2]14μm5000–7500 nm[15][(CH3)2Sn(PMT)2]61μm20000–60000 nm[16][(n-C4H9)2Sn(PMT)2]26μm700 nm[16][(C6H5)2Sn(PMT)2]21μm1000–2000 nm[16][(C6H5)3Sn(PMT)]17μm100 nm[16][*]: This work; HTBA: 2-thiobarbituric
acid; H2MNA:
2-mercapto-nicotinic acid;
MBZT: 2-mercapto-benzothiazole; MBZO: 2-mercapto-benzoxazole; CMBZT:
5-chloro-2-mercapto-benzothiazole; HPMT: 2-mercapto-pyrimidine.


## 2.6. Computational Methods–Docking Study

In
order to investigate further the complex-LOX interactions, we performed
computational molecular docking studies for the complexes1 and 2 were X-ray data
are available. The binding energy (E) of the
substrate (S: linoleic acid) to its binding site in the enzyme LOX (E)
when ES is the complex formed was E:−7.89 kcal/mole [13]. The corresponding binding energies of inhibitors 1 and 2 (I), in ESI, are calculated to −8.48 (1) and −8.23 (2) kcal/mol, respectively, while the binding energies of EI are estimated to −9.7 Kcal/mol (1) and −11.4 (2) kcal/mol. According to the binding
energy (E) values
of ES in contrast to those of EI or ESI, it is found that both ESI and EI
complexes could be formed.Figures3 and 4 show the
binding site of compound 1 toward LOX in ESI and EI, respectively.
Compounds 1 and 2 bind to both ESI and EI complexes at the same pocket where the strong inhibitors of LOX
bind [15], supporting its strong inhibition activity, found experimentally. Since high inhibition activity
of LOX has been detected
for all cytotoxic organotin(IV)-thione compounds tested previously, [13–17] strong activity would also be expected for compounds 1 and 2, although weaker
than the others, tested in this study.Binding sites of inhibitor1 toward LOX in ESI and EI, respectively.
(a)(b)Figure 4


## 3. Conclusion

Organotin(IV) complexes (1)–(7) are found to inhibit strongly the
peroxidation of linoleic acid by the enzyme lipoxygenase. Five-coordinated
organotin(IV) complexes 6, 4, and 5 (IC50 = 11, 19, and 24 μm, resp.) showed strongest LOX
inhibition activity than the corresponding six-coordinated one (Table 4). Compounds 1–6, also,
showed strong antitumor activity against sarcoma cells (Table 4). The highest antiproliferate
activity against sarcoma cell lines is also shown by the five-coordinated triphenyltin(IV)
complexes 4 and 6 (IC50 = 5–10 and 25–35 nm, resp.). Between tri- and diorganotin
complexes, five-coordinated organotin complexes which have one free
coordination position were found to exhibit stronger antiproliferative and LOX
inhibition activity. These findings are in accordance to Huber
et al. [12] who suggested that the
structures of organotin carboxylates antitumor active compounds are
characterized by (i) the availability of coordination positions at Sn and (ii)
the occurrence of relatively stable ligand-Sn bonds, for example, Sn-N and Sn-S
and their slow hydrolytic decomposition. Therefore, the geometrical feature of
this type of complexes (1–6) seems to
play important role in their antitumor
and LOX inhibition activity.


## 4. Experimental

### 4.1. Materials and Instruments

All solvents used were of reagent grade, while o-, p-hydroxybenzoic acid, and
organotins chlorides (Alderich,USA), (Merck, Germany)
were used with no further purification. Elemental analysis for C and H was carried out with a
Carlo Erba EA MODEL 1108. Infrared spectra in the region of 4000-370 cm−1 were obtained in KBr discs. The S119n Mössbauer spectra were
collected at 80 K, with a constant acceleration spectrophotometer equipped with
CaSnO3source kept at low temperature. A Jasco UV/Vis/NIR V570
series spectrophotometer was used to obtain electronic absorption spectra. The H1-NMR
spectra were recorded on a Bruker AC250 MHFT NMR instrument in DMSO-d6 solution. Chemical shifts δ are reported in ppm using H1 TMS as an
internal reference.Preparation of the Complexes [(CH3)2Sn(o-HBZA)2] (1), [(n-C4H9)2Sn(o-HBZA)2] (2), [(n-C4H9)3Sn(o-HBZA)2] (3), [(C6H5)3Sn(o-HBZA)2] (4), [(n-C4H9)3Sn(p-HBZA)2] (5), and [(C6H5)3Sn(p-HBZA)2] (6).
Complexes1-2 were
synthesized as follows: a suspension of the ligand (o-hydroxybenzoic acid,
0.138 gr, 1 mmol 1-2) in 5 cm−3 distilled water was treated with a solution of KOH 1 N (1 cm−3, 1 mmol 1-2) and a clear solution was immediately formed. 5 cm−3 methanolic solution of diorganotin(IV) chloride ((CH3)2SnCl2,
0.109 gr, 0.5 mmol for 1 and (n-C4H9)2SnCl2,
0.152 gr, 0.5 mmol for 2) was then added
to the above solution. A white precipitate formed and the mixture was stirred
for 4 hours. The precipitate was then filtered off, washed with 3 mL of
distilled water and dried in vacuo over silica gel. Crystals of 1 and 2 complexes suitable for X-ray analysis were growth by slow evaporation of CH3OH/CH3CN
solutions (1:1). Complexes 3–6 were
synthesized as follows: a suspension of the ligand (o-, p-hydroxybenzoic acid,
0.069 gr, 0.5 mmol 3–6) in 5 cm−3 distilled water was
treated with a solution of KOH 1 N (0.5 cm−3, 0.5 mmol 3–6) and a clear solution was immediately formed. 5 cm−3 methanolic solution of triorganotin(IV) chloride ((n-C4H9)3SnCl,
135.6 μL, 0.5 mmol for 3 and 5, (C6H5)3SnCl,
0.193 gr, 0.5 mmol for 4 and 6) was then added to the above
solution. A white precipitate formed and the mixture was stirred for 4 hours.
The precipitate was then filtered off, washed with 3 mL of distilled water, and
dried in vacuo over silica gel.
1 Yield 70.25%,
mp>250°C. Elemental analysis found C 45.21, H 3.95%; calcd for
C16H16O6Sn C 45.4, H 3.81%. IR (cm−1):
3467, 1631, 1444, 1388, 1157, 870, 700 580, 536, 446. H1-NMR
(DMSO-d6
, ppm): δ 10.18 (s, 1H, phenolic OH), 7.83, 6.82 (d, 4H, C6H4CO2OH),
0.83 (s, 6H, Sn-CH3).
2 Yield 65%,
mp 63°C. Elemental analysis found C 52.53, H 5.43%; calcd for C22H28O6Sn C 52.1, H 5.56%. IR (cm−1): 3450, 1628, 1419, 1334, 1159, 869,
702, 562, 530, 435. H1-NMR (DMSO-d6
, ppm): δ 10.16
(s, 1H, phenolic OH), 7.69, 6.75 (d, 4H, C6H4CO2OH),
0.86, 1.18, and 1.60 (t, m, 9H, Sn-C4H9).
3 Yield 55.30%,
mp>250°C. Elemental analysis found C 53.95, H 7.42%; calcd for
C19H32O3Sn C 53.43, H 7.55%. IR (cm−1):
3450, 1633, 1458, 1352, 1157, 866, 703, 564, 538, 445. H1-NMR (DMSO-d6
,
ppm): δ 9.91 (s, 1H, phenolic OH), 7.78, 6.66 (d, 4H, C6H4CO2OH),
0.88, 1.20, and 1.62 (t, m, 9H, Sn-C4H9).
4 Yield 54.35%, mp 160°C. Elemental
analysis found C 61.78, H 3.98%; calcd for C25H20O3Sn
C 61.64, H 4.14%. IR (cm−1): 3447, 1636, 1458, 1356, 1160, 863, 729,
600, 533, 420. H1-NMR (DMSO-d6
,
ppm): δ 9.95 (s, 1H, phenolic OH),
7.72,
6.73 (d, 4H, C6H4CO2OH), 7.40–7.64 (m, 15H, Sn-C6H5).
5 Yield 75.40%, mp>285°C.
Elemental analysis found C 53.66, H 8.25%; calcd for C19H32O3Sn
C 53.43, H 7.55%. IR (cm−1): 3190, 1636, 1458, 1419, 1165, 854, 702, 610, 509, 458. H1-NMR
(DMSO-d6, ppm): δ 9.87 (s, 1H, phenolic OH), 7.81, 6.69 (d,
4H, C6H4CO2OH), 0.90, 1.29, and 1.69 (t, m,
9H, Sn-C4H9). S119n-NMR: -20. UV-Vis (solvent) λmax (ε): (DMSO) 237 (11418),
(CHCl3) 228 (9796) and (MeOH) 227 (15576). ESI-MS (MeOH, m/z): 450.0 [{(n-C4H9)3Sn(p-HBZA)}+Na]+,
370.0 [(M)-(C4H9)]+, 336.0 [(M)-(C4H9)2]+, and
284.0 [{(M)-(C4H9)3}+Na]+.
6 Yield 50.05%, mp 160°C. Elemental analysis found C 61.96, H 4.20%; calcd
for C25H20O3Sn C 61.64,
H 4.14%. IR (cm−1): 3234, 1617, 1431, 1347, 1166, 857, 695, 569, 511,
450. H1-NMR (DMSO-d6
, ppm): δ
9.89 (s, 1H, phenolic OH), 7.75,
6.76 (d, 4H, C6H4CO2OH), 7.42–7.66 (m, 15H, Sn-C6H5). S119n-NMR: -212. UV-Vis (solvent) λmax (ε): (DMSO) 234
(5998), (CHCl3) 232 (13123) and (MeOH) 225 (9695) ESI-MS (MeOH, m/z): 510.0 [{(C6H5)3Sn(p-HBZA)}+Na]+ ions, 434.0 [{(M)-(C6H5)}+Na]+,and
356.0 [{(M)-(C6H5)2}+Na]+.


### 4.2. Study of the Lipoxygenase Inhibition and Biological Tests

Experimental details for LOX
inhibition activity of complexes 1–6 and their in
vitro cells toxicity studies were described earlier [13–15].


### 4.3. Computational Details

Computational details have been described elsewhere
[13–15].


### 4.4. X-Ray Structure Determination

Data
were collected by theω scan technique in the range 4.86°<2θ<24.71°on a KUMA KM4CCD four-circle diffractometer [37] with CCD
detector, using graphite-monochromated Mo Kα (λ = 0.71073 Å) at 293(2) K. Cell
parameters were determined by a least-squares fit [38]. All data were corrected
for Lorentz-polarization effects and absorption [38, 39].The structure was solved with
direct methods with SHELXS97 [40] and refined by full-matrix least-squares
procedures on F2
with SHELXL97 [41].
All nonhydrogen atoms were refined anisotropically, hydrogen atoms were located
at calculated positions and refined as a “riding model” with isotropic thermal
parameters fixed at 1.2 times the Ueq of appropriate carrier
atom.1.C16H16O6Sn: MW = 423.00, monoclinic, P21/n, a = 7.5321(3) Å, b = 21.8775(7) Å, c = 10.4440(4) Å, β = 105.505(4), V =
1658.37(11) Å, Z = 4, T = 293(1) K, ρ(cald) = 1.694 g cm−3, μ = 1.6 mm-1, R = 0.0218, wR = 0.0540.2.C22H26O6Sn: MW = 505.14, monoclinic, P21/c, a = 9.3545(16) Å, b = 24.135(4) Å, c = 10.8625(18) Å, β = 107.781(18), V = 2335.3(7) Å, Z = 4, T = 293(1) K, ρ(cald) = 1.440 g cm−3, μ = 1.1 mm-1, R = 0.0483, wR = 0.1007.Crystallographic data (excluding
structure factors) for the structures reported in this paper have been
deposited with the Cambridge Crystallographic Data Centre as supplementary
publication nos. CCDC 705791 (1) and CCDC 705792 (2). Copies of the data can be obtained free of charge on
application to CCDC (Cambridge, UK).


## 4.1. Materials and Instruments

All solvents used were of reagent grade, while o-, p-hydroxybenzoic acid, and
organotins chlorides (Alderich,USA), (Merck, Germany)
were used with no further purification. Elemental analysis for C and H was carried out with a
Carlo Erba EA MODEL 1108. Infrared spectra in the region of 4000-370 cm−1 were obtained in KBr discs. The S119n Mössbauer spectra were
collected at 80 K, with a constant acceleration spectrophotometer equipped with
CaSnO3source kept at low temperature. A Jasco UV/Vis/NIR V570
series spectrophotometer was used to obtain electronic absorption spectra. The H1-NMR
spectra were recorded on a Bruker AC250 MHFT NMR instrument in DMSO-d6 solution. Chemical shifts δ are reported in ppm using H1 TMS as an
internal reference.Preparation of the Complexes [(CH3)2Sn(o-HBZA)2] (1), [(n-C4H9)2Sn(o-HBZA)2] (2), [(n-C4H9)3Sn(o-HBZA)2] (3), [(C6H5)3Sn(o-HBZA)2] (4), [(n-C4H9)3Sn(p-HBZA)2] (5), and [(C6H5)3Sn(p-HBZA)2] (6).
Complexes1-2 were
synthesized as follows: a suspension of the ligand (o-hydroxybenzoic acid,
0.138 gr, 1 mmol 1-2) in 5 cm−3 distilled water was treated with a solution of KOH 1 N (1 cm−3, 1 mmol 1-2) and a clear solution was immediately formed. 5 cm−3 methanolic solution of diorganotin(IV) chloride ((CH3)2SnCl2,
0.109 gr, 0.5 mmol for 1 and (n-C4H9)2SnCl2,
0.152 gr, 0.5 mmol for 2) was then added
to the above solution. A white precipitate formed and the mixture was stirred
for 4 hours. The precipitate was then filtered off, washed with 3 mL of
distilled water and dried in vacuo over silica gel. Crystals of 1 and 2 complexes suitable for X-ray analysis were growth by slow evaporation of CH3OH/CH3CN
solutions (1:1). Complexes 3–6 were
synthesized as follows: a suspension of the ligand (o-, p-hydroxybenzoic acid,
0.069 gr, 0.5 mmol 3–6) in 5 cm−3 distilled water was
treated with a solution of KOH 1 N (0.5 cm−3, 0.5 mmol 3–6) and a clear solution was immediately formed. 5 cm−3 methanolic solution of triorganotin(IV) chloride ((n-C4H9)3SnCl,
135.6 μL, 0.5 mmol for 3 and 5, (C6H5)3SnCl,
0.193 gr, 0.5 mmol for 4 and 6) was then added to the above
solution. A white precipitate formed and the mixture was stirred for 4 hours.
The precipitate was then filtered off, washed with 3 mL of distilled water, and
dried in vacuo over silica gel.
1 Yield 70.25%,
mp>250°C. Elemental analysis found C 45.21, H 3.95%; calcd for
C16H16O6Sn C 45.4, H 3.81%. IR (cm−1):
3467, 1631, 1444, 1388, 1157, 870, 700 580, 536, 446. H1-NMR
(DMSO-d6
, ppm): δ 10.18 (s, 1H, phenolic OH), 7.83, 6.82 (d, 4H, C6H4CO2OH),
0.83 (s, 6H, Sn-CH3).
2 Yield 65%,
mp 63°C. Elemental analysis found C 52.53, H 5.43%; calcd for C22H28O6Sn C 52.1, H 5.56%. IR (cm−1): 3450, 1628, 1419, 1334, 1159, 869,
702, 562, 530, 435. H1-NMR (DMSO-d6
, ppm): δ 10.16
(s, 1H, phenolic OH), 7.69, 6.75 (d, 4H, C6H4CO2OH),
0.86, 1.18, and 1.60 (t, m, 9H, Sn-C4H9).
3 Yield 55.30%,
mp>250°C. Elemental analysis found C 53.95, H 7.42%; calcd for
C19H32O3Sn C 53.43, H 7.55%. IR (cm−1):
3450, 1633, 1458, 1352, 1157, 866, 703, 564, 538, 445. H1-NMR (DMSO-d6
,
ppm): δ 9.91 (s, 1H, phenolic OH), 7.78, 6.66 (d, 4H, C6H4CO2OH),
0.88, 1.20, and 1.62 (t, m, 9H, Sn-C4H9).
4 Yield 54.35%, mp 160°C. Elemental
analysis found C 61.78, H 3.98%; calcd for C25H20O3Sn
C 61.64, H 4.14%. IR (cm−1): 3447, 1636, 1458, 1356, 1160, 863, 729,
600, 533, 420. H1-NMR (DMSO-d6
,
ppm): δ 9.95 (s, 1H, phenolic OH),
7.72,
6.73 (d, 4H, C6H4CO2OH), 7.40–7.64 (m, 15H, Sn-C6H5).
5 Yield 75.40%, mp>285°C.
Elemental analysis found C 53.66, H 8.25%; calcd for C19H32O3Sn
C 53.43, H 7.55%. IR (cm−1): 3190, 1636, 1458, 1419, 1165, 854, 702, 610, 509, 458. H1-NMR
(DMSO-d6, ppm): δ 9.87 (s, 1H, phenolic OH), 7.81, 6.69 (d,
4H, C6H4CO2OH), 0.90, 1.29, and 1.69 (t, m,
9H, Sn-C4H9). S119n-NMR: -20. UV-Vis (solvent) λmax (ε): (DMSO) 237 (11418),
(CHCl3) 228 (9796) and (MeOH) 227 (15576). ESI-MS (MeOH, m/z): 450.0 [{(n-C4H9)3Sn(p-HBZA)}+Na]+,
370.0 [(M)-(C4H9)]+, 336.0 [(M)-(C4H9)2]+, and
284.0 [{(M)-(C4H9)3}+Na]+.
6 Yield 50.05%, mp 160°C. Elemental analysis found C 61.96, H 4.20%; calcd
for C25H20O3Sn C 61.64,
H 4.14%. IR (cm−1): 3234, 1617, 1431, 1347, 1166, 857, 695, 569, 511,
450. H1-NMR (DMSO-d6
, ppm): δ
9.89 (s, 1H, phenolic OH), 7.75,
6.76 (d, 4H, C6H4CO2OH), 7.42–7.66 (m, 15H, Sn-C6H5). S119n-NMR: -212. UV-Vis (solvent) λmax (ε): (DMSO) 234
(5998), (CHCl3) 232 (13123) and (MeOH) 225 (9695) ESI-MS (MeOH, m/z): 510.0 [{(C6H5)3Sn(p-HBZA)}+Na]+ ions, 434.0 [{(M)-(C6H5)}+Na]+,and
356.0 [{(M)-(C6H5)2}+Na]+.


## 4.2. Study of the Lipoxygenase Inhibition and Biological Tests

Experimental details for LOX
inhibition activity of complexes 1–6 and their in
vitro cells toxicity studies were described earlier [13–15].


## 4.3. Computational Details

Computational details have been described elsewhere
[13–15].


## 4.4. X-Ray Structure Determination

Data
were collected by theω scan technique in the range 4.86°<2θ<24.71°on a KUMA KM4CCD four-circle diffractometer [37] with CCD
detector, using graphite-monochromated Mo Kα (λ = 0.71073 Å) at 293(2) K. Cell
parameters were determined by a least-squares fit [38]. All data were corrected
for Lorentz-polarization effects and absorption [38, 39].The structure was solved with
direct methods with SHELXS97 [40] and refined by full-matrix least-squares
procedures on F2
with SHELXL97 [41].
All nonhydrogen atoms were refined anisotropically, hydrogen atoms were located
at calculated positions and refined as a “riding model” with isotropic thermal
parameters fixed at 1.2 times the Ueq of appropriate carrier
atom.1.C16H16O6Sn: MW = 423.00, monoclinic, P21/n, a = 7.5321(3) Å, b = 21.8775(7) Å, c = 10.4440(4) Å, β = 105.505(4), V =
1658.37(11) Å, Z = 4, T = 293(1) K, ρ(cald) = 1.694 g cm−3, μ = 1.6 mm-1, R = 0.0218, wR = 0.0540.2.C22H26O6Sn: MW = 505.14, monoclinic, P21/c, a = 9.3545(16) Å, b = 24.135(4) Å, c = 10.8625(18) Å, β = 107.781(18), V = 2335.3(7) Å, Z = 4, T = 293(1) K, ρ(cald) = 1.440 g cm−3, μ = 1.1 mm-1, R = 0.0483, wR = 0.1007.Crystallographic data (excluding
structure factors) for the structures reported in this paper have been
deposited with the Cambridge Crystallographic Data Centre as supplementary
publication nos. CCDC 705791 (1) and CCDC 705792 (2). Copies of the data can be obtained free of charge on
application to CCDC (Cambridge, UK).



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*Source: 542979-2009-04-15.xml*