Heptacoordinate tin(IV) compounds derived from pyridine schiff bases: Synthesis, characterization, in Vitro cytotoxicity, anti-inflammatory and antioxidant activity

Article abstract of DOI:10.1248/cpb.57.5

Tin(IV) complexes 2a-q derived from pyridine Schiff bases were prepared and characterized. Four complexes of this series were evaluated in vitro against different carcinogenic cell lines; besides their anti-inflammatory and antioxidant properties were also tested. Combination of mass spectrometry, multinuclear NMR and X-ray diffraction techniques evidenced the formation of heptacoordinated monomeric species. The X-ray diffraction analysis of 2a, 2b, 2i, 2j and 2n led to establish the heptacoordination around the tin atom in solid state and also revealed that the ligand occupies the equatorial positions of the distorted pentagonal bipyramidal geometry and the two alkyl or aryl groups the axial positions. The in-vitro study for complexes 2a-d against six tumor cell lines showed varied antiproliferative activity, the IC₅₀ for all tested complexes was lower than that of the cis-platin. Compounds 2a-d also exhibited anti-inflammatory activity where complex 2c resulted to be more active (IC₅₀=0.11 μm) than the indomethacin IC₅₀=0.27 μm which was used as reference. The antioxidant activity in rat brain homogenate on inhibition of thiobarbituric acid reactive substances (TBARS) indicated that 2c (IC₅₀=1.77 μm) is more active than the quercetine (4.11 μm) and α-tocopherol (IC₅₀=569.09 μm).

Full text of DOI:10.1248/cpb.57.5

January 2009
Chem. Pharm. Bull. 57(1) 5—15 (2009)
5
Heptacoordinate Tin(IV) Compounds Derived from Pyridine Schiff Bases:
Synthesis, Characterization, in Vitro Cytotoxicity, Anti-inflammatory and
Antioxidant Activity
Arturo GONZÁLEZ, Elizabeth GÓMEZ,* Armando CORTÉS-LOZADA, Simón HERNÁNDEZ,
Teresa RAMÍREZ-APAN, and Antonio NIETO-CAMACHO
Instituto de Química, Universidad Nacional Autónoma de México; Circuito Exterior, Ciudad Universitaria, México 04510,
D. F., México. Received June 10, 2008; accepted October 13, 2008; published online October 16, 2008
Tin(IV) complexes 2a—q derived from pyridine Schiff bases were prepared and characterized. Four com-
plexes of this series were evaluated in vitro against different carcinogenic cell lines; besides their anti-inflamma-
tory and antioxidant properties were also tested. Combination of mass spectrometry, multinuclear NMR and X-
ray diffraction techniques evidenced the formation of heptacoordinated monomeric species. The X-ray diffrac-
tion analysis of 2a, 2b, 2i, 2j and 2n led to establish the heptacoordination around the tin atom in solid state and
also revealed that the ligand occupies the equatorial positions of the distorted pentagonal bipyramidal geometry
and the two alkyl or aryl groups the axial positions. The in-vitro study for complexes 2a—d against six tumor cell
lines showed varied antiproliferative activity, the IC50 for all tested complexes was lower than that of the cis-
platin. Compounds 2a—d also exhibited anti-inflammatory activity where complex 2c resulted to be more active
(IC50ꢀ0.11 mM) than the indomethacin IC50ꢀ0.27 mM which was used as reference. The antioxidant activity in rat
brain homogenate on inhibition of thiobarbituric acid reactive substances (TBARS) indicated that 2c
(IC50ꢀ1.77 mM) is more active than the quercetine (4.11 mM) and a-tocopherol (IC50ꢀ569.09 mM).
Key words heptacoordinate tin(IV); cytotoxicity; antioxidant; anti-inflammatory
The organotin(IV) compounds have been the aim of sev- the biological activity of pentacoordinated tin complexes,
eral researches owing to both their versatile chemistry and few examples are known for seven coordinated tin complexes
potential as biologically active compounds. The longstanding where more than one type of biological activity has been re-
and growing interest in these compounds has encouraged ported.45) The aim of this work is to prepare and characterize
several studies which include preparation of catalysts for structurally heptacoordinated tin(IV) derivatives containing
transesterification,1) and for the synthesis of PGA (polymer pyridine moieties and evaluate their in-vitro anticancer, anti-
of glycolic acid),2) as well as in supramolecular architec- inflammatory and anti-oxidant properties.
ture.3) Among the most studied organotin(IV) complexes a
Experimental
special emphasis has been placed on the study of carboxyl-
2-Aminophenol, 2-amino-4-methylphenol, 2-amino-4-chlorophenol, 2-
ates as potential metallotherapeutic drugs,4) however, a wide
amino-4-nitrophenol, 2,6-diacetylpyridine, 2,6-dimethanolpyridine, sele-
nium oxide, dimethyl, diphenyl and dibutyltin oxide, were obtained from
spectrum of biological activities such as anti-microbial,5—10)
anti-inflammatory,11—15) anti-fungal,14) cardiovascular,5,10,16,17)
Aldrich Chemical Co. The 2,6-pyridinedicarboxaldehyde was prepared ac-
cording to the literature procedure.46) 1H-NMR, 13C- and 13C-CPMAS NMR
anti-tuberculosis18,19) and biocide among others remains a
spectra were recorded on a JEOL Eclipse ꢀ300 and Varian (75.4 MHz)
spectrometers, respectively. Chemical shifts (ppm) are relative to (CH3)4Si,
coupling constants are quoted in Hz. Melting points were measured on a
subject of intense study.20)
Schiff bases are of paramount importance as ligands in
metal coordination chemistry as they form stable complexes Fisher Johns apparatus and are uncorrected. Mass spectra were obtained
with a JEOL JMS-AX505 HA mass spectrometer. The DRIFTS spectra were
recorded on a Bruker Tensor 27 spectrophotometer. Compound samples (in
with most of transition metals. In the field of bioinorganic
chemistry they are mainly used as synthetic models for metal
KBr) were placed in a sample cup inside a diffuse reflectance unit. Spectra
containing sites in metalloproteins and enzymes.21,22) The
were averaged over 40 scans in the range (210—4000 cmꢁ1) to a nominal
4 cmꢁ1 resolution. The X-ray crystallographic studies were done on a Bruker
Smart Apex CCD diffractometer l(MoKa)ꢂ0.71073 Å, graphite monochro-
mator, at Tꢂ293 K. All structures were solved by direct methods; all nonhy-
drogen atoms were refined anisotropically, using full-matrix least squares
techniques. All hydrogen atoms were placed on idealized positions based on
hybridization with thermal parameters fixed at 1.2 times (for –CH) and 1.5
(for –CH3) the value of the attached atom. Structure solutions and refine-
ments were performed using SHELXTL v 6.10.47) Cell culture and assay for
cytotoxic activity protocol has been described previously.44)
CCDC 697623—697627 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
Schiff base–organotin complexes have received special atten-
tion in view of their chemistry and structural aspects of hy-
pervalent species.23—30) Regarding this, investigations con-
cerning chelating properties and coordinative effects of 2,6-
diacetylpyridine and its influence on the conformation and
geometry of heptacoordinated tin complexes derived of
hydrazones,31,32) semicarbazones, thiosemicarbazones,33—40)
acylhydrazones,41) have been undertaken. Our interest in or-
ganotin(IV) and organosilicon compounds containing pyri-
dine moieties let us to study the influence and nature of the
ligand substituents in the formation of pentacoordinate tin
and silicon derivatives.42,43) We recently reported the cyto-
toxic activity of pentacoordinated tin o-aminophenols deriva-
tives which displayed outstanding cytotoxic activity and less
damaged normal cells than the observed for the cis-platin.44)
General Procedure for the Preparation of Schiff Bases The corre-
sponding aminophenol and the appropriate aldehyde in a 1 : 2 molar ratio in
70 ml of ethanol or toluene were refluxed for the time indicated for each re-
action with constant stirring; the water was eliminated with a Dean Stark
funnel. After completion of the reaction, the solvent was removed under re-
Although there are a vast number of publications related to duced pressure. Compound 1a has been reported in the literature.48,49)
∗ To whom correspondence should be addressed. e-mail: eligom@servidor.unam.mx
© 2009 Pharmaceutical Society of Japan

6
Vol. 57, No. 1
1a N,Nꢃ-(2,6-Pyridinediyldimethylidyne)bis(2-hydroxybenzenamine): NMR (112.04 MHz, CDCl3) d: ꢁ401.6; IR nmax (KBr): 1573 (CꢂN), 1482
0.25 g (1.85 mmol) of 2,6-pyridinedicarboxaldehyde and 0.402 g (3.70
(CH2), 1317 (CH3), 635 (Sn–C), (Sn–O), 430 (Sn–N) cmꢁ1. MS (EIꢀ), m/z
mmol) of 2-aminophenol, ethanol, 6 h, 0.56 g (95%) yield, yellow solid; mp (%): [Mꢀ, 577] (3), [Mꢀꢁ57, 577] (100), [Mꢀꢁ2Bu, 463] (10), 328 (9),
1
183—189 °C; H-NMR (300 MHz, CDCl3) d: 6.94 (2H, td, Jꢂ7.98, 1.3 Hz, 313 (4), 252 (2). HR-MS (FABꢀ) m/z: 520.1047 Calcd for C25H25N3O2Sn.
H-7), 7.04 (2H, dd, Jꢂ8.2, 1.3 Hz, H-6), 7.26 (2H, td, Jꢂ8.2, 1.5 Hz, H-8),
7.43 (2H, dd, Jꢂ8.1, 1.3 Hz, H-9), 7.96 (1H, t, Jꢂ7.7 Hz, H-1), 8.28 ( 2H, d,
Jꢂ7.8 Hz, H-2), 8.88 (2H, s, H-4); 13C-NMR (75 MHz, CDCl3) d: 116.9 (C-
9), 120.1 (C-6), 120.3 (C-7), 123.5 (C-2), 129.0 (C-8), 137.1 (C-1), 138.1
(C-5), 152.1 (C-10), 155.0 (C-3), 159.1 (C-4); IR nmax (KBr): 3446 (O–H),
1623 (CꢂN) cmꢁ1; MS (EIꢀ), m/z (%): [Mꢀ, 317] (100), 210 (92), 197 (10).
Observed: 520.1055.
2c Dibutyl({2,2ꢃ-[2,6-pyridinediylbis(methylidynenitrilo)]bis(4-
chlorophenolato)}(2-))tin: 0.25 g (1.85 mmol) of 2,6-pyridinedicarboxalde-
hyde, 0.530 g (3.70 mmol) of 2-amino-4-chlorophenol and 0.46 g (1.85
mmol) of dibutyltin oxide, 8 h, 1.05 g (93%) yield, purple solid; mp 245 °C
(dec.); 1H-NMR (300 MHz, CDCl3) d: 0.50 (6H, t, Jꢂ5.7 Hz, H-14), 0.71—
1b N,Nꢃ-(2,6-Pyridinediyldimethylidyne)bis(2-hydroxy-5-methylben- 0.92 (12H, m, H-11, H-13, H-12), 7.01 (2H, d, Jꢂ9.0 Hz, H-8), 7.18 (2H, d,
zenamine): 0.25 g (1.85 mmol) of 2,6-pyridinedicarboxaldehyde and 0.455 g Jꢂ8.4 Hz, H-9), 7.49 (2H, s, H-6), 7.83 (2H, d, Jꢂ7.1 Hz, H-2), 8.19 ( 1H, t,
(3.70 mmol) of 2-amino-4-methylphenol, ethanol, 6 h, 0.61 g (98%) yield,
Jꢂ6.9 Hz, H-1), 8.69 (2H, s, H-4); 13C-NMR (75 MHz, CDCl3) d: 13.5 (C-
1
yellow solid; mp 170—174 °C; H-NMR (300 MHz, CDCl3) d: 1.65 (6H, s, 14), 26.4 (C-11), 27.6 (C-13), 31.1 (C-12), 116.4 (C-9), 119.8 (C-6), 124.2
H-11), 6.21 (2H, d, Jꢂ8.2 Hz, H-8), 6.33 (2H, dd, Jꢂ8.2, 1.5 Hz, H-9), 6.47
(2H, s, H-6), 7.33 (1H, t, Jꢂ 7.8 Hz, H-1), 7.81 ( 2H, d, Jꢂ7.8 Hz, H-2),
8.16 (2H, s, H-4); 13C-NMR (75 MHz, CDCl3) d: 20.1 (C-11), 115.7 (C-9),
118.3 (C-6), 123.0 (C-2), 128.3 (C-7), 129.1 (C-8), 135.3 (C-5), 136.8 (C-1),
149.5 (C-10), 154.2 (C-3), 157.1 (C-4); IR nmax (KBr): 3400 (O–H), 1624
(C-2), 125.8 (C-7), 130.1 (C-8), 133.9 (C-1), 138.0 (C-5), 140.9 (C-10),
148.6 (C-3), 165.0 (C-4); 119Sn-NMR (112.04 MHz, CDCl3) d: ꢁ397.5; IR
nmax (KBr): 1568 (CꢂN), 1472 (CH2), 1316 (CH3), 637 (Sn–C), 579
(Sn–O), 432 (Sn–N), cmꢁ1; MS (EIꢀ), m/z (%): [Mꢀ, 617] (4), [Mꢀꢁ57,
560] (100), [Mꢀꢁ2Bu, 503] (19), 383 (3), 348 (8), 272 (7). Anal. Calcd for
(CꢂN) cmꢁ1; MS (EIꢀ), m/z (%): [Mꢀ, 345] (42), 224 (65), 210 (27), 134 C27H29N3O2Cl2Sn: C, 52.51; H, 4.70; N, 6.80. Found C, 53.52; H, 4.59; N,
(48).
1c N,Nꢃ-(2,6-Pyridinediyldimethylidyne)bis(5-chloro-2-hydroxyben-
zenamine): 0.25 g (1.85 mmol) of 2,6-pyridinedicarboxaldehyde and 0.530 g phenolato)}(2-))tin: 0.25 g (1.85 mmol) of 2,6-pyridinedicarboxaldehyde,
(3.70 mmol) of 2-amino-4-chlorophenol, ethanol, 6 h, 0.59 g (84%) yield, 0.57.1 g (3.70 mmol) of 2-amino-4-nitrophenol and 0.46 g (1.85 mmol) of
6.44.
2d Dibutyl({2,2ꢃ-[2,6-pyridinediylbis(methylidynenitrilo)]bis(4-nitro-
1
1
brown solid; pf 180—185 °C; H-NMR (300 MHz, CDCl3) d: 6.87 (2H, d, dibutyltin oxide, 8 h, 1.17 g (99%) yield, dark red solid; mp ꢄ300 °C; H-
Jꢂ8.6 Hz, H-8), 7.03 (2H, d, Jꢂ8.2 Hz, H-9), 7.18 (2H, s, H-6), 7.91 (1H, t, NMR (300 MHz, CDCl3) d: 0.45 (6H, t, Jꢂ3.9 Hz, H-14), 0.68—0.85 (12H,
Jꢂ7.6 Hz, H-1), 8.42 ( 2H, d, Jꢂ7.3 Hz, H-2), 8.70 (2H, s, H-4); 13C-NMR m, H-11, H-13, H-12), 7.01 (2H, d, Jꢂ9.1 Hz, H-8), 7.18 (2H, d, Jꢂ7.1 Hz,
(75 MHz, CDCl3) d: 117.6 (C-9), 118.8 (C-6), 123.8 (C-2), 124.2 (C-7),
128.2 (C-8), 137.3 (C-5), 137.5 (C-1), 150.8 (C-10), 154.5 (C-3), 159.7 (C-
4); IR nmax (KBr): 3381 (O–H), 1624 (CꢂN) cmꢁ1; MS (EIꢀ), m/z (%):
[Mꢀ, 384] (11), 368 (5), 258 (13), 244 (100).
H-9), 7.49 (2H, s, H-6), 8.17 (2H, d, Jꢂ7.7 Hz, H-2), 8.34 ( 1H, t, Jꢂ7.9 Hz,
H-1), 9.41 (2H, s, H-4); 13C-NMR (75 MHz, CDCl3) d: 13.5 (C-14), 26.2
(C-11), 27.3 (C-13), 30.8 (C-12), 114.9 (C-9), 121.8 (C-6), 128.5 (C-2),
128.6 (C-7), 129.3 (C-8), 135.6 (C-1), 142.3 (C-5), 144.4 (C-10), 148.0 (C-
3), 171.0 (C-4); 119Sn-NMR (112.04 MHz, CDCl3) d: ꢁ400.9; IR nmax
1d N,Nꢃ-(2,6-Pyridinediyldimethylidyne)bis(2-hydroxy-5-nitroben-
zenamine): 0.25 g (1.85 mmol) of 2,6-pyridinedicarboxaldehyde and 0.571 g (KBr): 1570 (CꢂN), 1487 (CH2), 631 (Sn–C), 578 (Sn–O), 423 (N→Sn)
(3.70 mmol) of 2-amino-4-nitrophenol, toluene, 8 h, 0.68 g (91%) yield,
cmꢁ1; MS (FABꢀ), m/z (%): [Mꢀꢀ1, 640] (41), [Mꢀꢁ57, 582] (50),
1
green solid; mp 142—144 °C; H-NMR (300 MHz, CDCl3) d: 7.02 (2H, d, [Mꢀꢁ2Bu, 524] (28), 585 (24), 478 (5). Anal. Calcd for C27H29N5O6Sn: C,
Jꢂ8.5 Hz, H-9), 7.69 (2H, s, H-6), 8.06 (2H, br s, H-8), 8.01 (1H, t,
Jꢂ7.6 Hz, H-1), 8.47 ( 2H, d, Jꢂ7.6 Hz, H-2), 8.81 (2H, s, H-4); 13C-NMR
(75 MHz, CDCl3) d: 115.6 (C-9), 116.6 (C-6), 124.1 (C-2), 124.4 (C-7),
137.3 (C-8), 137.6 (C-1), 140.6 (C-5), 154.3 (C-10), 158.0 (C-3), 161.8 (C-
4); IR nmax (KBr): 3888 (O–H), 1624 (CꢂN) cmꢁ1; MS (EIꢀ), m/z (%):
[Mꢀ, 407] (25), 390 (33), 269 (8), 255 (20), 241 (64).
50.70; H, 4.53; N, 10.95. Found C, 49.78; H, 4.28; N, 10.13.
2e Dimethyl({2,2ꢃ-[2,6-pyridinediylbis(methylidynenitrilo)]bis(pheno-
lato)}(2-))tin: 0.25 g (1.85 mmol) of 2,6-pyridinedicarboxaldehyde, 0.402 g
(3.70 mmol) of 2-aminophenol and 0.305 g of (1.85 mmol) dimethyltin
oxide, 30 h, 0.78 g (90%) yield, red solid; pf 200 °C (dec.); 1H-NMR
(300 MHz, CDCl3) d: 0.20 (6H, s, 2J (119Sn–1H)ꢂ111.9 Hz, 2J (117Sn–
General Procedure for the Preparation of Tin Complexes Tin com- 1H)ꢂ111.6 Hz, Sn–CH3), 6.60 (2H, td, Jꢂ8.2, 1.2 Hz, H-7), 7.12 (2H,
plexes were prepared under anhydrous conditions in a solution of tolu- dd, Jꢂ8.2, 1.5 Hz, H-6), 7.28 (2H, td, Jꢂ8.6, 1.5 Hz, H-8), 7.52 (2H, dd,
ene/methanol (4 : 1 v/v 60 ml) using a 1 : 2 : 1 molar ratio of 2,6-pyridine-
Jꢂ8.2, 1.5 Hz, H-9), 7.76 (2H, dd, Jꢂ7.8, 1.0 Hz, H-2), 8.14 (1H, t,
dicarboxaldehyde, aminophenol and the corresponding tin oxide. The reac- Jꢂ7.8 Hz, H-1), 8.68 (2H, s, H-4); 13C-NMR (75 MHz, CDCl3) d: 11.9
tion mixture was refluxed with constant stirring for the time indicated for (Sn–CH3), 115.2 (C-9), 116.6 (C-6), 123.6 (C-7), 125.2 (C-2), 129.5 (C-8),
each compound, the solvent was removed under reduced pressure and tin 134.1 (C-1), 136.6 (C-5), 140.5 (C-10), 148.2 (C-3), 166.0 (C-4); 119Sn-
complexes were recrystallized from dichloromethane.
NMR (112.05 MHz, CDCl3) d: ꢁ398.2; IR nmax (KBr): 1565 (CꢂN), 1376
2a Dibutyl({2,2ꢃ-[2,6-pyridinediylbis(methylidynenitrilo)]bis(pheno- (CH3), 630 (Sn–C), 569 (Sn–O), 437 (Sn–N) cmꢁ1; MS (FABꢀ), m/z (%):
lato)}(2-))tin: 0.25 g (1.85 mmol) of 2,6-pyridinedicarboxaldehyde, 0.402 g [Mꢀꢀ1, 466 (11)], [MꢀꢁCH3, 450] (13), 435 (2), 154 (100). HR-MS
(3.70 mmol) of 2-aminophenol and 0.46 g (1.85 mmol) of dibutyltin oxide,
(FABꢀ) m/z: 466.0578 Calcd for C21H19N3O2Sn. Observed: 466.0574.
2f Dimethyl({2,2ꢃ-[2,6-pyridinediylbis(methylidynenitrilo)]bis(4-
8 h, 0.56 g (95%) yield, dark red solid; mp 275 °C; 1H-NMR (300 MHz,
CDCl3) d: 0.50 (6H, t, Jꢂ6.6 Hz, H-14), 0.71—0.92 (12H, m, H-11, H-13, methylphenolato)}(2-))tin: 0.25 g (1.85 mmol) of 2,6-pyridinedicarboxalde-
H-12), 6.57 (2H, t, Jꢂ7.3 Hz, H-7), 7.11 (2H, d, Jꢂ8.4 Hz, H-6), 7.23 (2H, hyde, 0.445 g (3.70 mmol) of 2-amino-4-methylphenol and 0.305 g (1.85
t, Jꢂ8.2 Hz, H-8), 7.52 (2H, t, Jꢂ7.9 Hz, H-9), 7.78 ( 2H, d, Jꢂ 7.6 Hz, H- mmol) of dimethyltin oxide, 30 h, 0.80 g (88%) yield, black solid; mp
2), 8.15 (1H, t, Jꢂ7.7 Hz, H-1), 8.71 ( 2H, s, H-4); 13C-NMR (75 MHz,
CDCl3) d: 13.5 (C-14), 26.6 (C-11), 27.7 (C-13), 31.1 (C-12), 115.0 (C-9),
116.7 (C-6), 123.3 (C-7), 125.2 (C-2), 130.1 (C-8), 134.0 (C-1), 137.0 (C-5),
250 °C; 1H-NMR (300 MHz, CDCl3) d: 0.03 (6H, s, 2J (119Sn–1H)ꢂ
114.0 Hz, 2J (117Sn–1H)ꢂ109.0 Hz, Sn–CH3), 2.50 (6H, s, CH3), 6.83 (2H, d,
Jꢂ8.5 Hz, H-8), 7.00 (2H, dd, Jꢂ8.6, 2.0 Hz, H-9), 7.53 (2H, s, H-6), 7.83
140.6 (C-10), 149.0 (C-3), 166.6 (C-4); 119Sn-NMR (112.04 MHz, CDCl3) (2H, d, Jꢂ7.8 Hz, H-2), 8.13 (1H, t, Jꢂ7.8 Hz, H-1), 8.76 (2H, s, H-4); 13C-
d: ꢁ404.5; IR nmax (KBr): 1568 (CꢂN), 1472 (CH2), 633 (Sn–C), 564 NMR (75 MHz, CDCl3) d: 12.1 (C-11, J (119Sn–13C)ꢂ1224.1 Hz, J (117Sn–
(Sn–O), 436 (Sn–N) cmꢁ1; MS (EIꢀ), m/z (%): [Mꢀ, 549] (3), [Mꢀꢁ57, 13C)ꢂ1171.1 Hz), 20.6 (C-12), 116.9 (C-9), 122.4 (C-6), 124.1 (C-2), 126.0
492] (100), [Mꢀꢁ2Bu, 435] (9), 315 (13), 239 (8). HR-MS (FABꢀ) m/z:
492.0734 Calcd for C23H21N3O2Sn. Observed: 492.0737.
(C-7), 129.1 (C-8), 135.1 (C-1), 137.9 (C-5), 141.0 (C-10), 148.1 (C-3),
163.5 (C-4); 119Sn-NMR (112.05 MHz, CDCl3) d: ꢁ392.8; IR nmax (KBr):
2b Dibutyl({2,2ꢃ-[2,6-pyridinediylbis(methylidynenitrilo)]bis(4- 1575 (CꢂN), 1392 (CH3), 635 (Sn–C), 438 (Sn–N) cmꢁ1; MS ( FABꢀ), m/z
methylphenolato)}(2-))tin: 0.25 g (1.85 mmol) of 2,6-pyridinedicarboxalde- (%): [Mꢀ1, 494], [MꢀꢁCH3, 478] (22). [Mꢀꢁ2CH3, 463] (5), 448 (1) 330
hyde, 0.445 g (3.70 mmol) of 2-amino-4-methylphenol and 0.46 g (1.85 (2). HR-MS (FABꢀ) m/z: 494.0891 Calcd for C23H23N3O2Sn. Observed:
mmol) of dibutyltin oxide, 8 h, 0.94 g (93%) yield, black solid; mp 160 °C; 494.0896.
1H-NMR (300 MHz, CDCl3) d: 0.50 (6H, t, Jꢂ6.2 Hz, H-14), 0.71—0.92
(12H, m, H-11, H-13, H-12), 2.27 (6H, s, H-15), 7.01 (2H, d, Jꢂ8.6 Hz, H-
9), 7.10 (2H, dd, Jꢂ8.6, 1.9 Hz, H-8), 7.31 (2H, s, H-6), 7.71 (2H, d,
2g Dimethyl({2,2ꢃ-[2,6-pyridinediylbis(methylidynenitrilo)]bis(4-
chlorophenolato)}(2-))tin: 0.25 g (1.85 mmol) of 2,6-pyridinedicarboxalde-
hyde, 0.530 g (3.70 mmol) of 2-amino-4-chlorophenol and 0.305 g (1.85
Jꢂ7.7 Hz, H-2), 8.11 ( 1H, t, Jꢂ7.7 Hz, H-1), 8.67 (2H, s, H-4); 13C-NMR mmol) of dimethyl tin oxide, 30 h, 0.94 g (95%) yield, red solid; mp
(75 MHz, CDCl3) d: 13.5 (C-14), 20.7 (C-15), 26.5 (C-11), 27.7 (C-13),
31.0 (C-12), 116.2 (C-9), 123.0 (C-6), 124.0 (C-2), 124.7 (C-7), 129.5 (C-8),
135.5 (C-1), 136.0 (C-5), 140.3 (C-10), 149.1 (C-3), 164.8 (C-4); 119Sn-
220 °C (dec.); 1H-NMR (300 MHz, CDCl3) d: 0.05 (6H, s, 2J (119Sn–
1H)ꢂ111.5 Hz, Sn–CH3), 6.85 (2H, d, Jꢂ8.9 Hz, H-8), 7.08 (2H, d, Jꢂ
8.4 Hz, H-9), 7.58 (2H, s, H-6), 7.95 (2H, d, Jꢂ7.4 Hz, H-2), 8.20 (1H, t, Jꢂ

January 2009
7
7.1 Hz, H-1), 8.94 (2H, s, H-4); 13C-NMR (75 MHz, CDCl3) d: 12.0
(Sn–CH3), 117.2 (C-9), 119.4 (C-6), 123.7 (C-2), 127.1 (C-7), 130.0 (C-8),
133.3 (C-1), 140.6 (C-5), 141.5 (C-10), 147.8 (C-3), 163.7 (C-4); 119Sn-
NMR (112.04 MHz, CDCl3) d: ꢁ388.9; IR nmax (KBr): 1569 (CꢂN), 1387
(CH3), 635 (Sn–C), 437 (N–Sn) cmꢁ1; MS (FABꢀ), m/z (%): [Mꢀꢀ1, 534]
(10), [MꢀꢁCH3, 518] (13), [Mꢀꢁ2CH3, 503] (2), 377(1). HR-MS (FABꢀ)
m/z: 533.9798 Calcd for C21H17N3O2Cl2Sn. Observed: 533.9796.
13.6 (Sn–(CH2)3–CH3),19.0 (CH3), 26.4 (Sn–CH2–(CH2)2–CH3), 28.0
(Sn–(CH2)2–CH2–CH3), 31.7 (Sn–CH2–CH2–CH2–CH3), 118.0 (C-9), 122.2
(C-6), 123.1 (C-2), 123.9 (C-7), 131.5 (C-8), 131.9 (C-1), 141.2 (C-5), 151.0
(C-10), 151.9 (C-3), 164.5 (C-4); 119Sn-NMR (112.04 MHz, CDCl3) d:
ꢁ392.1; IR nmax (KBr): 1582 (CꢂN), 1366 (CH3), 583 (Sn–O), 431
(N→Sn) cmꢁ1; MS (FABꢀ) m/z (%): [(Mꢀꢀ1), 646] (4), [(Mꢀꢁ57), 588]
(8), [(Mꢀꢁ2Bu), 531] (2) 516 (2), 307 (25). HR-MS (FABꢀ) m/z: 588.0268
Calcd for C25H23N3O2Cl2Sn. Observed: 588.0259.
2h Dimethyl({2,2ꢃ-[2,6-pyridinediylbis(methylidynenitrilo)]bis(4-nitro-
phenolato)}(2-))tin: 2,6-Pyridinedicarboxaldehyde, 0.57 g (3.70 mmol) of 2-
amino-4-nitrophenol and 0.305 g (1.85 mmol) of dimethyl tin oxide, 30 h,
0.92 g (90%) yield, orange solid; mp ꢄ300 °C; 13C-NMR CPMAS
(75.4 MHz) d: 11.8 (Sn–CH3), 13.6 (Sn–CH3), 118.1 (C-9), 121.6 (C-6),
123.6, 127.1, 127.7, 130.5 (arom), 134.6 (C-1), 137.0, 137.9 (arom), 143.4
(C-5), 146.3 (C-10), 147.4 (C10ꢃ), 150.5 (C-3), 170.4 (C-4), 172.5 (C-4ꢃ)
127.1 (C-7), 130.0 (C-8), 133.3 (C-1), 140.6 (C-5), 141.5 (C-10), 147.8 (C-
2m Dibutyl({2,2ꢃ-[2,6-pyridinediylbis(ethylidynenitrilo)]bis(4-nitrophe-
nolato)}(2-))tin: 0.25 g (1.53 mmol) of 2,6-diacetylpyridine, 0.472 g (3.06
mmol) of 2-amino-4-nitrophenol and 0.381 g (1.85 mmol) dibutyltin oxide,
1
8 h, 0.96 g (94%) yield, orange solid; H-NMR (300 MHz, CDCl3) d: 0.52
(6H, t, Jꢂ6.7 Hz, Sn–(CH2)3–CH3), 0.68—0.94 (12H, m, Sn–CH2–CH3),
3.04 (6-H, s, CH3), 7.10 (2H, d, Jꢂ9.3 Hz, H-9), 8.18 (2H, d, Jꢂ9.4, 2.7 Hz,
H-8), 8.23 (2H, d, Jꢂ7.8 Hz, H-2), 8.41 (2H, d, Jꢂ2.9 Hz, H-6), 8.45 (1H,
t, Jꢂ8.1 Hz, H-1); 13C-NMR (75 MHz, CDCl3) d: 13.5 (Sn–(CH2)3–CH3),
19.3 (CH3), 26.2 (Sn–CH2–(CH2)2–CH3), 28.0 (Sn–(CH2)2–CH2–CH3), 31.9
(Sn–CH2–CH2–CH2–CH3), 120.0 (C-9), 121.5 (C-6), 125.3 (C-2), 127.9
(C-7), 130.0 (C-8), 135.1 (C-1), 142.2 (C-5), 150.6 (C-10), 155.5 (C-3),
171.4 (C-4); 119Sn-NMR (112.04 MHz, CDCl3) d: ꢁ392.4; IR nmax (KBr):
3), 163.7 (C-4); IR nmax (KBr): 1594 (CꢂN), 646 (Sn–C), 568 (Sn–O) cmꢁ1
;
MS (FABꢀ), m/z (%): [Mꢀꢀ1, 556] (3), [MꢀꢁCH3, 540] (2), [Mꢀꢁ2CH3,
525] (1). Anal. Calcd for C21H17N5O6Sn: C, 45.40; H, 3.06; N, 12.61. Found
C, 46.35; H, 3.96; N, 12.23.
2i Diphenyl({2,2ꢃ-[2,6-pyridinediylbis(methylidynenitrilo)]bis(pheno-
lato)}(2-))tin: 0.25 g (1.85 mmol) of 2,6-diacetylpyridine, 0.402 g (3.70
mmol) of 2-aminophenol and 0.534 g (1.85 mmol) diphenyltin oxide, 24 h,
1585 (CꢂN), 1366 (CH3), 618 (Sn–C), 573 (Sn–O), 435 (N→Sn) cmꢁ1
;
MS (FABꢀ) m/z (%): [(Mꢀꢀ1), 668] (4), [(Mꢀꢁ57), 611] (2), 307 (19).
HR-MS (FABꢀ) m/z: 610.0749 Calcd for C25H23N5O6Sn. Observed:
610.0758.
1
0.98 g (90%) yield, dark red solid; H-NMR (300 MHz, DMSO-d6) d: 6.51
(2H, td, Jꢂ6.9, 1.2 Hz, H-7), 6.82—6.90 (6H, m, H-13, H-14 arom), 6.93
(2H, dd, Jꢂ7.1, 1.1 Hz, H-6), 7.05—7.09 (4H, m, H-12 arom), 7.15 (2H, td,
Jꢂ8.4, 1.1 Hz, H-8), 7.54 (2H, d, Jꢂ7.4 Hz, H-9), 7.99 (2H, d, Jꢂ7.6 Hz, H-
2), 8.24 (1H, t, Jꢂ7.6 Hz, H-1), 9.05 (2H, s, H-4); 13C-NMR CPMAS
(75.4 MHz) d: 117.4 (C-9), 118.8 (C-6), 120.5 (C-7), 124.6 (C-2), 127.0,
131.1, 133.2 arom, 134.9 (C-1), 137.6 arom, 139.7 (C-11), 145.8 (C-10),
147.9 (C-10ꢃ), 154.4 (C-3), 156.4 (C-3ꢃ), 165.7 (C-4); 119Sn-NMR
(112.05 MHz, DMSO-d6) d: ꢁ521.0; IR nmax (KBr): 1561 (CꢂN), 633
(Sn–C), 565 (Sn–O), 412 (Sn–N) cmꢁ1; MS (FABꢀ) m/z (%): [(Mꢀꢀ1),
590] (8), [(Mꢀꢁ77) 512] (20), [(Mꢀꢁ2Ph) 434] (4), 391 (20). HR-MS
(FABꢀ) m/z: 512.0421 Calcd for C25H17N3O2Sn. Observed: 512.0405.
2j Dibutyl({2,2ꢃ-[2,6-pyridinediylbis(ethylidynenitrilo)]bis(pheno-
lato)}(2-))tin: 0.25 g (1.53 mmol) of 2,6-diacetylpyridine, 0.334 g (3.06
mmol) of 2-aminophenol and 0.381 g (1.53 mmol) of dibutyltin oxide, 8 h,
0.82 g (93%) yield, orange solid; 1H-NMR (300 MHz, CDCl3) d: 0.48 (6H, t,
Jꢂ6.8 Hz, Sn–(CH2)3–CH3), 0.71—0.94 (12H, m, Sn–CH2–CH3), 2.88 (6-H,
s, CH3), 6.56 (2H, td, Jꢂ8.3, 1.6 Hz, H-7), 7.13 (2H, dd, Jꢂ8.5, 1.6 Hz, H-
6), 7.22 (2H, td, Jꢂ8.5, 1.6 Hz, H-8), 7.35 (2H, dd, Jꢂ8.2, 1.3 Hz, H-9),
7.99 (2H, d, Jꢂ7.8 Hz, H-2), 8.24 (1H, t, Jꢂ7.5 Hz, H-1); 13C-NMR
(75 MHz, CDCl3) d: 13.6 (Sn–(CH2)3–CH3), 19.0 (CH3), 26.5 (Sn–CH2–
(CH2)2–CH3), 28.0 (Sn–(CH2)2–CH2–CH3), 31.6 (Sn–CH2–CH2–CH2–CH3),
113.5 (C-9), 122.3 (C-6), 122.9 (C-7), 123.3 (C-2), 131.6 (C-8), 132.0
(C-1), 140.8 (C-5), 150.5 (C-10), 151.2 (C-3), 166.1 (C-4); 119Sn-NMR
(112.05 MHz, CDCl3) d: ꢁ398.2; IR nmax (KBr): 1582 (CꢂN), 1365 (CH3),
574 (Sn–O), 434 (N→Sn) cmꢁ1; MS (FABꢀ) m/z (%): [(Mꢀꢀ1), 578] (29),
[(Mꢀꢁ57), 520] (56), [(Mꢀꢁ2Bu), 463] (13), 448 (15), 307 (61). HR-MS
(FABꢀ) m/z: 578.1830 Calcd for C29H35N3O2Sn. Observed: 578.1828.
2k Dibutyl({2,2ꢃ-[2,6-pyridinediylbis(ethylidynenitrilo)]bis(4-methylphe-
nolato)}(2-))tin: 0.25 g (1.53 mmol) of 2,6-diacetylpyridine, 0.377 g (3.06
mmol) of 2-amino-4-methylphenol and 0.381 g (1.53 mmol) of dibutyl-
tin oxide, 8 h, 0.86 g (93%) yield, dark red solid; 1H-NMR (300 MHz,
CDCl3) d: 0.48 (6H, t, Jꢂ6.8 Hz, Sn–(CH2)3–CH3), 0.68—0.94 (12H, m,
Sn–(CH2)3–CH3), 2.27 (6H, s, CH3), 2.88 (6-H, s, CH3), 7.04 (2H, d,
Jꢂ1.2 Hz, H-8), 7.16 (2H, s, H-6), 7.25 (2H, s, H-9), 7.96 (2H, d, Jꢂ7.8 Hz,
H-2), 8.22 ( 1H, t, Jꢂ7.7 Hz, H-1); 13C-NMR (75 MHz, CDCl3) d: 13.5
(Sn–(CH2)3–CH3), 19.0 (CH3), 20.7 (CH3), 26.5 (Sn–CH2–(CH2)2–CH3),
28.0 (Sn–(CH2)2–CH2–CH3), 31.5 (Sn–CH2–CH2–CH2–CH3), 121.9 (C-9),
122.4 (C-6), 122.8 (C-2), 123.0 (C-7), 130.8 (C-8), 133.2 (C-1), 140.6 (C-5),
149.7 (C-10), 151.3 (C-3), 164.0 (C-4); 119Sn-NMR (112.05 MHz, CDCl3)
d: ꢁ396.3; IR nmax (KBr): 1584 (CꢂN), 1366 (CH3), 617 (Sn–C), 587
(Sn–O), 432 (N→Sn) cmꢁ1; MS (FABꢀ) m/z (%): [(Mꢀꢀ1), 606] (65),
[(Mꢀꢁ57), 548] (100), [(Mꢀꢁ2Bu), 491] (40), 476 (12), 307 (36). HR-MS
(FABꢀ) m/z: 606.2143 Calcd for C31H39N3O2Sn. Observed: 606.2149.
2l Dibutyl({2,2ꢃ-[2,6-pyridinediylbis(ethylidynenitrilo)]bis(4-chlorpheno-
lato)}(2-))tin: 0.25 g (1.53 mmol) of 2,6-diacetylpyridine, 0.439 g (3.06
mmol) of 2-amino-4-chlorophenol and 0.381 g (1.53 mmol) of dibutyl-
tin oxide, 8 h, 0.87 g (88%) yield, purple solid; 1H-NMR (300 MHz, CDCl3)
d: 0.49 (6H, t, Jꢂ6.3 Hz, Sn–(CH2)3–CH3), 0.67—0.94 (12H, m, Sn–
(CH2)3–CH3), 2.88 (6-H, s, CH3), 7.04 (2H, d, Jꢂ8.9 Hz, H-8), 7.15 (2H,
dd, Jꢂ8.9, 2.0 Hz, H-9), 7.33 (2H, d, Jꢂ1.9 Hz, H-6), 8.04 (2H, d, Jꢂ
7.8 Hz, H-2), 8.28 (1H, t, Jꢂ7.8 Hz, H-1); 13C-NMR (75 MHz, CDCl3) d:
2n Dimethyl({2,2ꢃ-[2,6-pyridinediylbis(ethylidynenitrilo)]bis(pheno-
lato)}(2-))tin: 0.25 g (1.53 mmol) of 2,6-diacetylpyridine, 0.334 g (3.06
mmol) of 2-aminophenol and 0.252 g (1.53 mmol) dimethyltin oxide, 45 h,
0.73 g (96%) yield, red solid; 1H-NMR (300 MHz, CDCl3) d: ꢁ0.31 (6H, s,
2J (119Sn–1H)ꢂ114.0 Hz, 2J (117Sn–1H)ꢂ107.2 Hz, Sn–CH3), 2.73 (6-H, s,
CH3), 6.18 (2H, td, Jꢂ8.4, 1.5 Hz, H-7), 6.61 (2H, dd, Jꢂ8.3, 1.3 Hz, H-6),
6.79 (2H, td, Jꢂ8.5, 1.6 Hz, H-8), 7.03 (2H, dd, Jꢂ8.2, 1.3 Hz, H-9), 7.78
(2H, d, Jꢂ7.8 Hz, H-2), 7.97 (1H, t, Jꢂ7.4 Hz, H-1); 13C-NMR (75 MHz,
CDCl3) d: 12.3 (Sn–CH3), 18.8 (CH3), 113.7 (C-9), 121.5 (C-6), 123.0 (C-
7), 124.1 (C-2), 130.8 (C-8), 131.5 (C-1), 141.3 (C-5), 149.8 (C-10), 151.5
(C-3), 164.7 (C-4); 119Sn-NMR (112.05 MHz, CDCl3) d: ꢁ388.6; IR nmax
(KBr): 1583 (CꢂN), 1367 (CH3), 576 (Sn–O), 435 (N→Sn) cmꢁ1; EM
(FABꢀ) m/z (%): [(Mꢀꢀ1), 494] (28), [(Mꢀꢁ15), 478] (40), [(Mꢀꢁ2CH3),
463] (5), 448 (8). HR-MS (FABꢀ) m/z: 494.0891 Calcd for C23H23N3O2Sn.
Observed: 494.0883.
2o Dimethyl({2,2ꢃ-[2,6-pyridinediylbis(ethylidynenitrilo)]bis(4-meth-
ylphenolato)}(2-))tin: 0.25 g (1.53 mmol) of 2,6-diacetylpyridine, 0.377 g
(3.06 mmol) of 2-amino-4-methylphenol and 0.252 g (1.53 mmol) dimethyl-
tin oxide, 45 h, 0.73 g (91%) yield, dark red solid; 1H-NMR (300 MHz,
CDCl3) d: 0.10 (6H, s, 2J (119Sn–1H)ꢂ111.9 Hz, 2J (117Sn–1H)ꢂ107.1 Hz,
Sn–CH3), 2.27 (6-H, s, CH3), 2.86 (6-H, s, CH3), 7.04 (2H, H-8), 7.17 (2H,
s, H-6), 7.25 (2H, s, H-9), 7.97 (2H, d, Jꢂ7.9 Hz, H-2), 8.22 (1H, t,
Jꢂ7.7Hz, H-1); 13C-NMR (75 MHz, CDCl3) d: 12.5 (C–Sn–CH3), 19.0
(CH3), 20.9 (CH3), 122.1 (C-9), 122.9 (C-6), 123.3 (C-2), 128.2 (C-7), 130.6
(C-8), 133.3 (C-1), 140.8 (C-5), 149.8 (C-10), 150.6 (C-3), 163.2 (C-4);
119Sn-NMR (112.05 MHz, CDCl3) d: ꢁ381.8; IR nmax (KBr): 1585 (CꢂN),
1368 (CH3), 617 (Sn–C), 587, (Sn–O), 424 (Sn–N) cmꢁ1; EM (FABꢀ) m/z
(%): [(Mꢀꢀ1), 522] (28), [(Mꢀꢁ15), 506] (50), [(Mꢀꢁ2CH3), 491] (8),
476 (12), 307 (21). HR-MS (FABꢀ) m/z: 522.1204 Calcd for C25H27N3O2Sn.
Observed: 522.1198.
2p Dimethyl({2,2ꢃ-[2,6-pyridinediylbis(ethylidynenitrilo)]bis(4-chlo-
rophenolato)}(2-))tin: 0.25 g (1.53 mmol) of 2,6-diacetylpyridine, 0.439 g
(3.06 mmol) of 2-amino-4-chlorophenol and 0.252 g (1.53 mmol) of dimethy-
ltin oxide, 45 h, 0.60 g (70%) yield, purple solid; 1H-NMR (300 MHz,
CDCl3) d: 0.11 (6H, s, 2J (119Sn–1H)ꢂ111.3 Hz, 2J (117Sn–1H)ꢂ106.8 Hz,
Sn–CH3), 2.88 (6-H, s, H-12), 7.03 (2H, d, Jꢂ8.9 Hz, H-8), 7.16 (2H, dd,
Jꢂ8.9, 2.4 Hz, H-9), 7.35 (2H, d, Jꢂ2.3 Hz, H-6), 8.05 (2H, d, Jꢂ7.8 Hz,
H-2), 8.28 (1H, t, Jꢂ7.8 Hz, H-1); 13C-NMR (75 MHz, CDCl3) d: 12.5
(CH3–Sn, J (119Sn–13C)ꢂ1200 Hz, J (117Sn–13C)ꢂ1155.3 Hz), 19.0 (CH3),
118.6 (C-9, J (119Sn–13C)ꢂ557.6 Hz), 122.4 (C-6), 123.2 (C-2), 124.2 (C-7),
131.0 (C-8), 132.1 (C-1), 141.3 (C-5), 150.3 (C-10), 151.8 (C-3), 163.6
(C-4); 119Sn-NMR (112.04 MHz, CDCl3) d: ꢁ376.2; IR nmax (KBr): 1584
(CꢂN), 1369 (CH3), 583 (Sn–O), 437 (N→Sn) cmꢁ1; EM (FABꢀ) m/z
(%): [(Mꢀꢀ1), 562] (20), [(Mꢀꢁ15), 546] (36), [(Mꢀꢁ2CH3), 531] (4), 516
(5), 307(18). HR-MS (FABꢀ) m/z: 562.0111 Calcd for C23H21N3O2Cl2Sn.
Observed: 562.0118.
2q Dimethyl({2,2ꢃ-[2,6-pyridinediylbis(ethylidynenitrilo)]bis(4-nitrophe-
nolato)}(2-))tin: 0.25 g (1.53 mmol) of 2,6-diacetylpyridine, 0.472 g (3.06
mmol) of 2-amino-4-nitrophenol and 0.252 g (1.53 mmol) dimethyltin oxide,
45 h, 0.85 g (95%) yield, orange solid; 13C-NMR CPMAS (75.4 MHz) d:

8
Vol. 57, No. 1
14.3 (Sn–CH3), 19.4 (CH3), 122.4, 127.0, 130.3 (arom), 135.0 (C-1), 146.1
(C-10), 150.2 (C-10ꢃ) 157.9 (C-3), 159.7 (C-3ꢃ) 171.0 (C-4); IR nmax (KBr):
1581 (CꢂN), 574 (Sn–O), 432 (N→Sn) cmꢁ1; EM (FABꢀ) m/z (%):
[(Mꢀꢀ1), 584] (0.6), [(Mꢀꢁ15), 568] (0.5), [(Mꢀꢁ2CH3), 553] (1),
307(22). Anal. Calcd for C23H21N5O6Sn: C, 47.34; H, 3.60; N, 12.00. Found
C, 47.02; H, 3.44; N, 11.79.
for 10 min, then was centrifuged at 10000 rpm for 5 min and finally heated at
95 °C in a boiling water bath for 30 min. After cooling on ice, the ab-
sorbance of supernatant (200 ml) was measured at 540 nm in a microplate
reader Elx808 BIO-TEK instruments. a-Tocopherol was used as a positive
control. Concentration of TBARS was calculated by interpolation in a stan-
dard curve of tetrametoxipropane (TMP).56) Final results were expressed as
nmoles of TBARS per mg of protein. The inhibition ration (%) was calcu-
lated using the following formula:
Anti-inflammatory Activity. Mouse Ear Edema The assay of TPA-
induced ear edema in mice was based on the method described by Merlos et
al.50) A group of six male NIH mice were anesthetized with Sedaphorte® and
a solution of 12-O-tetradecanoylphorbol-13-acetate (2.5 mg) dissolved in
ethanol (10 ml) was topically applied to both faces of the right ear of the
mice (5 ml each face). The left ear received only ethanol (10 ml). After
10 min of TPA-treatment, doses of 0.031 to 1.0 mmol of the test compounds,
or indomethacin as reference, dissolved in 20 ml of acetone were applied to
both faces of the right ear (10 ml each face). Control animals received only
acetone–dichloromethane. Four hours later the animals were sacrificed by
cervical dislocation and a plug (7 mm diameter) was removed from each ear.
The edematous response was measured as the weight difference between
the two plugs. The % inhibition of edema was calculated by the equation:
%ꢂ[(edema Aꢁedema B)/edema A]ꢅ100. Edema Aꢂedema induced by
TPA alone and edema Bꢂedema induced by TPA plus sample. Data were
analyzed by one-way analysis of variance followed by Dunnett’s test, which
was used to compare several group with a control. The IC50 values were esti-
mated from linear regression equation.
Inhibition of TBARS Formation in Rat Brain Homogenate Animals:
Adult male Wistar rats (200—250 g) were provided by the Instituto de Fisi-
ología Celular, UNAM, and approved by the Animal Care and Use Commit-
tee (Nom 087-ECOL-SSA 1-2002).51) They were maintained at 23ꢆ2 °C on
a 12/12 h light–dark cycle with free access to food and water.
Rat Brain Homogenate: The animals sacrifice was carried out avoiding
unnecessary pain. Rats were sacrificed under mild ether anesthesia and cere-
bral tissue (whole brain) was rapidly dissected and homogenized as previ-
ously described,52) in phosphate-buffered saline (PBS; 0.2 g KCl, 0.2 g
KH2PO4, 8 g NaCl and 2.16 g NaHPO4·7H2O/l, pH 7.4) to produce a 1/10
homogenate, w/v. The homogenate was centrifuged for 10 min at 3400 rpm
to yield a pellet that was discarded, protein content in the supernatant was
measured using the Folin and Ciocalteu’s phenol reagent53) and adjusted to
2.35 mg protein/ml with PBS.
inhibition ration (%)ꢂ(CꢁE)/Cꢅ100%
Where: C was the absorbance of control group and E the absorbance of test
group.
Statistical Analysis: All data were represented as meanꢆstandard error of
mean (S.E.M.). Data were analyzed by one-way ANOVA followed by Dun-
nett’s test for comparisons against control. Values of pꢇ0.05 (∗) and pꢇ0.01
(∗∗) were considered statistically significant. The inhibitory concentration
50 (IC50), were estimated by means of a linear regression equation.
Results and Discussion
The Schiff bases derived from 2,6-pyridinedicarboxialde-
hyde 1a—d were prepared by reaction of the corresponding
aminophenol with 2,6-diacetyl pyridine, the isolated Schiff
base was reacted with the appropriate tin oxide leading to the
corresponding complexes in 30% yield. In order to improve
the yield, the reactions were carried out in one pot in a mix-
ture of toluene–methanol (4 : 1) (Chart 1) the synthesis of n-
BuSn(IV) derivatives was accomplished after 8—45 h of re-
fluxing, except for the Ph2SnO derivative in which longer re-
action time was necessary. Following this methodology the
yields of all reactions improved dramatically (88—99%). All
compounds are stable under atmospheric conditions; the
butyltin derivatives are slightly more soluble than the methyl
and phenyl tin complexes.
Lipid Peroxidation: The supernatant (425 ml) was incubated at 37 °C for
30 min in presence of test sample (25 ml) dissolved in DMSO. Lipid peroxi-
dation was started adding 50 ml of freshly prepared 100 mM FeSO4 solution
(final concentration 10 mM) and incubated at 37 °C for 60 min.54) TBARS
were determined as described by Ohkawa et al.55) with some modifications,
adding 0.5 ml of the TBA reagent (1% TBA in 0.05 N NaOH and 30%
trichloroacetic acid in 1 : 1 proportion). The final solution was cooled on ice
DRIFT Spectroscopy Infrared spectra of complexes
2a—q showed vibrational bands in the range of 1565—
1594 cmꢁ1 due to the n(NꢂC). These bands are shifted to
lower wave number with respect to the free Schiff base
(1627—1623 cmꢁ1) for derivatives 2a—i which can be at-
tributed to the Sn–N coordination (Table 1). Although Schiff
Chart 1. Preparation of Complexes 2a—q

January 2009
9
Table 1. IR Bands (cmꢁ1) of Complexes 2a—q
ligand. The pyridinic C-3 and the iminic C-4, by contrast, are
shifted to high frequencies (Ddꢂca.6 and 7) which could be
provoked by the presence of the coordinative N→Sn bond,
this behavior has also been observed for other pyridine tin
complexes.42) As regards compounds 2f and 2p, the 119Sn
satellite signals allowed us to measure coupling constants J
(13C–119Sn)ꢂ1224.1 for 2f and J (13C–119Sn)ꢂ1200 Hz for
2p, which were used to calculate the angle of the fragment
C–Sn–C resulting in 184° and 182° for 2f and 2p, respec-
tively.61) The 119Sn-NMR of 2a—g and 2j—p exhibited sig-
nals in the range of ꢁ370 to ꢁ404 ppm for seven-coordi-
nated compounds.58—60) Combination of the information ob-
tained from the Mass spectrometry and Multinuclear NMR
led us to assume that all compounds are monomeric species
possessing heptacoordinated geometry in solution. The solu-
tion-NMR spectral data for compounds 2h, 2i and 2q were
not recorded due to their lack of solubility in most common
solvents.
X-Ray Structural Studies Single crystals for complexes
2a, 2b, 2i, 2j and 2n suitable for X-ray diffraction study were
obtained. The ortep drawings for the five compounds are de-
picted in Fig. 1. The crystallographic data are shown in Table
3; selected bond distances and angles are summarized in
Table 4. Unit cell of 2a consists of two crystallographically
independent but structurally similar molecules whereas for 2j
it is formed by one and a half molecules; the disorder of
butyl substituents of these complexes generates two different
positions. Complexes 2b and 2i crystallized as methanol and
dichloromethane solvates.
Complex
n (cmꢁ1) NꢂC
n (cmꢁ1) N→Sn
1a
1b
1c
1d
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
1623
1624
1624
1627
1568
1573
1568
1570
1595
1565
1575
1569
1594
1582
1584
1582
1585
1583
1585
1584
1581
436
430
432
423
437
438
437
434
432
431
432
435
424
437
432
2m
2n
2o
2p
2q
bases 1j—q where not isolated, similar pattern in their in-
frared spectral bands could also be envisaged. This fact has
been associated with the displacement of the electron density
from the nitrogen to tin atom.23,57) Most of these complexes
displayed stretching bands in the range of 431—435 cmꢁ1
which arise from the n(Sn–N) as a result of the Sn–N coordi-
native bonds. The IR bands that occur between 617 and
580 cmꢁ1 are attributable to n(Sn–C) and n(Sn–O), respec-
tively. Besides those features relevant differences which may
originate from the substituents attached to the tin atom were
not observed.
The examination of the molecular complexes revealed that
the structural geometry is pentagonal-bipyramidal (PBP) for
all complexes. The equatorial plane is constituted of two
oxygen atoms, the azomethine and the pyridine nitrogen
atoms whereas the axial positions are occupied by the two
Mass Spectrometry The mass spectrometry of com- alkyl or phenyl groups forming angles in the range of 169.3
pounds 2a—q displayed the molecular ion corresponding to (3) to 176.0 (3) which favor a distorted geometry around the
the monomeric compounds; all complexes exhibited a similar tin atom. The angle O–Sn–O is considerably greater than the
fragmentation pattern. In the first stage the loss of alkyl O–Sn–N which is closer to the ideal angle 72°, however, the
group attached to the tin atom (fragments ions C5H3N– N–Sn–N bond angles are in the range of 65 to 66° which ac-
(CHꢂN–C6H4NO2)2SnRꢀ, C5H3N–(CHꢂN–C6H4NO2)2Snꢀ) count for the distortion.
was observed.
The Sn–N bond distances of five complexes are in the
NMR Spectroscopy The proton NMR spectroscopy of range of 2.36 to 2.44 Å, which are much lower than the sum
dibutyltin derivatives compounds 2a—g (Table 2) showed of the van der Waals radii (3.75 Å) indicating the presence of
signals for the iminic proton in the range of 8.4 to 8.94, in stable coordinative Sn–N bonds. The examination of the
the case of complexes 2b, 2f and 2g this signal is slightly structures 2j and 2n showed that the bond lengths Sn–N
shifted to lower frequencies with respect to the free ligand, (pyridine–nitrogen atom) are slightly shorter than Sn–N
however, for complexes whit butyl substituents bonded to the (imine–nitrogen atom), these differences are associated with
tin atom only multiple signals were observed. The proton the presence of methyl group anchored to the iminic carbon
NMR spectra of dimethyltin derivative compounds 2e—g although for complexes 2a, 2b and 2i the behavior is the op-
and 2o, p showed single signals for the methyl groups in the posite. Similar results have been described by Pelizzi et al.
range of ꢁ0.31 to 0.2 ppm as well as the corresponding satel- for heptacoordinated, 2,6-diacetylpyridine hydrazone tin de-
1
lites as a result of the spin–spin coupling H–119Sn and rivatives.31)
1H–117Sn. It is known that the magnitude of |2J (1H–119Sn)|
Cytotoxic Activity From the series of synthesized com-
spin–spin constant coupling is function of the coordination plexes only the butyl tin derivatives were chosen for the eval-
number, for compounds 2e—g and 2o, p these values are in uation of their biological activity, the rest of compounds were
the range of 109—119 Hz and correspond to seven coordi- discarded because of low solubility. The complexes 2a—d
nated complexes, regarding this, Willem et al. have calcu- were screened in vitro against six human cancer cell lines
lated similar values for heptacoordinated dimethyltin salicyl- HTC-15 (human colorectal adenocarcinoma) MCF7 (human
aldoximates.58—60) The 13C-NMR signals for the aromatic mammary adenocarcinoma), K-562 (human chronic myel-
rings C-10 and C-1 of 2a—i showed a slight shift to low fre- ogenous leukemia), U251 (human gliblastoma), PC-3
quencies (Ddꢂca. 10 and 7) respectively, with respect to free (human prostatic adenocarcinoma) SKLU-1 (human lung

10
Vol. 57, No. 1

January 2009
11
Fig. 1. Perspective View of Molecular Structures of Complexes 2a, 2b, 2i, 2j and 2n ORTEP
Thermal ellipsoids at 30% of probability level minor component of disordered side chain drawn using open ellipsoids and broken lines.
Table 3. Crystallographic Data for Compounds 2a, 2b, 2i, 2j and 2n
2a
2b
2i
2j
2n
Formula
C27H31N3O2Sn
548.24
0.35ꢅ0.32ꢅ0.05
Red
Monoclinic
P21/n
19.666(1)
14.100(1)
19.898(1)
90
112.71
90
5089.6(4)
8
1.431
41037
C29H35N3O2Sn·CH2Cl2 C31H23N3O2Sn·0.5CH3OH
C88H105N9O7Sn3
1756.88
0.36ꢅ0.16ꢅ0.15 0.40ꢅ0.26ꢅ0.16
Red
Monoclinic
C2/c
C23H23N3O2Sn
492.13
Formula weight (g molꢁ1
)
661.22
0.38ꢅ0.33ꢅ0.05
Red
620.26
0.294ꢅ0.228ꢅ0.106
Red
Crystal size (mm)
Color
Crystal system
Space group
a (Å)
Red
Monoclinic
C2/c
15.187(8)
9.830(5)
14.772(7)
90
110.22(1)
90
2069.3(18)
4
1.580
8229
Monoclinic
C2/c
Monoclinic
P21/n
21343(1)
14.816(1)
22.084(1)
90
12.285(1)
14.855(1)
15.763(1)
90
29.041(1)
b (Å)
c (Å)
18.130(1)
17.304(1)
90
104.26
90
8830.5(7)
6
1.322
35692
7772
a (°)
b (°)
115.17(1)
90
108.72(1)
90
g (°)
V (Å3)
6320.3(7)
8
2724.5(4)
4
Z
Dcalc. (g cmꢁ3
)
1.390
1.512
No. of collected reflections
No. of independent reflections (Rint)
No. of observed reflections
No. of parameters
25538
22497
8951
8951
623
0.061
5572(0.0442)
5572
4960(0.0338)
4960
1824
1824
135
0.019
7772
489
414
391
Ra)
0.061
0.0310
0.068
0.140
1.023
b)
Rw
0.101
0.967
0.111
0.0778
0.052
1.059
GOF
0.971
1.057
a) Rꢂ∑||Fo|ꢁ|Fc||/∑|Fo|, b) Rw(Fo)2ꢂ[∑ w(Fo2ꢁFc2)2/∑ wFo4]1/2
.
adenocarcinoma) and the IC50 values are presented in Table exhibited by compounds 2c and 2d, although the latter dis-
5. The screening results of compounds 2a—d complexes ex- played the lowest IC50 values the tendency remained constant
hibited higher activity than the cis-platin which was used as for all cell lines evaluated, which may be associated with the
reference. However, compound 2d possesses the highest ac- electrowithdrawing character of Cl and NO2 positioned at the
tivity against the six cell lines tested followed by complex 2a aromatic ring. In similar way compounds 2a and 2b showed
which showed important inhibitory efficiency for MCF7, K- consistent pattern in their inhibition activity with all cell
562, U251, and SKLU-1 lines. In the case of HTC-15 and lines except for K-562, apparently, Cl and NO2 substituents
PC-3 cell lines the second more active complexes were 2c at C-5 of the aromatic ring improve significantly the cyto-
and 2b, respectively, which showed certain cyto-selectivity toxic activity. In this line we recently reported a study of pen-
against these cell lines. Figure 2 shows a trend in the activity tacoordinated tin complexes aminophenol derivatives, in

12
Vol. 57, No. 1

January 2009
13
Table 5. In Vitro Cytotoxicity Assay for Complexes 2a—d IC50 (mM) Values
Compound
HTC-15
MCF7
K-562
U251
PC-3
SKLU-1
2a
2b
2c
4.1ꢆ0.05
6.4ꢆ0.40
3.04ꢆ0.30
0.51ꢆ0.09
13.83ꢆ0.7
1.9ꢆ0.09
2.3ꢆ0.30
3.5ꢆ0.50
1.01ꢆ0.10
13.03ꢆ1.3
0.97ꢆ0.2
3.7ꢆ0.30
2.9ꢆ0.10
0.29ꢆ0.01
15.20ꢆ1.4
1.6ꢆ0.10
2.4ꢆ0.10
4.5ꢆ0.10
0.78ꢆ0.08
9.09ꢆ0.8
4.9ꢆ0.30
4.8ꢆ0.30
5.3ꢆ0.30
1.62ꢆ0.14
15.94ꢆ1.2
1.8ꢆ0.10
2.1ꢆ0.30
2.1ꢆ0.06
0.57ꢆ0.05
7.13ꢆ0.2
2d
cis-Platin
Table 6. In-Vivo Anti-inflammatory Activity IC50 Values for Compounds
2a—d
Doses
(mmol/ear)
Edema
(mg)
Inhibition
(%)
Compound
IC50
2a
0
12.96ꢆ0.78
12.30ꢆ1.78
10.45ꢆ0.79*
5.85ꢆ1.20*
2.43ꢆ0.75*
—
5.2
19.46
54.91
81.31
0.031
0.1
0.31
1
0.29 mmol/ear
2b
2c
2d
0
14.74ꢆ0.33
—
0.031
0.1
0.31
1
11.55ꢆ0.25*
10.75ꢆ0.85**
5.73ꢆ1.43**
2.70ꢆ0.20**
21.64
27.07
61.16
81.86
0.24 mmol/ear
0.11 mmol/ear
Fig. 2. IC50 (mM) Values in Cytotoxic Activity of Compounds 2a—d and
the Tested Cell Lines
0
15.62ꢆ0.42
—
which complex with Cl substituent at the aromatic ring ex-
hibited the best performance for different carcinogenic cell
lines.44)
0.031
0.1
0.31
1
12.20ꢆ0.82*
10.24ꢆ1.19**
2.55ꢆ0.64**
12.96ꢆ0.92**
21.91
34.47
83.68
86.39
Anti-inflammatory Activity The anti-inflammatory ac-
tivity of the organotin derivatives was also evaluated in vivo
using the TPA induced ear edema bioassay in mice where in-
domethacin was used as standard. The percentage of inhibi-
tion values are given in Table 6. The results indicated that all
complexes have positive effect on induced ear edema which
depends on the dose. The anti-inflammatory activity of com-
pounds decrease in the following order: 2cꢄ2bꢄ2aꢄ2d
(IC50 0.11, 0.24, 0.29, 0.56). However, complex 2c resulted
to be more potent than the indomethacin in two orders of
magnitude. Relevant differences in the anti-inflammatory ac-
tivity between complexes 2a and 2b were not observed; in-
stead they exhibited a similar profile to the reference.
Anti-oxidant Activity The antioxidant ability of the
compounds prepared has been checked through the study of
0
14.56ꢆ0.32
14.36ꢆ0.68
13.48ꢆ0.37
11.00ꢆ0.40**
7.54ꢆ1.01**
3.48ꢆ0.55**
—
0.031
0.1
0.31
0.56
1
1.37
7.42
24.45
48.21
76.1
0.56 mmol/ear
0.27 mmol/ear
Indomethacin
0
16.24ꢆ0.86
10.53ꢆ1.04*
8.18ꢆ0.34*
7.10ꢆ1.34*
4.97ꢆ1.70*
1.57ꢆ0.33*
—
0.13
0.24
0.42
0.75
1.3
35.14
48.18
56.28
69.42
89.19
The value pꢇ0.05 (∗) and pꢇ0.01 (∗∗) were considered as significant difference
with respect to the standard.
lipid peroxidation in rat brain homogenate, the antioxidant tested lines HTC-15, MCF7, K-562, U251, PC-3 and SKLU-
effect was evaluated as the inhibition of formation of thiobar- 1, where the most active compound was 2d, however, certain
bituric acid-reactive substances (TBARS) caused by com- selectivity towards specific cell lines was observed for com-
plexes 2a—d, where a-tocopherol and quercetine were used plexes 2a, 2b and 2c. Parallelism between the character of
as positive controls. The complexes 2b and 2c showed supe- substituents at the aminophenol fragment and the cytotoxic-
rior lipid peroxidation inhibition activities in comparison to ity of these compounds lead us to conclude that an electronic
references as shown in Table 7, complex 2b exhibits the best effect around the tin atom might be involved in the mecha-
inhibition effect as compared to the other complexes of this nism of inhibition. As regards the anti-inflammatory activity
series. The nitro derivative was essentially inactive 2d. In the most active species resulted to be the complex 2c, com-
general, the heptacoordinated tin complexes evaluated ex- plexes 2a, and 2b exhibited similar activity and 2d showed
hibit better activity than the pentacoordinated diphenyl tin less activity than the standard. Meanwhile, for the antioxi-
salicyliden-ortho-aminophenols recently reported.62)
dant activity by the TBARS method the 2b complex showed
the best inhibitory activity. This contribution demonstrated
the interest in heptacoordinated tin Schiff base derivatives
Conclusions
The preparation and characterization of seven coordinated which exhibit remarkable cytotoxicity, anti-inflammatory and
monomeric tin complexes derived from pyridine Schiff bases anti-oxidant activity which is assumed to be strongly depend-
were completed. High yields were obtained when the reac- ent on the nature of substituents attached to the aminophenol
tion was carried out in one pot-step. The series 2a—d exhib- moiety. Indeed these complexes are more active than
ited significant biologic activity against the six cell lines aminophenol and salicyliden-ortho-aminophenol pentacoor-

14
Vol. 57, No. 1
Table 7. Anti-oxidant Activity IC50 Values for Compounds 2a—d in Inhibition of Lipid Peroxidation TBARS
Concentration
TBARS
(nmol/mg prot.)
Inhibition
(%)
Complex
IC50
(mM)
2a
0
0.32
1
3.16
10
8.93ꢆ0.26
8.96ꢆ0.17
8.30ꢆ0.26
6.90ꢆ0.25*
4.50ꢆ0.54**
2.74ꢆ0.77**
1.18ꢆ1.18**
—
0.41ꢆ1.48
7.09ꢆ1.40
22.82ꢆ1.45
50.06ꢆ4.68
69.85ꢆ8.08
87.06ꢆ5.00
15.08ꢆ2.09 mM
1.77ꢆ0.06 mM
2.11ꢆ0.09 mM
31.62
100
2b
2c
2d
0
1
8.60ꢆ0.09
—
6.67ꢆ0.15**
5.09ꢆ0.39**
1.10ꢆ0.26**
0.53ꢆ0.10**
0.42ꢆ0.06**
22.49ꢆ1.80
40.94ꢆ4.20
87.2ꢆ3.06
93.86ꢆ1.12
95.17ꢆ0.69
1.78
3.16
5.62
10
0
1
8.63ꢆ0.12
—
6.74ꢆ0.22**
5.70ꢆ0.50**
5.57ꢆ0.31**
0.59ꢆ0.12**
0.42ꢆ0.05**
21.77ꢆ3.57
33.81ꢆ6.50
70.33ꢆ3.31
93.53ꢆ1.14
95.16ꢆ0,53
1.78
3.16
5.62
10
0
0.32
1
3.16
10
12.70
12.32
11.81
10.43
9.88
—
2.99
7.02
17.88
22.25
26.88
35.55
ꢄ100 mM
31.62
100
9.29
8.19
Quercetine
0
1
9.52ꢆ0.19
8.33ꢆ0.33
7.64ꢆ0.47*
6.21ꢆ0.24*
3.20ꢆ0.55*
1.27ꢆ0.29*
—
11.70ꢆ2.14
19.29ꢆ3.32
34.16ꢆ3.05
66.05ꢆ5.62
86.61ꢆ2.92
1.78
3.16
5.62
10
4.11ꢆ0.26 mM
569.09ꢆ24.54 mM
a-Tocopherol
0
100
177.83
316.23
562.34
1000
9.48ꢆ0.79
8.43ꢆ0.45
8.01ꢆ0.35
7.49ꢆ0.16*
5.09ꢆ0.37*
1.66ꢆ0.44*
—
11.25ꢆ2.71
15.65ꢆ2.07
21.39ꢆ1.20
46.36ꢆ3.38
82.28ꢆ4.80
Each value represents the mean of 3—4 observations. The value pꢇ0.05 (∗) and pꢇ0.01 (∗∗) were considered as significant difference with respect to the standard.
834 (2005).
dinated tin derivatives.
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Acknowledgements The author thanks DGAPA (IN 203908) for the fi-
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