Syntheses, molecular structures, electrochemical behavior, theoretical study, and antitumor activities of organotin(IV) complexes containing 1-(4-chlorophenyl)-1-cyclopentanecarboxylato ligands

Article abstract of DOI:10.1021/ic200635g

The organotin(IV) compounds [Me₂Sn(L)₂] (1), [Et ₂Sn(L)₂] (2), [ⁿBu₂Sn(L) ₂] (3), [ⁿOct₂Sn(L)₂] (4), [Ph ₂Sn(L)₂] (5), and [PhOSnL]₆ (6) have been synthesized from the reactions of 1-(4-chlorophenyl)-1-cyclopentanecarboxylic acid (HL) with the corresponding diorganotin(IV) oxide or dichloride. They were characterized by IR and multinuclear NMR spectroscopies, elemental analysis, cyclic voltammetry, and, for 2, 3, 4 and 6, single crystal X-ray diffraction analysis. While 1-5 are mononuclear diorganotin(IV) compounds, the X-ray diffraction of 6 discloses a hexameric drumlike structure with a prismatic Sn₆O₆ core. All these complexes undergo irreversible reductions and were screened for their in vitro antitumor activities toward HL-60, BGC-823, Bel-7402, and KB human cancer cell lines. Within the mononuclear compounds, the most active ones (3, 5) are easiest to reduce (least cathodic reduction potentials), while the least active ones (1, 4) are the most difficult to reduce. Structural rearrangements (i.e., Sn-O bond cleavages and trans-to-cis isomerization) induced by reduction, which eventually can favor the bioactivity, are disclosed by theoretical/electrochemical studies.

Full text of DOI:10.1021/ic200635g

ARTICLE
pubs.acs.org/IC
Syntheses, Molecular Structures, Electrochemical Behavior,
Theoretical Study, and Antitumor Activities of Organotin(IV)
Complexes Containing 1-(4-Chlorophenyl)-1-
cyclopentanecarboxylato Ligands
Xianmei Shang,†,# Xianggao Meng,‡ Elisabete C.B.A. Alegria,†,§ Qingshan Li,|| M.Fꢀatima C. Guedes da Silva,†,^
Maxim L. Kuznetsov,† and Armando J.L. Pombeiro*,†
†Centro de Química Estrutural, Complexo I, Instituto Superior Tꢀecnico, Technical University of Lisbon, Av. Rovisco Pais,
1049À001 Lisbon, Portugal
‡Department of Chemistry, Central China Normal University, 430079 Wuhan, China
§ꢀ
Area Departamental de Engenharia Química, ISEL, R. Conselheiro Emídio Navarro, 1950-062 Lisbon, Portugal
School of Pharmaceutical Science, Shanxi Medical University, 86 South Xinjian Road, 030001 Taiyuan, China
^Universidade Lusꢀofona de Humanidades e Tecnologias, ULHT Lisbon, Av. do Campo Grande, 376, 1749-024 Lisbon, Portugal
#Tongji School of Pharmacy, Huazhong University of Science and Technology, 13 Hangkong Road, 430030 Wuhan, China
S Supporting Information
b
ABSTRACT: The organotin(IV) compounds [Me2Sn(L)2]
(1), [Et2Sn(L)2] (2), [nBu2Sn(L)2] (3), [nOct2Sn(L)2] (4),
[Ph2Sn(L)2] (5), and [PhOSnL]6 (6) have been synthesized
from the reactions of 1-(4-chlorophenyl)-1-cyclopentanecar-
boxylic acid (HL) with the corresponding diorganotin(IV)
oxide or dichloride. They were characterized by IR and multinuclear NMR spectroscopies, elemental analysis, cyclic voltam-
metry, and, for 2, 3, 4 and 6, single crystal X-ray diffraction analysis. While 1À5 are mononuclear diorganotin(IV) compounds,
the X-ray diffraction of 6 discloses a hexameric drumlike structure with a prismatic Sn6O6 core. All these complexes undergo
irreversible reductions and were screened for their in vitro antitumor activities toward HL-60, BGC-823, Bel-7402, and KB human
cancer cell lines. Within the mononuclear compounds, the most active ones (3, 5) are easiest to reduce (least cathodic reduction
potentials), while the least active ones (1, 4) are the most difficult to reduce. Structural rearrangements (i.e., SnÀO bond
cleavages and trans-to-cis isomerization) induced by reduction, which eventually can favor the bioactivity, are disclosed by
theoretical/electrochemical studies.
human tumor cell lines,1,18,19,36 and that the presence of
1. INTRODUCTION
4-chlorophenyl group can result in an enhanced activity of
The potential of organotin(IV) compounds as biologically
such complexes.18 In the present work, we have selected a
active metallopharmaceuticals has been recognized,1À24 but their
ligand, 1-(4-chlorophenyl)-1-cyclopentanecarboxylate (LÀ),
antitumor action mechanism is still unclear, although some
which bears the 4-chlorophenyl group and a cycloalkyl ring
evidence is consistent with their binding directly to DNA.25À28
connected to the carboxylate group and whose coordination
Investigations on metal-based drugs “activated by reduction”
have become popular with platinum(IV) and ruthenium(III)
chemistry and reactivity still remain almost unexplored. More-
over, the presence of the cycloalkyl moiety should increase the
compounds,29À35 since various metal complexes can exist in
lipophilicity of the complex with expected promotion of
rather inert high oxidation states in aqueous solution but are
cellular uptake and biological action.37,38
more labile and active in reduced oxidation states. It is believed
that reduction to Pt(II) and Ru(II) is essential for the antic-
Hence, in this study we prepared six organotin(IV) com-
plexes bearing that ligand (Figure 1) and various R2Sn groups
ancer activity of many Pt(IV) and Ru(III) complexes.29À35
and checked their in vitro cytotoxic activities against four
Inspired by the reduction mechanism of these metal-based
antitumor complexes, we decided to check if the reduction
potential of organotin(IV) complexes could relate to their
different human cell lines [promyelocyticfina leukemic (HL-
60), hepatocellular carcinoma (Bel-7402), nasopharyngeal car-
cinoma (KB), and gastric carcinoma (BGC-823)]. Moreover,
biological activity. To our knowledge, no well established
information has yet been given on this matter.
Moreover, it is known that organotin(IV) carboxylates
exhibit rather promising in vitro antitumor activities against
Received: March 28, 2011
Published: July 27, 2011
r
2011 American Chemical Society
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Inorganic Chemistry
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Figure 1. Structures of the ligand and complexes 1À6.
we performed cyclic voltammetric measurements of their re-
duction potential toward the eventual recognition of a redox
potentialÀactivity relationship.
2.2. Synthesis. Atom labeling, used for NMR assignment, for R =
nBu, Ph, follows:
Other main aims of this work, also with significance to the
hypothesis of the mechanism of action by reduction are as
follows: to get an insight into the reactions involved upon
reduction of the Sn(IV) complexes (by performing theoretical
calculations) which eventually could play a promoting role of the
drug antitumor activity, a type of study that, to our knowledge,
had not yet been applied to tin complexes.
2.2.1. Synthesis of [Me2SnL2] (1). [Me2SnCl2] (0.110 g, 0.50 mmol)
was added to an undried methanolic solution (10 mL) of 1-(4-
chlorophenyl)-1-cyclopentanecarboxylic acid (HL, 0.224 g, 1.0 mmol)
and KOH (0.056 g, 1.0 mmol). The solution was stirred at room
temperature overnight. Water (10 mL) was then added leading to the
formation of a white precipitate of [Me2SnL2], which was then
separated by filtration, recrystallized from methanol, and dried in
vacuo. Yield: 40%. Anal. Calcd for C26H30Cl2O4Sn (596.13): C 52.38,
H 5.07. Found: C 52.11, H 5.24. IR (KBr): 2921, 1559 (COOasym),
2. EXPERIMENTAL SECTION
2.1. GeneralRemarks.1-(4-Chlorophenyl)-1-cyclopentanecarboxylic
acid, [Me2SnCl2], [Et2SnCl2], [nBu2SnO], [nOct2SnO], [Ph2SnCl2], and
[Ph2SnO] were purchased from Aldrich or Alfa and used as received.
The other reagents were of analytical grade. C and H elemental
analyses were carried out by the Microanalytical Service of the Instituto
Superior Tꢀecnico. Infrared spectra (4000À400 cmÀ1) were recorded
1
1384 (COOsym), 580 (SnÀC), 431 (SnÀO) cmÀ1. H NMR (400.0
MHz, CDCl3): δ = 7.38 (s, 4H, H-9, H-11), 7.27 (s, 4H, H-8, H-12),
1.80À1.70 (m, 16H, H-3, H-4, H-5, H-6), 0.42 (s, 3H, Sn-CH3), 0.24
(s, 3H, Sn-CH3). 13C NMR (100.6 MHz, CDCl3): δ = 179.3 (C-1);
144.1 (C-10), 132.2 (C-9, C-11), 128.2 (C-7, C-8, C-12), 36.2 (C-2),
23.6 (C-3.C-4, C-5, C-6), 8.1 (Sn-CH3), 6.5 (Sn-CH3). 119Sn NMR
(149.2 MHz, CDCl3): δ = À177.7.
with a Biorad FTS 3000MX instrument in KBr pellets. The 1H and 13
C
(Me4Si internal standard) and 119Sn (Me4Sn external standard) NMR
spectra were recorded on a Bruker Avance II+ 400 MHz (UltraShield
Magnet) spectrometer. Electrochemical measurements were per-
formed on an EG&G PAR273A potentiostat/galvanostat connected
to a personal computer through a GPIB interface. Cyclic voltammo-
grams (CV) were obtained using a two-compartment three-electrode
cell, at Pt disk working (d = 1.0 mm) and Pt wire counter electrodes, in
0.2 M [nBu4N][BF4]/THF solution. Controlled-potential electrolyses
(CPE) were carried out in electrolyte solutions with the above-
mentioned composition, in a three-electrode H-type cell. The com-
partments were separated by a sintered glass frit and equipped with
platinum gauze working and counter electrodes. For both CV and CPE
experiments, a Luggin capillary connected to a silver wire pseudo-
reference electrode was used to control the working electrode potential.
The CPE experiments were monitored regularly by cyclic voltammetry
(CV), thus assuring no significant potential drift occurred along the
electrolyses. The redox potentials of the complexes were measured by
2.2.2. Synthesis of [Et2SnL2] (2). Compound 2 was prepared by
following the method and conditions described for 1 and using HL
(0.224 g, 1.0 mmol) and [Et2SnCl2] (0.124 g, 0.50 mmol). The white
product was recrystallized from ethanol and dried in vacuo. Yield: 38%.
Anal. Calcd for C28H34Cl2O4Sn (624.14): C 53.88, H 5.49. Found: C
53.41, H 5.52. IR (KBr): 2954, 2872, 1565 (COOasym), 1365 (COOsym),
507 (SnÀC), 436 (SnÀO) cmÀ1. 1H NMR (400.0 MHz, CDCl3): δ =
7.38À7.27 (m, 8H, H-8, H-9, H-11, H-12), 1.90À1.02 (m, 20H, H-3,
H-4, H-5, H-6, Sn-CH2), 0.84 (t, J = 7.6 Hz, 6H, 2CH3). 13C NMR
(100.6 MHz, CDCl3): δ = 186.4 (C-1); 142.0 (C-10), 132.6 (C-5),
128.4 (C-9, C-11), 128.2 (C-8, C-12), 58.6 (C-2), 36.4 (C-3, C-6), 23.7
(C-4, C-5), 17.5 (Sn-CH2), 8.5 (Sn-CH2CH3). 119Sn NMR (149.2
MHz, CDCl3): δ = À163.3.
2.2.3. Synthesis of [nBu2SnL2] (3). Dibutyltin(IV) oxide (0.5 mmol)
was added to a dry methanol/benzene (60 mL, 1:3 v/v) solution of HL
(1.0 mmol) which was refluxed for 6 h. The solvent was then evaporated
to dryness. The residue was recrystallized from ethanol and dried in
CV in the presence of ferrocene as internal standard, and their values
are quoted relative to the SCE by using the [Fe(η5-C5H5)2]0/+ (E1/2
=
OX
0.545 vs SCE) redox couple in 0.2 M [nBu4N][BF4]/THF.39
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Inorganic Chemistry
ARTICLE
vacuo. Yield: 72%. Anal. Calcd for C32H42Cl2O4Sn (680.25): C 56.50, H
parameters for all the non-hydrogen atoms and isotropic for the
remaining atoms were employed.
6.22. Found: C 56.72, H 6.40. IR (KBr): 2957, 2872, 1566 (COOasym),
1
1360 (COOsym), 510 (SnÀC), 436 (SnÀO) cmÀ1. H NMR (400.0
Crystal data and refinement parameters are shown in Table S1,
Supporting Information. CCDC numbers 783753À783756 contain 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/datarequest/cif.
2.4. Cytotoxicity Study. The following human cell lines were used
for screening: promyelocytic leukemic (HL-60), hepatocellular carcino-
ma (BEL-7402), gastric carcinoma (BGC-823), and nasopharyngeal
carcinoma (KB) cell lines. All of them were grown and maintained in
RPMI-1640 medium supplemented with 10% fetal bovine serum,
penicillin (100 U/mL), and streptomycin (100 μg/mL) at 37 ꢀC in
humidified incubators in an atmosphere of 5% CO2.
MHz, CDCl3): δ = 7.38À7.25 (m, 8H, H-8, H-9, H-11, H-12),
1.88À1.08 (m, 28H, H-3, H-4, H-5, H-6, R-H, β-H, γ-H), 0.74 (t, J =
7.2 Hz, 6H, δ-H). 13C NMR (100.6 MHz, CDCl3): δ = 186.1 (C-1);
142.0 (C-10), 132.5 (C-5), 128.5 (C-9, C-11), 128.2 (C-8, C-12), 58.7
13
(C-2), 36.3 (C-3, C-6), 23.6 (C-4, C-5), 26.3 (R-C, 1J (119SnÀ C) =
675 Hz), 26.0 (β-C), 24.9 (γ-C), 13.4 (δ-C). 119Sn NMR (149.2 MHz,
CDCl3): δ = À156.7.
2.2.4. Synthesis of [nOct2SnL2] (4). Dioctyltin(IV) oxide (0.5 mmol)
was added to a dry methanol/benzene (60 mL, 1:3 v/v) solution of HL
(1.0 mmol) which was refluxed for 6 h. The solvent was then evaporated
to dryness. The residue was recrystallized from methanol/n-hexane and
dried in vacuo. Yield: 66%. Anal. Calcd for C40H58Cl2O4Sn 2CH3OH
Cell proliferation in compound-treated cultures was evaluated by
using a system based on the tetrazolium compound (MTT)44 and
sulforhodamine B (SRB) methods45 in the State Key Laboratory of
Natural and Biomimetric Drugs, Beijing Medical University (China). All
cell lines were seeded into 96 well plates at a concentration of about
50 000 cells/mL and were incubated in an atmosphere of 5% CO2 for
24 h. Then, 20 μL of the sample (organotin complex) were added, and
further incubation was carried out at 37 ꢀC for 48 h. To prepare these
samples of the complexes, they were first dissolved in DMSO at a
concentration of 10À1 M and diluted with medium to concentrations
between 10À4 and 10À6 M. The final concentration of DMSO was less
than 1%, and at this concentration it did not affect cell growth.46 A 50 μL
portion of 0.1% MTT or SRB (Sigma) was added to each well. After 4 h
incubation, the culture medium was removed, and 150 μL of isopropa-
nol were added to dissolve the insoluble blue formazan precipitates
produced by MTT reduction. The plate was shaken for 20 min on a plate
shaker to ensure complete dissolution. The optical density of each well
was measured at 570 nm (MTT) or 540 nm (SRB) wavelengths. The
antitumor activity was determined three times in independent experi-
ments, using four replicate wells per toxicant concentration (10, 1,
0.1 μM), and the mean optical densities for drug-treated cells at each
concentration were obtained as a percentage of that of untreated cells.
2.5. Computational Details. The full geometry optimization of
the complexes has been carried out in Cartesian coordinates at the DFT/
HF hybrid level of theory using Becke’s three-parameter exchange
functional47 in combination with the gradient-corrected correlation
functional of Lee, Yang, and Parr48 (B3LYP) with the help of the
Gaussian-9849 program package. The restricted approximation for
structure 1 with closed electron shells and the unrestricted method for
the reduced complexes 1À and 12À have been employed. For the doubly
reduced species 12À, both singlet and triplet spin states have been
calculated, and the former one was found as the ground state. Symmetry
operations were not applied for all structures. A quasirelativistic Stuttgart
pseudopotential described 46 core electrons, and the corresponding
basis set50 for the tin atom and the 6-31G(d) basis set for other atoms
were used. The Hessian matrix was calculated analytically to prove the
location of correct minima (no imaginary frequencies were found) and
to estimate the thermodynamic parameters, the latter being calculated at
25 ꢀC. The electronic structures of 1À and 12À were additionally
examined using the natural bond orbital (NBO) analysis.51 The experi-
mental X-ray geometry of 2 was taken as a basis for the initial geometry
of the optimization processes.
3
(856.59): C 58.89, H 7.77. Found: C 58.89, H 8.03. IR (KBr): 2924, 2853,
1566 (COOasym), 1368 (COOsym), 512 (SnÀC), 435 (SnÀO) cmÀ1. 1H
NMR (400.1 MHz, CDCl3): δ = 7.38À7.26 (m, 8H, H-8, H-9, H-11,
H-12), 1.88À1.10 (brm, 44H, H-3, H-4, H-5, H-6, Sn-(CH2)7-), 0.91 (m,
6H, 2CH3). 13C NMR (100.6 MHz, CDCl3): δ = 186.2 (C-1); 142.3 (C-
10), 132.7 (C-5), 128.4 (C-9, C-11), 128.2 (C-8, C-12), 58.6 (C-2), 36.3,
33.1, 31.8, 29.1, 29.0, 25.1, 24.3, 23.6, 22.6 (C-3, C-4, C-5, C-6,
Sn-(CH2)7-), 14.1 (CH3). 119Sn NMR (149.2 MHz, CDCl3): δ =
À157.2.
2.2.5. Synthesis of [Ph2SnL2] (5). Diphenyltin(IV) oxide (0.5 mmol)
was added to a dry methanol/benzene (60 mL, 1:3 v/v) solution of HL
(1.0 mmol) which was refluxed for 6 h. The solvent was then evaporated
to dryness. The residue was recrystallized from benzene and dried in
vacuo. Yield: 66%. Anal. Calcd for C36H34Cl2O4Sn (720.27): C 60.03, H
4.76. Found: C 60.12, H 4.70. IR (KBr): 1522 (COOasym), 1394
1
(COOsym), 517 (SnÀC), 404 (SnÀO) cmÀ1. H NMR (400.1 MHz,
CDCl3): δ = 7.35À7.24 (m, 18H, H-8, H-9, H-11, H-12, H-2*, H-3*,
H-4*), 2.74À2.70, 1.91À1.61 (m, 16H, H-3, H-4, H-5, H-6). 13C NMR
(100.6 MHz, CDCl3): δ = 180.4(C-1), 141.5 (C-10), 138.2 (C-1*),
136.6, 135.1, 130.5, 128.8 (C-2*, C-3*, C-4*, C-7, C-8, C-9, C-11, C-12),
58.7 (C-2), 36.3, 23.6 (C-3, C-4, C-5, C-6). 119Sn NMR (149.2 MHz,
CDCl3): δ = À320.5.
2.2.6. Synthesis of [PhSnOL]6 (6). A solution of HL (1.0 mmol)
in ethanol (25 mL) was added to a solution of [Ph2SnCl2] (344 mg,
1.0 mmol) in 25 mL of ethanol. The reaction mixture was stirred at 25 ꢀC
for 6 h. The solution was filtered and left to slow evaporation at room
temperature. Colorless crystals were formed from this solution after 6 d,
washed with n-hexane, and dried in vacuo. Yield: 55%. Anal. Calcd for
C
108H102Cl6O18Sn6 C6H14 (2699.12): C 50.73, H 4.33. Found: C
3
50.67, H 3.70. IR (KBr): 1589 (COOasym), 1398 (COOsym), 729, 623,
559, 499, 438 cmÀ1. 1H NMR (400.1 MHz, CDCl3): δ = 7.40À6.67 (m,
54H, H-8, H-9, H-11, H-12, H-2*, H-3*, H-4*), 2.51À2.48, 2.40À2.37,
1.79À1.74, 1.64À1.57 (m, 48H, H-3, H-4, H-5, H-6). 13C NMR (100.6
MHz, CDCl3): δ = 184.1 (C-1); 143.3 (C-10), 143.3 (C-1*), 141.3 (C-
2*), 140.8 (C-3*), 134.2 (C-4*), 128.4 (C-7), 128.0 (C-9, C-11), 127.9
(C-8, C-12), 60.3 (C-2), 36.8, 31.5 (C-3, C-6), 23.5, 23.3, 22.6, 14.1
(C-4, C-5). 119Sn NMR (149.2 MHz, CDCl3): δ = À541.1.
2.3. Structural Determination and Refinement. Suitable
single crystals of the complexes were mounted in glass capillaries for
X-ray structural analysis. Intensity data were collected at room
temperature, using a Bruker AXS-KAPPA APEX II diffractometer
with graphite monochromated Mo KR (λ 0.710 73 Å) radiation. Cell
parameters were retrieved using Bruker SMART software and refined
using Bruker SAINT40 on all the observed reflections. Absorption
corrections were applied using SADABS.38 Structures were solved by
direct methods by using the SHELXS-97 package41 and refined with
SHELXL-97.42 Calculations were performed using the WinGX System-
Version 1.80.03.43 All hydrogen atoms were inserted in calculated
positions. Least-squares refinements with anisotropic thermal motion
3. RESULTS AND DISCUSSION
3.1. Syntheses. The 1:2 alkyltin(IV) substituted cyclopenta-
necarboxylates [R2SnL2] 1-2 (R = Me and Et) were obtained by
reaction of the appropriate dialkyltin(IV) dichloride, in an
undried methanolic solution, with 1-(4-chlorophenyl)-1-cyclo-
pentanecarboxylic acid (HL) and KOH (both in a 2-fold molar
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Figure 2. Crystal structure of 2 with atomic numbering scheme
(hydrogen atoms are omitted for clarity). Atoms drawn at 30% prob-
ability. Selected bond lengths (Å) and angles (deg): Sn1ÀC1 2.096(5),
Sn1ÀC3 2.110(5); Sn1ÀO1 2.497(3), Sn1ÀO2 2.126(2), Sn1ÀO3
2.129(3), C1A-O11.246(5), C1A-O2 1.281(5); C1ÀSn1ÀC3 150.6(2),
C1ÀSn1ÀO2 101.59(14), C3ÀSn1ÀO2 102.03(15), C1ÀSn1ÀO3
100.33(16), C3ÀSn1ÀO3 99.92(17), O2ÀSn1ÀO3 82.30(10), C1À
Sn1ÀO1 88.37(16), C3ÀSn1ÀO1 90.66(16), O2ÀSn1ÀO1
55.72(10), O3ÀSn1ÀO1 138.01(9), C2ÀC1ÀSn1 116.1(4).
Figure 3. Structural representation of 2 showing the linkage of neigh-
boring tin(IV) molecules via intermolecular SnÀO contact interactions,
generating distorted pentagonal bipyramid dinuclear aggregates. H
atoms are omitted for clarity.
The 1H and 13C NMR data of complexes 1À6 are given in the
Experimental Section (2.2), and the observed resonances have
been assigned on the basis of their integration and coupling
amount relatively to the tin complex), while the compounds 3À5
(R = nBu, nOct and Ph) were synthesized by reaction of HL with
di-n-butyltin (di-n-octyltin or diphenyltin, respectively) oxide
in dry methanol/benzene (1:3, v/v). The drum (see below)
phenyltin(IV) complex [PhSnOL]6 6 was produced by reaction
of [Ph2SnCl2] with HL in ethanol solution at room temperature.
The complexes were isolated as white solids in moderate to
good (40À72%) yields. They are stable in air, insoluble in water,
and soluble in chloroform, acetone, DMSO, and mixtures of
water/DMSO. The complexes with ethyl, n-butyl, n-octyl, and
phenyl groups tend to exhibit higher solubility in organic
solvents than that with methyl groups. The complexes were
characterized by FT-IR, 1H, 13C, 119Sn NMR spectroscopies and
elemental analysis, as well as by single-crystal X-ray diffraction
analysis for [Et2SnL2] (2), [nBu2SnL2] (3), [nOct2SnL2] (4),
and [PhSnOL]6 (6), representing the two types of diorganotin-
(IV) substituted cyclopentanecarboxylates.
3.2. Spectroscopic Data. The assignments of IR bands for all
the complexes were done by comparing with the IR spectra of the
free acid and related organotin compounds. 1-(4-Chlorophenyl)-
1-cyclopentanecarboxylic acid displays a band at 1695 cmÀ1
which is assigned to the ν(OCO)asym stretching vibration. The
considerable shift of this vibration upon coordination in the
organotin(IV) complexes is due to the binding to the metal
through the carbonyl oxygen atom.52 The criterion of the
separation between the symmetric and asymmetric stretching
n
n
constants. The different R groups (Me, Et, Bu, Oct, Ph)
attached to the tin atom gave signals in the expected region.
The 119Sn NMR resonances of complexes 1À4 occur at chemical
shifts in the δ À156 to À177 range, while those for 5 and 6 are
markedly shifted upfield (δ À320.5 and À541.1, respectively).
According to the X-ray diffraction data (see the following
section) all the compounds are six-coordinate with the possibility
for heptacoordination in 1À5 if the species are visualized as
oxygen-bridged dimers. According to examples found in the
literature,55À59 those values are acceptable for five-, six-, or even
seven-coordinate tin(IV) compounds. Therefore, on the basis of
119Sn NMR data alone, we cannot ascertain the geometry of the
complexes in solution.
3.3. X-ray Diffraction Analysis. The molecular structures of
the complexes 2, 3, 4, and 6 were authenticated by single-
crystal X-ray diffraction analyses. Selected experimental infor-
mation is given in Table S1, and a summary of the most
relevant bond distances and angles is given in the legends of
Figures 2, S1, and S2.
The structures of complexes 2À4 (Figures 2 for complex 2;
Figures S1 and S2 for 3 and 4, respectively) are quite similar.
They are monomeric with the tin atoms in skewed trapezoidal
bipyramidal environments formed by four O atoms derived from
two carboxylates in the equatorial positions and two C atoms of
the alkyl groups in the apical (trans) positions. However, these
complexes also feature 2-fold linkages of neighboring units via
intermolecular contacts, giving rise to the formation of dimeric
tin aggregates (Figure 3). In such a situation, each tin metal can
be considered as taking up a pentagonal bipyramid geometry
wavenumbers of the carboxylate moiety, Δ = [ν(OCO)asym
À
ν(OCO)sym], has been applied to ascertain its bidentate/chela-
tion or monodentate coordination type.53 Although a clear line
between the two categories cannot be drawn, values lower than
240 cmÀ1 can be indicative of bidenticity and those higher than
260 cmÀ1 point out monodenticity.54 The observed values for all
the compounds of this work are in the 128À206 cmÀ1 range (the
smallest value found in 5 and the highest one in 3) indicating a
bidentate mode of the ligand. This is in agreement with X-ray
crystallography results (see below) which disclose such a type of
coordination with a bridging interaction.
where the intermolecular Sn O bond distances assume values
3 3 3
of 2.971(3) (2), 3.0026(19) (3), and 3.038(5) (4) Å. The
carboxylate groups coordinate in an asymmetric mode forming
both short and long SnÀO bonds as observed in other tin(IV)
complexes.60,61
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Figure 4. Molecular structure of 6. For clarity, atoms are drawn at 10% probability, hydrogen atoms are omitted and only the labels of tin, chlorides, and
some of the oxygen atoms are included. Selected bond lengths (Å) and angles (deg): Sn1ÀO1 2.136(3), Sn2ÀO2 2.173(3), Sn3ÀO3 2.164(3),
Sn1ÀO4 2.153(2), Sn2ÀO5 2.175(2); O7ÀSn1ÀO9a 104.77(10), O7ÀSn1ÀO8 78.14(9), O9aÀSn1ÀO8 77.92(9), O7ÀSn1ÀC37 100.98(13),
O9aÀSn1ÀC37 104.65(12), O8ÀSn1ÀC37 177.43(12), O7ÀSn1ÀO1 162.13(10), O9aÀSn1ÀO1 84.22(10), O8ÀSn1ÀO1 88.97(10),
C37ÀSn1ÀO1 91.36(13), O7ÀSn1ÀO4 88.89(10), O9ÀSn1ÀO4 155.65(10), O8ÀSn1ÀO4 85.52(9), C37ÀSn1ÀO4 92.06(13), O1ÀSn1ÀO4
77.70(11). Symmetry operation to generate equivalent atoms: (a) 1 À x, 2 À y, 1 À z.
Table 1. Cyclic Voltammetric Dataa for Complexes 1À6, Free
HL, and Chlorobenzene (PhCl)
IEp
(Ired
IEp
IIEp
Ep
red
ox
ox
ox
compd
)
(Iox)b
(IIox)b
(HL,PhCl)b
1
À1.18
À1.12
À1.04
À1.32
À0.99
À0.94
À1.43
À0.85
0.17
0.14
0.09
0.71
0.65
0.55
0.78
0.57
0.53
2
3
4
Figure 5. Perspective representations (arbitrary views) of the central
drum-type tinÀoxygen core in 6.
5
0.05
6
HLc
chlorobenzenec
0.98
0.34
The interesting structure of compound 6 (Figure 4) com-
prises a Sn6O6 core and belongs to the known family of drum
compounds among organostannoxanes.62À64 The Sn6O6 core
contains two fused Sn3O3 (the basal hexagonal faces of the
drum) and Sn2O2 four-membered rings forming the six lateral
faces of the drum (Figure 5). All tin atoms are six-coordinate
and held together by six L anions on the periphery which
bridge, through isobidentate carboxylate moieties, alternate Sn
atoms. The tin-coordinated phenyl rings are displayed above
and below the hexagonal faces of the drum. Relevant inter-
molecular hydrogen bonds could also be found in this struc-
ture. Indeed, while the C1 > C6 phenyl centroids of L act as
acceptors of the phenyl H50 of the nearest molecules
a Values in V (0.04 relative to SCE measured in 0.2 M [nBu4N][BF4]/
THF solution (v = 200 mVsÀ1). Complex concentrations: 1.4À2.9 mM.
b Detected only upon scan reversal following the cathodic wave.
c Included for comparative purposes.
3.4. Electrochemical and Theoretical Studies. The redox
properties of compounds 1À6, as well as, for comparative
purposes, of 1-(4-chlorophenyl)-1-cyclopentanecarboxylic acid
(HL) and chlorobenzene, have been investigated by cyclic
voltammetry (CV), at a Pt electrode (d = 1 mm) in 0.2 M
[nBu4N][BF4]/THF solution, at 25 ꢀC, and the measured
redox potentials (in V vs. SCE) are given in Table 1. The
tin(IV) complexes show a two-electron (as confirmed by
controlled-potential electrolysis) irreversible reduction process
(broad wave Ired) at IEpred in the range from ca. À0.9 to À1.3 V
vs SCE (Figure 6, for complex 1). Moreover, upon scan reversal
[d(H
centroid) 2.629 Å], thus expanding the structure
3 3 3
along the crystallographic R axis, the Cl2 chloride atoms act
as acceptors of the phenyl H40 hydrogen atoms of vicinal
molecules [d(H
Cl) 2.921 Å] expanding the structure to a
3 3 3
second dimension.
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Figure 6. Cyclic voltammograms of complex 1 (a) and HL (b), initiated by the cathodic sweep, at a Pt electrode, in 0.2 M [nBu4N][BF4]/THF solution
(v = 200 mV/s). [Complex] = 1.4 mM; [HL] = 3.9 mM.
after the reduction wave, one or two irreversible oxidation
processes are detected at Epox in the ranges of ca. 0.1À0.2 (wave
Iox) and ca. 0.5À0.8 (wave IIox) V vs SCE. These oxidations
concern species formed at the cathodic wave.
In accord with the weaker electron-donor character of
phenyl relatively to alkyl groups, the reduction potential values
for the phenyl complexes 5 and 6 (À0.99 and À0.94 V vs SCE,
respectively) are less cathodic than those of the alkyl com-
plexes 1À4. The dependence of the redox potential of a
complex on the electronic properties of its ligands has been
well documented.65À74
at the C(1A) atom) and the Ph ring (the C(10A) and C(7A)
atoms) of the bidentate LÀ ligand. This is confirmed by the
composition of the single occupied MO (SOMO) (Figure 7) and
the natural bond orbital (NBO) analysis (the R spin-NBO
corresponding to the unpaired electron on the C(1A) atom
was found with the occupancy of 0.81 e and the sp4.67 hybridiza-
tion type). Thus, the one-electron reduction affects both the LÀ
ligands, one of them becoming monodentate and the other one
remaining bidentate but acquiring the excess negative charge
(Scheme 1, first step).
The LUMO of 1aÀ (130 R-MO and 129 β-MO) is localized
on the Ph group of the nonreduced monodentate ligand LÀ
(Figure 7). However, the two-electron reduction of trans-1
affects the Sn atom rather than the ligands LÀ, lowering the
metal oxidation state from +IV in trans-1 to +II in 12À
(Scheme 1, first and second steps). Indeed, the geometry
optimization of the doubly reduced species resulted in the
location of the equilibrium structure 12À. Complex 12À has the
coordination polyhedron of a sawhorse (seesaw) type with two
monodentate ligands LÀ and the Me ligands tending to a cis
position (CÀSnÀC angle of ca. 95ꢀ), thus structurally differing
markedly from trans-1 (Figure S3). Such a structural type as
well as the HOMO composition of 12À (Figure 7) indicate the
presence of the lone electron pair at the Sn atom, and the
corresponding natural bond orbital was also found by the NBO
analysis (occupancy 1.98 e).
Somehow related behaviors, under similar conditions, are
exhibited by the free ligand itself in the neutral protonated
form (1-(4-chlorophenyl)-1-cyclopentanecarboxylic acid, HL)
and by chlorobenzene; i.e., they undergo a single-electron
irreversible reduction process at À1.43 (HL) and À0.85
ox
(PhCl) V vs SCE followed by an anodic wave at Ep = 0.98
(HL) and 0.34 (PhCl) V vs SCE upon potential scan reversal.
However, despite the analogies, which suggest that the reduc-
tion of the complexes can be ligand centered, the electroche-
mical study cannot establish unambiguously which site(s) of
the molecule (the LÀ ligand or/and the metal center) is (are)
involved in the reduction and become more affected. To clarify
this situation and to interpret the electrochemical behavior of
the [R2SnL2] complexes, quantum-chemical calculations of the
complex 1 and the corresponding singly and doubly reduced
species 1À and 12À have been carried out at the DFT (B3LYP)
level of theory.
The calculated structural parameters of 1 (herein denoted by
trans-1) are in good agreement with the experimental X-ray data
for the similar complex 2 (denoted by trans-2). The maximum
deviation was found for the SnÀC bonds (0.033À0.047 Å) and
does not exceed 0.03 Å for the other bonds, often lying within
the 3σ interval of the experimental data. The analysis of the
frontier MO composition indicates that the LUMO of trans-1 is
centered on the phenyl moiety and the carboxylate group of
both ligands LÀ with no involvement of the metal orbitals
(Figure 7).
The calculated first and second adiabatic electron affinities of
1 are very similar (À0.05 and À0.13 eV in terms of ΔG). This
indicates the possibility of overlap of the two possible single-
electron reduction waves of trans-1, resulting in one broad two-
electron reduction wave which is observed experimentally by
cyclic voltammetry. In accord, a close inspection of the broad
reduction wave Ired (Figure 6a) reveals an ill-defined shoulder
I
red
at a slightly less cathodic potential (ca. À0.8 V) than Ep
.
Hence, interestingly, although complex trans-1 undergoes two
sequential one-electron reductions centered at the phenylcar-
boxylate ligands, the final doubly reduced complex displays
only the Sn atom in the reduced (+II) state. The overall 2e-
reduction results in the SnIV f SnII reduction which, however,
occurs stepwise via the ligands reductions rather than by the
direct reduction of the metal.
The geometry optimization of the singly reduced complex led
to the cleavage of the SnÀO(4) bond to give 1aÀ. As a result, one
of the LÀ ligands in 1aÀ acquired a monodentate coordination
mode while the other one remains bidentate (Figure S3). The
spin density in 1aÀ is localized on the carboxylate group (mostly
Let us consider now what occurs in the oxidation of the reduced
species 12-, i.e., uponscan reversalfollowingthereductionwaveIred
.
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Scheme 1. Simplified Representation of the Electronic and
Structural Rearrangements Occurring upon Two Sequential
One-Electron Reductions of [Me2Sn(L)2] (1)a and Following
Oxidationsb
a CV reduction wave Ired. b CV oxidation waves Iox and IIox in the anodic
sweep upon scan reversal after Ired wave.
Table 2. Inhibition [%] of Compounds 1À6 [dose level of
10.00 μM] against Human Tumor Cells
compd
HL-60
BGC-823
Bel-7402
KB
1
7.8
16.4
16.4
88.8b
12.8
13.3
7.1
10.9
8.7
2
22.4
34.0
8.6
6.7
3
89.4a
12.6
17.4
12.7
4.5
39.2
4
5
21.5
26.9
1.2
24.4
19.5
6
HL
cisplatin
56.5
90.8c
79.1d
69.4
a IC50 = 4.9 μM. b IC50 = 5.2 μM. c IC50 = 6.5 μM38. d IC50 = 8.1 μM38.
Structural rearrangements and bond cleavages induced by elec-
tron transfer are well documented,37,76À83 and those observed
in this study are a rare combination of the following types:
(i) cathodically induced metalÀligand bond cleavage and trans/
cis isomerization; (ii) anodically induced metalÀligand bond
formation.
3.5. Anticancer Activity of 1À6. All the synthesized com-
pounds were screened for the preliminary in vitro anticancer
activity against four different human cell lines: a promyelocy-
ticfina leukemic cell line (HL-60), a hepatocellular carcinoma
cell line (Bel-7402), a gastric carcinoma cell line (BGC-823),
and nasopharyngeal carcinoma (KB), at three different con-
centrations. Because most of compounds showed inhibition
activity at concentration of >10 μM, we herein merely list the
biological results at the concentration of 10 μM in Table 2 for
the purpose of discussing any eventual structureÀactivity
relationships.
Among the six organotin(IV) complexes checked, only com-
pound 3 exhibits a strong activity against Bel-7402 and BGC-823,
being even slightly more active than cisplatin, which is clinically
widely used. Hence, the IC50 values for 3 and cisplatin are 5.2 and
8.138 μM (for Bel-7402), and 4.9 and 6.538 μM (for BGC-823),
respectively.
On the basis of the data analysis, possible structureÀactivity
relationships could be outlined as follows: (i) As observed in
previous studies,1,9,18À20,84,85 the organo-ligand R appears to
Figure 7. Plots of the frontier MOs of [Me2Sn(L)2] (trans-1), reduced
forms 1aÀ and 12À, and reoxidized forms 1bÀ and cis-1.
The geometry optimization of the singly reduced species
starting from the equilibrium geometry of 12À resulted into
another structure, 1bÀ, which is different from 1aÀ and more
stable by 23.6 kcal/mol. Both LÀ ligands in 1bÀ remain mono-
dentate, the Me ligands keep the equatorial positions, and the
polyhedron is still of a sawhorse (seesaw) type (Figure S3)
(Scheme 1, third step). This structural type as well as the SOMO
composition (Figure 7) and the NBO analysis indicate that the
unpaired electron in 1bÀ is located on the metal which, thus, has
the oxidation state +III (the spin density on the Sn atom is 0.72 e).
Finally, the geometry optimization of 1 starting from the equilib-
rium structures of 1bÀ or 12À revealed that the product of the
oxidation of the reduced species is the cis-isomer of 1 (cis-1)
(Scheme 1, fourth step) instead of the more stable (by 2.5 kcal/
mol) initial trans-1. Thus, the back oxidation of 12À to 1 occurs via
the pathway 12À f 1bÀ f cis-1 which is different from the route
of the reduction of trans-1 (trans-1 f 1aÀ f 12À).75
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play an important role. Indeed, the di-n-butyltin complex
exhibits the strongest antitumor activity, while the diorganotin
derivatives with a too short (methyl) or a too long (n-octyl)
carbon chain length exhibit very low activities. The activity of
the diphenyltin complex (5) is also very weak, although usually
better than those of dimethyltin (1), diethyltin (2), and di-n-
octyltin (4). Hence, for this class of diorganotin complexes, the
activity follows the order nBu > Ph g Et g nOct, Me for most of
the tumor cells. (ii) The hexanuclear phenyltin compound (6)
shows a weak activity against nearly all the tumor cells,
indicating that a polynuclear character, per se, does not result
in a high biological activity for organotin compounds. Probably,
for 6, the high coordination number and steric hindrance
around tin are important factors for the weak activities, which
limit the access of tin to the target. (iii) In comparison with
other diorganotin(IV) carboxylate complexes,86,87 this class of
compounds shows lower antitumor activity against HL-60 and
KB cell lines. However, for the dibutyltin(IV) derivatives, 3 is
more active than many diorganotin(IV) hydroxamates18À20,85
against BGC-823 and Bel-7402 cell lines.
before any clear redox potential-activity relationship can be
proposed.
’ ASSOCIATED CONTENT
S
Supporting Information. Additional table and figures.
b
This material is available free of charge via the Internet at http://
pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: pombeiro@ist.utl.pt. Fax: +351 218464455.
’ ACKNOWLEDGMENT
This work has been partially supported by the Foundation for
Science and Technology (FCT) (its PEst-OE/QUI/UI0100/
2011 project, and Grant SFRH/BPD/44773/2008), Portugal,
and the New Drug Development Programme from the Ministry
of Science and Technology of China (No. 2009ZX09103-104).
’ REFERENCES
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