Synthesis and characterization of tributyltin derivatives from 4-oxo-4-(arylamino)butanoic acids and their in vitro biological activity against cervical cancer cell lines

Article abstract of DOI:10.1002/aoc.3231

Uterine (cervix and corpus) cancer is one of the major causes of mortality in women in Mexico. Organotin carboxylated derivatives have shown high cytotoxic activity against various cell lines of human origin. We describe the synthesis of three new tri-n-b

Full text of DOI:10.1002/aoc.3231

Full Paper
Received: 10 July 2014
Revised: 4 September 2014
Accepted: 15 September 2014
Published online in Wiley Online Library: 20 October 2014
(wileyonlinelibrary.com) DOI 10.1002/aoc.3231
Synthesis and characterization of tributyltin
derivatives from 4-oxo-4-(arylamino)butanoic
acids and their in vitro biological activity against
cervical cancer cell lines
Irma Rojas-Oviedoa*, Carlos Camacho-Camachoa, Luis Sánchez-Sánchezb,
Jorge Cárdenasc, Hugo López-Muñozb, Hugo Eugenio-Robledoa,
Israel Velázqueza and Rubén Alfredo Toscanoc
Uterine (cervix and corpus) cancer is one of the major causes of mortality in women in Mexico. Organotin carboxylated derivatives have
shown high cytotoxic activity against various cell lines of human origin. We describe the synthesis of three new tri-n-butyltin derivatives
from 4-oxo-4-(arylamino)butanoic acids; their structures were confirmed using spectral data (1H NMR, 13C NMR, 119Sn NMR and infrared),
elemental analyses, mass spectrometry and X-ray diffraction. All the tri-n-butyltin carboxylates exhibit 1 J (119/117Sn–13C) coupling satel-
lites in solution and lie in the range 357 to 339 Hz, suggesting a tetrahedral geometry around the tin atom. The polymeric structures of
two of the derivatives and the monomeric structure of another were confirmed using X-ray crystallography. Using succinic anhydride
as raw material, five N-substituted succinamic acid compounds were synthesized by the acylation reaction with aniline, 4-nitroaniline,
4-nitro-3-(trifluoromethyl)aniline, 2-amino-5-nitrothiazole and 4-aminoantipyrine. From these compounds, five tin derivatives were
prepared and their in vitro anti-proliferative effect on HeLa, CaSki and ViBo cell lines was screened. All of the compounds showed
potency against all three strains and null or low cytotoxic activity (necrotic) as well. The most potent of our derivatives as an anti-
proliferative agent against the three cell lines was tributylstannyl 4-oxo-4-[(3-trifluoromethyl-4-nitrophen-1-yl)amino]butanoate,
exhibiting an IC50 value of 0.43 μM against the HeLa cell line. Copyright © 2014 John Wiley & Sons, Ltd.
Additional supporting information may be found in the online version of this article at the publisher’s web-site.
Keywords: tributyltin(IV); 4-oxobutanoic acid; X-ray diffraction; HeLa; CaSki; ViBo
ring moiety in some compounds contributed to high giardicidal
Introduction
bioactivity in the nanomolar range.[10]
Tri-n-butyl- and tri-phenyltin(IV) carboxylated derivatives have been
shown to have high cytotoxic activity against various cell lines of
human origin as described in the literature.[1–5]
An increased concentration of intracellular calcium ions appears to
be a contributing factor to triorganotin-induced apoptosis in many
cell lines.[6]
In Mexico, uterine (cervix and corpus) cancer is one of the
major causes of mortality in women followed by breast cancer.
In 2007 the number of deaths per 100 000 women from uterine
and breast cancer was 4540 and 4518, respectively.[7] Further-
more, cervical carcinoma is the third most common malignant
disease in women worldwide.[8]
Jha et al. have shown that only the methyl ester of 1,4-dioxo-2-
butenyl group in derivatives of arylamines has activity against hu-
man Molt 4/C8 and CEM T-lymphocytes as well as murine L1210
cells, with IC50 values in the range 2.2–37 μM.[11]
Recently Nitulescu et al. described evidence of the inhibitory
potency of 3-aminopyrazole derivatives on protein kinases which
play a central role in cell signaling and are involved in malignant
pathologies.[12]
Based on our experience and a literature survey, compounds 3a–e
were chosen as synthetic targets (Scheme 1).
For the aforementioned reason, our group continues to search
for new organotin compounds that are effective antineoplastic
agents. In order to set up structure–activity relationships for tributyl-
tin compounds with 4-oxo-4-arylaminobutanoic ligands, the influ-
ence of the type of aromatic ring and the nitro- or trifluoromethyl
substituents on the anti-proliferative activity was studied.
In a literature search, a report was found in which 2-substituted
thiazole analogs connected to 3-(substituted amino)propanamido
function contributed to antitumor activity against several cell
lines.[9] Furthermore, the incorporation of a 5-nitro-2-aminothiazole
*
Correspondence to: Irma Rojas-Oviedo, Departamento de Sistemas Biológicos,
Universidad Autónoma Metropolitana-Xochimilco, Calzada del Hueso 1100, Col.
Villa Quietud, CP 04960, México. E-mail: irma19@correo.xoc.uam.mx
a Departamento de Sistemas Biológicos, Universidad Autónoma Metropolitana-
Xochimilco, Calzada del Hueso 1100, Col. Villa Quietud, CP 04960, México
b Unidad Multidisciplinaria de Investigación Experimental Zaragoza, Avenida
Batalla del 5 de Mayo s/n, Colonia Ejercito de Oriente, CP 09230, México
c
Instituto de Química, Universidad Nacional Autónoma de México, Circuito
Exterior, Ciudad Universitaria, Coyoacán 04510, México
Appl. Organometal. Chem. 2014, 28, 884–891
Copyright © 2014 John Wiley & Sons, Ltd.

Tributyltin derivatives as potential agents against cervical cancer
supplemented with 5% NCS per well. Cells were allowed to grow
for 24 h in the culture medium prior to determining the IC50 values
for compounds. DMSO vehicle (1%) was added to control cells.
Anti-proliferative activity (IC50) was determined after 24h using
crystal violet staining.[14] Growth inhibition was determined by
measuring the absorbance at 590nm with an enzyme-linked
immunosorbent assay plate reader (Tecan, USA).
Determination of Cytotoxicity
The cytotoxic activity was determined using an LDH Cytotoxicity
Assay Kit (BioVision, USA) following the manufacturer’s instruc-
tions. LDH (lactate dehydrogenase) oxidizes lactate to pyruvate
which then reacts with the tetrazolium salt 2-(4-iodophenyl)-3-
(4-nitrophenyl)-5-phenyltetrazolium to form formazan. The
increase in the amount of formazan produced in the culture su-
pernatant directly correlates with the increase in the number of
lysed cells. The formazan dye is water-soluble and can be
detected with a spectrophotometer at 500 nm.[15] Experimental
data are presented as the mean standard deviation (SD) of
three independent experiments with three repetitions;
*p < 0.05 versus 0 mg mlꢀ1 (Tukey’s t-test).
Scheme 1. Synthesis of tributyltin derivatives from 4-oxo-4-(arylamino)
butanoic acids.
Experimental
Bis-tri-n-butyltin oxide, diazabicyclo[5.4.0]undec-7-ene (DBU), aniline,
4-nitroaniline, 5-nitro-2-aminopyrazol-5-one and 5-nitrothiazole were
purchased from Aldrich and used without further purification.
Succinic anhydride and 4-nitro-3-(trifluoromethyl)aniline were pre-
pared by known methods. All solvents were freshly distilled before
use following standard procedures.
1H NMR spectra were obtained with a Varian spectrometer at
300 MHz. 13C NMR and 119Sn NMR spectra were recorded at
300 MHz with a Bruker Avance instrument operating at 75.43 MHz
for 13C and 111.17 MHz for 119Sn using CDCl3 and CD3COCD3 as sol-
vents for compounds 3a–d and DMSO-d6 for 2b, 2d and 2e, and
tetramethylsilane as the internal standard for 1H and tetramethyltin
for 119Sn. Multiplicity is given as s = singlet, d = doublet, t = triplet,
brt= broad triplet, m = multiplet. Infrared spectra were recorded
using a PerkinElmer Spectrum RXI spectrophotometer with the in-
tensity of bands described as s, m and w for strong, medium and
weak, respectively. Mass spectral analysis was varied out with a
JEOL JMS AX505HA spectrometer at 70 eV and a JEOL AccuTOF
DART. Ligands are denoted by L, and all m/z values are related to
the most abundant natural isotope, 120Sn. The relative abundance
is given in parentheses. X-ray crystallographic data for 3a–c were
collected at 123 K using graphite monochromated Mo Kα
(λ = 0.71073Å) radiation with a Bruker SMART APEX CCD diffrac-
tometer. The structures were solved by direct methods and refined
using the full-matrix least squares procedure based on F2 using the
SHELXL-97 program.[13] Crystallographic data for structures 3a–c
have been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication numbers CCDC 1011611,
CCDC 1011612 and CCDC 1011613. Elemental analyses were per-
formed with an Eager 300 analyzer. Melting points were measured
with a Fischer-Johns apparatus and are uncorrected.
Statistical Analysis
The median and SD were calculated using Excel (Microsoft Office,
version 2007). Statistical analysis of differences was performed by
analysis of variance using SPSS 10.0 for Windows. A p-value of less
than 0.05 (Tukey’s t-test) was considered to be significant.
General Procedure for Synthesis of 4-Oxo-4-(arylamino)butanoic
Acids (2a–e)
DBU (1.5 mol) was added dropwise to a solution of succinic anhy-
dride (1.5mol) and the appropriate amine (1.0mol) in a mixture of
1,1,2,2-tetrachloroethane–carbon tetrachloride (3:1) in a flask under
a nitrogen atmosphere. The mixture was stirred and refluxed for
24 h. After reflux, the reaction mixture was cooled to room temper-
ature and most of the solvent evaporated. The organic layer was
washed with 3 × 30 ml of 20% K2CO3 (aq.). The combined aqueous
layer was acidified with 20% HCl until a solid formed (pH = 2–3).
The product was filtered under suction and washed thoroughly
with water.
The characterizations of compounds 2a, 2b, 2d, 2e, 3a and 3b
are given in the supporting information.
4-Oxo-4-(phenylamino)butanoic acid (2a)
Succinic anhydride (0.230 g, 2.298 mmol), 0.1426 g (1.532mmol) of
aniline, 12.0 ml of carbon tetrachloride and 4.0ml of 1,1,2,2-
tetrachloroethane were used. The product was a white solid; m.p.
148–149 °C (lit.[16] 148.0 °C); yield 0.33 g (89.0%).
Cell Culture
HeLa, CaSki and ViBo cell lines were purchased from the American
Type Culture Collection (Rockville, MD) and were cultured in RPMI-
1640 medium (Gibco, USA) containing 5% newborn calf serum
(NCS; Gibco, USA) with phenol red, supplemented with benzy-
lpenicillin. Cultures were maintained in a humidified atmosphere
with 5% CO2 at 37 °C. All cell-based assays were performed using
cells in the exponential growth phase.
4-Oxo-[(4-nitrophenyl)amino]butanoic acid (2b)
Succinic anhydride (0.212 g, 2.11 mmol), 0.195 g (1.412 mmol) of
4-nitroaniline, 6.0 ml of carbon tetrachloride, 2.0 ml of 1,1,2,2-
tetrachloroethane and 0.21 g (2.11 mmol) of DBU were used. The
product was a yellow solid; m.p. 167–168 °C (lit. 196–197 °C[17a]
and 201 °C[17b]); yield 0.246 g (73.1%).
Cell Proliferation Assay
4-Oxo-4-[(3-trifluoromethyl-4-nitrophen-1-yl)amino]butanoic acid (2c)
Assays were performed by seeding 7500 cells per well in 96-well
tissue culture plates in a volume of 100 ml of RPMI-1640 medium
Succinic anhydride (0.430 g, 4.27 mmol), 0.600 g (2.91 mmol) of
4-nitro-3-(trifluoromethyl)aniline, 9.0ml of carbon tetrachloride,
Appl. Organometal. Chem. 2014, 28, 884–891
Copyright © 2014 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

I. Rojas-Oviedo et al.
Tributylstannyl 4-oxo-4-[(3-trifluoromethyl-4-nitro-phen-1-yl)amino]butanoate (3c)
3.0ml of 1,1,2,2-tetrachloroethane and 0.654g (6.57 mmol) of DBU
were used. The product was a light-brown solid; m.p. 161–165 °C;
yield 0.462g (51.7%). 1H NMR (300 MHz, CDCl3–CD3COCD3, δ,
ppm): 10.40 (brs, 1H, COOH), 9.91 (s, 1H, NH), 8.31 (m, 1H, C2′-H),
8.08 (m, 2H, C5′-H, C6′-H), 2.78 (m, 2H, C3-H), 2.70 (m, 2H, C2-H).
13C NMR (75.43 MHz, CDCl3–CD3COCD3, δ, ppm): 174.1 (C1), 172.2
(C4), 144.6 (C1′), 142.9 (C4′), 128.1 (C5′), 124.9 (C3′) (q, 2 J (19 F–13C)
= 32.8 Hz), 123.2 (CF3) (q, 1 J (19 F–13C) = 270 Hz), 122.8 (C6′), 118.2
(C2′) (q, 3 J (19 F–13C)= 5.5Hz), 32.3 (C3), 28.9 (C2). FT-IR (KBr disc,
cmꢀ1): 3368 s, 3097 m, 3057 m, 2939 m, 1722 s, 1615 s, 1553 s,
1518 s, 1437 m, 1421 m, 1331 s, 1275 s, 1249 s, 1156 s, 1140 s,
1040 m, 908 m, 858 w, 839 w, 801 w, 707 w, 669, 634 w, 516 w,
450 w. Anal. Found (calcd for C11H9N2O5F3) (%): C, 43.09 (43.14); H,
2.91 (2.96); N, 9.06 (9.14). HRMS (ESI): calcd for C11H10N2O5F3:
307.0541 [M + H+], found: 307.0502.
Bis(tributyltin)oxide (464mg, 0.78 mmol), 200mg (0.65mmol) of 2c,
12.0 ml of dry toluene and 4.0ml of absolute ethanol were used.
The product was an orange oil. Recrystallization from dichlo
romethane–hexane gave 94 mg of orange crystals; m.p. 55–58 °C;
yield 24.2%.
1H NMR (300 MHz,CDCl3, δ, ppm): 9.64 (s, 1H, NH), 7.95–7.86 (m,
3H, C6′-H, C5′-H, C2′-H), 2.81–2.77 (m, 2H, CH2COO), 2.68–2.64 (m,
2H, CH2CON), 1.65–1.55 (m, 6H, Hβ), 1.40–1.17 (m, 12H, Hα,Hγ),
0.89 (t, 9H, J = 7.2 Hz, Hδ). 13C NMR (75.43 MHz, CDCl3, δ, ppm):
179.1 (C1), 171.6 (C4), 142.7 (C4′/C1′),142.4 (C1′/C4′), 127.0 (C5′),
121.8 (CF3) (q, 1 J (19 F–13C)= 274Hz), 125.1 (C3′) (q, 2 J (19 F–13C)
= 34 Hz), 121.5 (C6′), 117.8 (C2′) (q, 3 J (19 F–13C)= 6 Hz), 33.6 (C2),
29.7 (C3), 27.7 (2 J(119/117Sn–13C)= 18 Hz] (Cβ), 26.9 (3 J(119/
117Sn–13C)= 62 Hz) (Cγ), 16.7 (1 J(119/117Sn–13C)= 352/337 Hz) (Cα),
13.5 (Cδ). 119Sn NMR (111.81 MHz, CDCl3, δ, ppm): 129.1. FT-IR (KBr
disc, cmꢀ1): 3037 m, 3021 s, 2961 w, 2926 w, 2872 w, 1705 m,
1630 m, 1616 m, 1529 s, 1419 m, 1349 m, 1321 m, 1224 s, 1206 s,
1160 m, 1044 w, 927 w. Anal. Found (calcd for C23H35F3N2O5Sn)
4-Oxo-4-[(5-nitro-1,3-thiazol-2-yl)amino]butanoic acid (2d)
Succinic anhydride (0.723 g, 7.234 mmol), 0.70 g (4.822 mmol) of
2-amino-5-nitrothiazole (previously decolorized with activated
charcoal in ethanol–acetone and recrystallized), 40.0 ml of carbon
tetrachloride, 20.0 ml of 1,1,2,2-tetrachloroethane and 1.101 g
(7.234 mmol) of DBU were used. The product was a light-brown solid;
m.p. 228 °C (dec.) (lit.[19a] 274 °C); yield 0.858 g (72.6%).
(%): C, 46.39 (46.41); H, 5.93 (5.92); N, 4.69 (4.70). MS m/z (%):
+
[Sn2Bu6COOH+] 625 (100), [SnBu3
235 (21.97), [SnBuH2 ] 179 (96.15).
]
291 (35.71), [SnBu2H+]
+
Tributylstannyl 4-oxo-4-[(5-nitro-1,3-thiazol-2-yl)amino]butanoate (3d)
4-Oxo-4-[(2,3-dimethyl-5-oxo-1-phenyl-1,5-dihydro-1H-pyrazol-4-yl)amino]butanoic
acid (2e)
Bis(tributyltin) oxide (1.096 g, 1.839 mmol), 0.410g (1.672 mmol) of
2d, 30.0ml of dry toluene and 10.0ml of absolute ethanol were
used. The product was a brown-orange oil. Recrystallization from
dichloromethane–hexane gave 0.505 g of brown-orange crystals;
m.p. 134–135 °C; yield 56.5%.
Succinic anhydride (0.134 g, 1.343 mmol), 0.210 g (1.033 mmol) of
4-aminoantipyrine and 20.0 ml of dichloromethane were used.
The product was isolated by filtration and washed with dichloro-
1H NMR (300 MHz, CDCl3, δ, ppm): 11.46 (s, 1H, NH), 8.58 (s, 1H,
HC¼), 2.79 (s, 4H, CH2COO, CH2CON), 1.59 (dt, 6H, J= 15.6, 7.5 Hz,
Hβ), 1.37–1.25 (m, 12H, Hα, Hγ), 0.89 (t, 9H, J= 7.2Hz, Hδ). 13C NMR
(75.43 MHz, CDCl3, δ, ppm): 177.8 (C1), 171.2 (C4), 161.5 (C2′), 143.3
(C5), 140.9 (C4′), 32.2 (C2), 29.9 (C3), 27.6 (2 J(119/117Sn–13C) = 20 Hz)
(Cβ), 26.9 (3 J(119/117Sn–13C) = 64 Hz) (Cγ), 16.7 (1 J(119/117Sn–13C)
= 353/338Hz) (Cα), 13.5 (Cδ). 119Sn NMR (111.81 MHz, CDCl3, δ,
ppm):128.6. FT-IR (KBr disc, cmꢀ1): 3420 w, 3164 w, 2958 s, 2923 s,
2855 m, 1711 m, 1615 s, 1559 s, 1495 s, 1395 m, 1351 s, 1311 m,
1177 s, 1154 m, 1121 w, 880 w, 816 w, 670 w. Anal. Found (calcd
for C19H33N3O5SSn) (%): C, 42.60 (42.71); H, 6.18 (6.23); N, 7.75 (7.87).
MS m/z (%): [SnBu+3] 291 (100), [LSnBu2+] 478 (18.3), [SnBu2H+], 235
(52.11), [SnBu+] 177 (60.56).
methane to give
a
white solid; m.p. 194–196 °C (lit.[19b]
204–205 °C); yield 0.308 g (98.4%).
General Procedure for Synthesis of Tributyltin Esters (3a–e)
The method used is similar to that described in our earlier work.[20]
Bis-tri-n-butyltin oxide (1.2 mmol) was added to the corresponding
succinamic acids 2a–e (1 mmol) in a mixture of absolute ethanol
and dry toluene (1:3), and placed in a flask equipped with a
Dean–Stark moisture trap, which was filled with dry toluene. The
mixture was stirred and refluxed for 24 h. After reflux, the solvent
was removed under reduced pressure. The resulting product was
crystallized from dichloromethane–hexane.
Tributylstannyl 4-oxo-4-[(2,3-dimethyl-5-oxo-1-phenyl-1,5-dihydro-1H-pyrazol-
4-yl)amino]butanoate (3e)
Tributylstannyl 4-oxo-4-(phenylamino)butanoate (3a)
Bis(tributyltin)oxide (0.352 g, 0.597 mmol), 0.103 g (0.536 mmol) of 2a,
21 ml of dry toluene and 7.0 ml of absolute ethanol were used. The
product was a colorless oil. Recrystallization from dichloromethane–
Bis(tributyltin) oxide (0.7193g, 1.206 mmol), 0.305 g (1.005 mmol) of
2e, 40.0 ml of dry toluene and 13.5ml of absolute ethanol were
used. The product was a light-yellow oil. Recrystallization from
dichloromethane–hexane gave 0.470 g of white crystals; m.p.
140–141 °C; yield 78.9%.
hexane gave 0.087 g of white crystals; m.p. 60–61 °C (lit. 61–62 °C[21a]
,
lit. oil[21b]); yield 25.8%.
1H NMR (300 MHz, CDCl3, δ, ppm): 7.90 (s, 1H, NH), 7.46–7.36 (m,
3H, C3″-H, C4″-H), 7.29–7.24 (m, 2H, C2″-H, C6″H), 3.04 (s, 3H, N–
CH3), 2.64 (m, 2H, C2-H), 2.60 (m, 2H, C3-H), 2.20 (s, 3H, ¼C–CH3),
1.63–1.55 (m, 6H, Hβ), 1.36–1.21 (m, 12H, Hα, Hγ), 0.90 (t, 9H,
J = 7.2 Hz, Hδ). 13C NMR (75.43 MHz, CDCl3, δ, ppm): 177.8 (C1),
171.3 (C4), 161.8 (C5′), 149.9 (C3′), 109.0 (C4′), 134.7 (C1″), 129.1
(C3″), 124.0 (C2″), 126.6 (C4″), 31.8 (C2), 36.2 (N–C), 30.2 (C3), 27.7
(2 J(119/117Sn–13C)= 19 Hz) (Cβ), 26.9 (3 J(119/117Sn–13C)= 65 Hz) (Cγ),
16.4 (1 J(119/117Sn–13C) = 357/342 Hz) (Cα), 14.0 (¼C–C), 13.6 (Cδ).
119Sn (111.81 MHz, CDCl3, δ, ppm): 109.1. FT-IR (KBr disc, cmꢀ1):
3239 m, 2955 s, 2924 s, 2869 m, 1687 s, 1643 s, 1624 s, 1580 s,
Tributylstannyl 4-oxo-[(4-nitrophenyl)amino]butanoate (3b)
Bis(tributyltin) oxide (0.6456 g, 1.083 mmol), 0.215 g (0.902 mmol) of
3b, 12 ml of dry toluene and 4 ml of absolute ethanol were used.
The product was a brown-yellow oil. Recrystallization from
dichloromethane–hexane gave 0.344 g of brown-yellow crystals;
m.p. 85–86 °C (lit.[22] 132–133 °C); yield 72.3%.
Anal. Found (calcd for C22H36N2O5Sn) (%): C, 50.07 (50.12); H, 6.77
(6.88); N, 5.32 (5.31). MS m/z (%): [LSnBu2+] 471 (100), [LSnBu3-H+]
527 (12.72), [LSnBu+] 357 (15.19), [SnBu3+] 291 (18.02), [SnBu2H+]
235 (10.06), [SnBu+] 177 (13.99).
wileyonlinelibrary.com/journal/aoc
Copyright © 2014 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2014, 28, 884–891

Tributyltin derivatives as potential agents against cervical cancer
Table 1. Crystallographic data for compounds 3a, 3b and 3c
Compound
3a
3b
3c
Formula
C
22H37NO3Sn
C44H72N4O10Sn2
1054.43
C23H35F3N2O5Sn
595.22
Formula weight
482.21
Crystal system, space group
Monoclinic, P21/c
Monoclinic, P21/c
—
Monoclinic, P2
0.467(18)
Flack parameter
—
a (Å)
b (Å)
c (Å)
α (°)
10.5400(16)
15.8466(16)
15.0360(15)
22.650(2)
18.094(2)
14.642(2)
10.478(1)
15.809(3)
28.130(3)
90
90
90
β (°)
97.214
105.34
94.606 (2)
γ (°)
90
90
90
Volume (Å3)
Z
2420.5(7)
5204.5(9)
5315.8(11)
8
4
4
Calculated density (Mg mꢀ3
μ (mmꢀ1
)
1.323
1.346
1.487
)
1.075
1.013
1.016
θ range (°) for data collection
Reflections collected/unique
Data/restraints/parameters
Goodness-of-fit on F2
1.903 to 27.484
16064/5519
5519/0/250
1.030
1.644 to 27.491
35080/11888
11888/678/705
1.013
1.77 to 25.40
41397/19192
19192/530/1375
1.078
Final R indicesa (I > 2σ(I))
R indicesa (all data)
R1 = 0.0256, wR2 = 0.0.626
R1 = 0.0306, wR2 = 0.0659
0.667 and ꢀ0.373
R1 = 0.0586, wR2 = 0.1294
R1 = 0.1022 wR2 = 0.1561
1.285 and ꢀ0.713
R1 = 0.0514, wR2 = 0.1094
R1 = 0.0633 wR2 = 0.1149
2.133 and ꢀ0.850
Δρmax/Δρmax (e Åꢀ3
)
h
h
i
h
ii
1=2
ꢀ
ꢁ
ꢀ
ꢁ
2
2
aR1 = ∑||F0|/|Fc||∑|F0|; wR2 ¼ ∑ w F20 ꢀ Fc2 =∑ w F20
.
Table 2. Selected bond lengths (Å) and angles (°) for compounds 3a–c
3a 3b
3c
Sn(1)–C(19)
Sn(1)–C(11)
Sn(1)–C(15)
Sn(1)–O(1)
2.134(2)
2.139(2)
2.148(2)
2.148(1)
Sn(1)–C(19)
Sn(2)–C(49)
Sn(1)–C(11)
Sn(2)–C(41)
Sn(1)–C(15)
Sn(2)–C(45)
Sn(1)–O(1)
Sn(2)–O(6)
2.148(7)
2.168(7)
2.132(4)
2.142(8)
2.124(5)
2.115(7)
2.120(3)
2.099(4)
Sn(1)–C(116)
2.130(6)
2.120(6)
2.115(7)
2.087(9)
2.127(5)
2.147(6)
2.115(6)
2.164(10)
2.154(6)
2.153(6)
2.152(6)
2.107(9)
2.071(4)
2.042(4)
2.044(5)
2.055(5)
Sn(2)–C(216)
Sn(3)–C(316)
Sn(4)–C(416)
Sn(1)–C(112)
Sn(2)–C(212)
Sn(3)–C(312)
Sn(4)–C(412)
Sn(1)–C(120)
Sn(2)–C(220)
Sn(3)–C(320)
Sn(4)–C(420)
Sn(1)–O(101)
Sn(2)–O(201)
Sn(3)–O(301)
Sn(4)–O(401)
Interaction not observed
Sn(1)–O(3)
O(1)–C(1)
2.572(1)
1.282(2)
Sn(1)–O(8)
Sn(2)…O(3)I
O(1)–C(1)
2.672(3)
3.090(5)
1.289(5)
O(101)–C(101)
O(201)–C(201)
O(301)–C(301)
O(401)–C(401)
O(102)–C(101)
O(202)–C(201)
O(302)–C(301)
O(402)–C(401)
O(103)–C(104)
O(203)–C(204)
O(303)–C(304)
O(403)–C(404)
1.310(7)
1.302(7)
1.311(7)
1.285(8)
1.228(7)
1.242(7)
1.204(7)
1.240(7)
1.216(8)
1.214(8)
1.206(8)
1.213(8)
(Continues)
O(6)–C(31)
O(2)–C(1)
O(7)–C(31)
O(3)–C(4)
O(8)–C(34)
1.291(6)
1.227(5)
1.223(5)
1.223(6)
1.230(5)
O(2)–C(1)
O(3)–C(4)
1.239(2)
1.234(2)
Appl. Organometal. Chem. 2014, 28, 884–891
Copyright © 2014 John Wiley & Sons, Ltd.
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I. Rojas-Oviedo et al.
Table 2. (Continued)
3a
3b
3c
N(1)–C(4)
1.343 (2)
1.419 (3)
122.99 (8)
111.91 (8)
122.82 (8)
96.17 (7)
99.06 (7)
89.30 (7)
N(1)–C(4)
N(3)–C(34)
N(1)–C(5)
N(3)–C(35)
1.350(6)
1.352(6)
1.409(6)
1.404(6)
115.2(6)
131.3(6)
124.1(4)
104.3(6)
116.4(2)
113.9(6)
100.1(6)
93.3(5)
N(101)–C(104)
1.363(8)
1.359(8)
1.361(8)
1.375(8)
1.394(8)
1.401(9)
1.403(8)
1.394(8)
113.6(2)
111.4(3)
113.4(3)
125.0(5)
110.2(2)
112.2(2)
112.3(3)
116.2(4)
121.6(2)
121.8(2)
121.3(3)
106.5(5)
94.9(2)
N(201)–C(204)
N(301)–C(304)
N(401)–C(404)
N(1)–C(5)
N(101)–C(105)
N(201)–C(205)
N(301)–C(305)
N(401)–C(405)
C(19)–Sn(1)–C(11)
C(19)–Sn(1)–C(15)
O(1)–Sn(1)–C(19)
O(1)–Sn(1)–C(19)
O(1)–Sn(1)–C(11)
O(1)–Sn(1)–C(15)
C(19)–Sn(1)–C(11)
C(41)–Sn(2)–C(49)
C(19)–Sn(1)–C(15)
C(45)–Sn(2)–C(49)
C(11)–Sn(1)–C(15)
C(45)–Sn(2)–C(41)
O(1)–Sn(1)–C(19)
O(6)–Sn(2)–C(49)
O(1)–Sn(1)–C(11)
O(6)–Sn(2)–C(41)
O(1)–Sn(1)–C(15)
O(6)–Sn(2)–C(45)
C(112)–Sn(1)–C(120)
C(212)–Sn(2)–C(220)
C(312)–Sn(3)–C(320)
C(420)–Sn(4)–C(412)
C(116)–Sn(1)–C(120)
C(216)–Sn(2)–C(220)
C(316)–Sn(3)–C(320)
C(416)–Sn(4)–C(420)
C(116)–Sn(1)–C(112)
C(216)–Sn(2)–C(212)
C(316)–Sn(3)–C(312)
C(416)–Sn(4)–C(412)
O(101)–Sn(1)–C(120)
O(201)–Sn(2)–C(220)
O(301)–Sn(3)–C(320)
O(401)–Sn(4)–C(420)
O(101)–Sn(1)–C(112)
O(201)–Sn(2)–C(212)
O(301)–Sn(3)–C(312)
O(401)–Sn(4)–C(412)
O(101)–Sn(1)–C(116)
O(201)–Sn(2)–C(216)
O(301)–Sn(3)–C(316)
O(401)–Sn(4)–C(416)
Interaction not observed
Interaction not observed
Interaction not observed
Interaction not observed
96.6(3)
95.4(3)
107.2(3)
105.4(2)
107.0(2)
105.9(2)
99.3(5)
100.69(17)
107.3(6)
89.96(19)
100.9(6)
107.2(2)
104.2(2)
104.3(3)
97.8(3)
C(19)–Sn(1)–O(3)II
C(11)–Sn(1)–O(3) II
C(15)–Sn(1)–O(3) II
O(1)–Sn(1)–O(3) II
87.96 (7)
81.80 (7)
85.57 (7)
174.36 (5)
C(19)–Sn(1)–O(8)
C(11)–Sn(1)–O(8)
C(15)–Sn(1)–O(8)
O(1)–Sn(1)–O(8)
83.7(6)
84.46(16)
81.49(19)
171.34(11)
Symmetry code: I, ꢀ1 + x, y, z; II, x, ꢀy + 3/2, z ꢀ 1/2.
1488 m, 1426 m, 1386 m, 1341 s, 1313 s, 1193 s, 1169 m, 1075 w, 878
w, 761 m, 693 m, 670 m, 642 w, 568 w, 448 w. Anal. Found (calcd for
C27H43N3O4Sn) (%): C, 54.60 (54.75); H, 7.23 (7.32); N, 7.01 (7.09). MS
m/z (%): [L-OH+] 285 (100), [LSnBu3H+] 594 (5.65), [LSnBu+2] 536
(24.38), [SnBu+] 177 (9.86).
compounds are new and structures for all compounds are shown
in Scheme 1.
Compound 2a was prepared by Schreiber and Fernandez to in-
vestigate the reduction of succinimides, but there are no spectral
data.[16a] Lee et al. presented the NMR analysis of 2a.[16b] Com-
pound 2b was obtained by Neidle and co-workers as an intermedi-
ate in their work,[17b] and Rath et al. studied its X-ray diffraction.[17c]
A Japanese patent has reported some proton signals for compound
2c.[18] Antimicrobial activity has been found for compound 2e and
its 1H NMR analysis reported.[19b] Samuel-Lewis et al.[21] and Kumar
Das et al.[21] have reported the melting point and some IR bands for
compound 3a. Compound 3b was reported by Shahid et al. and its
insecticidal and antifungal activity was tested but its spectral data
showed some incorrect assignments, such as the signals of the 1H
NMR spectrum in which the ethylene moiety is described at the
highest downfield shift, and a triplet signal is assigned to the butyl
groups. The 13C NMR spectrum did not report the signals for the
Results and Discussion
Syntheses
With succinic anhydride as the raw material, five N-substituted
succinamic acid compounds 2a–e were synthesized by the acylation
reaction with the selected amine in the presence of DBU and yields
ranging from 51 to 98% were obtained. Compounds 3a–e were
prepared by condensation of the appropriate compound 2a–e with
bis-tri-n-butyltin oxide in toluene–ethanol. Three of the organotin
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Appl. Organometal. Chem. 2014, 28, 884–891

Tributyltin derivatives as potential agents against cervical cancer
Figure 1. Molecular structure and crystallographic numbering scheme for 3a. Ellipsoids represent a 50% probability level.
satellites in solution in the range
357 to 339 Hz, suggesting a tet-
rahedral geometry around the
tin atom.[23]
The 119Sn NMR spectra of
compounds 3a–e exhibit a single
resonance in solution (CDCl3),
with chemical shifts of 117.6,
124.8, 129.1, 128.6 and 109.1, re-
spectively, which is characteristic
of four-coordinated tri-n-butyl
compounds.[24]
FT-IR Spectroscopy
The formation of compounds 2a–
e is supported by the appearance
of the C¼O band from the car-
boxyl group and the C¼O band
of the amide group in the regions
1687–1724 and 1560–1697 cmꢀ1
,
respectively.
In the spectra of the
triorganotin derivatives 3a–e,
the absence of the O–H broad
Figure 2. Molecular structure and crystallographic numbering scheme for 3b. The probability level of ellipsoids is
30% (disorder not shown).
carboxylate group and for the ethylene moiety.[22] In our study,
these compounds were obtained in greater yields and the crystallo-
graphic data of compounds 3a–c are presented.
band between 3300 and 2800 cmꢀ1 indicates the deprotonation of
the COOH group during complex formation. The difference
Δν =νasym(OCO) ꢀ νsym(OCO) has been used for determining the
structure of complexes.[25] It has been reported that differences
larger than 250 cmꢀ1 suggest that the ligand behaves as a
monodentate one and differences less than 200 cmꢀ1 are indicative
of bridging. The Δν values for our compounds range from 157 to
286 cmꢀ1 and are as follows (cmꢀ1): 3a, Δν =1654ꢀ 1445 = 209;
3b, Δν = 1670 – 1513 = 157; 3c, Δν =1705 – 1419 = 286; 3d,
Δν = 1711 – 1495 = 216; 3e, Δν = 1687 – 1488 = 199. From these
results we can assume that in the solid state the compounds 3a,
3b, 3d and 3e present bridging structures, and the X-ray diffraction
patterns of 3a and 3b agree with this assumption; each ligand
1H NMR, 13C NMR and 119Sn NMR Spectroscopy
The 1H NMR assignments of compounds 2c–e and 3c–e are de-
scribed in the experimental section. Those of 2a, 2b and 3b are
given in the supporting information.
The assignment of 13C NMR resonances of n-butyl groups in each
n
of compounds 3a–e is determined from the coupling constants J
(
119/117Sn–13C) which are important parameters for characterization.
All the tri-n-butyltin carboxylates exhibit 1 J (119/117Sn–13C) coupling
Appl. Organometal. Chem. 2014, 28, 884–891
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I. Rojas-Oviedo et al.
bridges two triorganotin moieties. For compound 3c, a monodentate
structure is expected, which is also confirmed by X-ray analysis.
Mass Spectrometry
Tin is the only element that has ten naturally occurring iso-
topes, and the mass spectra obtained for compounds 3a–d
show the characteristic peak patterns of molecules containing
one tin atom.[26] The molecular ion peak in all derivatives is
not observed, but the cleavage of butyl groups takes place
with the successive loss of the second butyl group followed
by the loss of the ligand. The fragment ions given in the ex-
perimental section are in good agreement with the expected
structure of the compounds.
Figure 4. Structural arrangement of the tributyltin compounds.
compounds 3a and 3b of type A (Fig. 4) is therefore lost in solution
to generate a four-coordinated tetrahedral structure of type B, whereas
compound 3c in the solid state shows a monomeric structure of type B.
Besides the similar conformation of the ligands (scorpion-like) of the
three complexes, one can observe a shortening of the C¼O bond
length in the oxo moiety and a lengthening of the C–N bonds of the
amide moiety from complex 3a to complex 3c (Table 2). This trend
could be due to the presence of the substituents in the arylamine for
which the CF3 group has a greater electron-withdrawing power than
the NO2 group, and therefore precluding the formation of a bridge be-
tween a second tin atom and the amido carbonyl group.
X-ray Diffraction
The molecular structures for the complexes 3a–c are
established using X-ray diffraction. Complexes 3b and 3c dis-
play orientational disorder of several of the n-butyl groups at-
tached to the tin atoms, which is resolved as splitting of the
groups over two main orientations. Table 1 gives a summary
for the crystals and refined structures, while the selected
bond lengths and bond angles are given in Table 2. The mo-
lecular structures of compounds 3a and 3b show that, in both
In Vitro Anti-proliferative Screening
With respect to the anti-proliferative activity of compounds
3a–e, our findings establish that all compounds affect the
proliferative potential of tumor cells, particularly 3c which shows
the highest anti-proliferative activity in the three tumor lines
cases, the 4-oxo-4-arylaminobutanoic acid behaves as
a
bidentate ligand, bridging two tin metal centers with the car-
boxylate group and the amido carbonyl group, giving rise to a
five-coordinated tin structure (Figs. 1 and 2). The overall ge-
ometry of tin is a distorted trigonal bipyramid in which the
equatorial plane is formed from the butyl groups of the
triorganotin moiety, while the carboxyl oxygen and the
carboxamide oxygen occupy the apical positions in 3a and
3b. Distortion from the ideal trigonal bipyramidal geometry
for compounds 3a and 3b can be observed from small devia-
tions (174.36(5)° and 171.34(11)°) from the ideal 180° for api-
Table 3. Anti-proliferative activity( IC50, μM) of tributyltin compounds
3a–e on human Hela, CaSki and ViBo cells lines
Compound
HeLa
CaSki
ViBo
3a
3b
3c
3d
3e
0.56 0.03
0.95 0.07
0.43 0.02
24.0 1.4
18.8 1.3
4.9 0.3
1.3 0.1
18.4 1.3
20.6 1.5
0.78 0.05
19.3 1.1
15.2 0.9
cal positions. Compound 3c shows
a
distorted four-
1.05 0.08
4.7 0.3
coordinated geometry and the 4-oxo-4-(arylamino)butanoic
acid behaves as a monodentate ligand (Fig. 3). The butyl groups are
involved in the disorder. The polymeric structure of the solid state for
1.22 0.1
(Table 3), indicating that the ar-
omatic ring with the CF3 group
is important for potentiating
the anti-proliferative activity of
these compounds over the
other substituents present in
the aromatic ring. Importantly,
all the compounds have null or
low cytotoxic activity (necrotic)
in the three tumor cell lines,
suggesting that the side effects
associated with cytotoxic activ-
ity present in the compounds
used could be decreased con-
siderably (Table 4). It will be
important in the future to test
these compounds in non-
tumor cell cultures with the in-
tent of establishing whether
Figure 3. Molecular structure and crystallographic numbering scheme for 3c, with ellipsoids at 40% probability level
(only one of the four independent molecules is shown).
these compounds have
a
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Tributyltin derivatives as potential agents against cervical cancer
Table 4. Cytotoxicity SD of tributyltin compounds 3a–e
Triton X-100
Control
DMSO
3a
3b
3c
3d
3e
HeLa (%)
CaSki (%)
ViBo (%)
100 1.7
100 1.8
100 1.5
17.5 1.2
19.5 1.1
1.4 0.05
11.5 0.4
13.2 0.7
4.4 0.2
18.6 1.2
3.9 0.2
3.8 0.1
18.3 1.5
2.7 0.1
2.9 0.1
18.3 0.7
24.6 01.3
1.8 0.9
9.0 0.3
4.4 0.2
5.4 0.3
10.6 0.8
2.4 0.1
2.1 0.1
selective action. It is known that cisplatin affects the proliferative
potential of the Jurkat (T lymphocyte leukemic) cell line at a
concentration of 10 μM, whereas in the cervical cancer cell lines
HeLa, SiHa and C33-A, it is 5.91 0.30, 25.9 0.51 and 13.25
1.98 μM, respectively, suggesting that 3a–c are more potent
in HeLa cells than cisplatin. The fact that compounds 3a–e
exhibit anti-proliferative activity without showing cytotoxic
activity makes them strong candidates to be studied as potential
therapeutic agents against cancer.
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The coupling constants 1 J (119/117Sn–13C) of the tributyltin group
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The values of Δν from the carboxylate groups in compounds 3a,
3b, 3d and 3e suggest that they form a bridging structure, whereas
for 3c its FT-IR data demonstrate that Δν from the carboxylate
group is typical for a monodentate structure in agreement with
its X-ray analysis. The mass spectra of all obtained compounds
show the characteristic peak patterns of molecules containing
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butanoic acid 3a and 3b in the solid state with the external amide
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X-ray crystallography. In contrast, 3c was found to be a monomeric
species.
In relation to the geometries in the solid state, X-ray analysis indi-
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gonal bipyramidal geometry towards tetrahedral geometry due to
the increasing electron-withdrawing effect of the substituents in
the aromatic ring.
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3a–e, it was found that all of them showed potency against all
three strains investigated and null or low cytotoxic activity (ne-
crotic). It was determined that the presence of the CF3 group in
compound 3c provided it with the highest anti-proliferative ac-
tivity in the three tumor lines compared to the other substitu-
ents present in the aromatic ring. The results make these
compounds strong candidates to be studied as potential thera-
peutic agents against cancer.
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Acknowledgments
Supporting Information
We gratefully acknowledge Ruben Gaviño for recording the NMR
spectra, Maria de la Paz Orta Perez for the elemental analysis, Liliana
Rivera for the mass analysis and Eileen Philips.
Additional supporting information may be found in the online ver-
sion of this article at the publisher’s web-site.
Appl. Organometal. Chem. 2014, 28, 884–891
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