Diorganotin(IV) derivatives of arylhydroxamic acids: Synthesis, properties and antitumor activity

Article abstract of DOI:10.1016/j.jorganchem.2004.08.025

Series of diorganotin(IV) complexes of para-substituted benzohydroxamic acid, [R₂SnL₂] and [R₂Sn(L)]₂O, have been prepared and characterized. Their in vitro antitumor activity against a series of human tumor cell lines was tested and, in a few of them, is identical to, or higher than, that of cisplatin. Series of diorganotin(IV) complexes of 4-X-benzohydroxamic acid [X = NH₂ (HL₁), NO₂ (HL₂) or F (HL₃)] formulated as [R₂SnL ₂] and [R₂Sn(L)]₂O (R = Me, Et, nBu or Ph) have been prepared and characterized by FT-IR, ¹H, ¹³C and ¹¹⁹Sn NMR spectroscopies, elemental analyses, FAB⁺-MS and melting point determination. They are stable in air, soluble in alcohols and in hydroalcoholic solution and, in some cases, in water. Their in vitro antitumor activity against a series of human tumor cell lines was tested and, in a few of them, is identical to, or even higher than, that of cisplatin. For the mononuclear dialkyltin compounds, the activity generally increases with the length of the carbon chain of the alkyl ligand, being higher for the complexes with benzohydroxamato ligands bearing an electron-acceptor substituent (X = NO₂ or F). No structure-activity relationship based on the Hammett's σ_p constant, or related ones, has been recognized.

Full text of DOI:10.1016/j.jorganchem.2004.08.025

Journal of Organometallic Chemistry 689 (2004) 4584–4591
www.elsevier.com/locate/jorganchem
Diorganotin(IV) derivatives of arylhydroxamic acids:
synthesis, properties and antitumor activity
, M. Fatima C. Guedes da Silva a,c, Zhao Jinghua ,
a,b
b
*
´
Armando J.L. Pombeiro
Qingshan Li
a,
*
a
´
Complexo I, Instituto Superior Tecnico, Avenida Rovisco Pais, 1049-001 Lisbon, Portugal
School of Pharmaceutical Science, Shanxi Medical University, Taiyuan 030001, PR China
b
c
´
Universidade Lusofona de Humanidades e Tecnologias, Campo Grande 376, 1749-024 Lisbon, Portugal
Received 10 May 2004; accepted 17 August 2004
Available online 17 September 2004
Abstract
Series of diorganotin(IV) complexes of 4-X-benzohydroxamic acid [X = NH2 (HL1), NO2 (HL2) or F (HL3)] formulated as
[R2SnL2] and [R2Sn(L)]2O (R = Me, Et, nBu or Ph) have been prepared and characterized by FT-IR, 1H, 13C and 119Sn NMR spec-
troscopies, elemental analyses, FAB+-MS and melting point determination. They are stable in air, soluble in alcohols and in hydro-
alcoholic solution and, in some cases, in water. Their in vitro antitumor activity against a series of human tumor cell lines was tested
and, in a few of them, is identical to, or even higher than, that of cisplatin. For the mononuclear dialkyltin compounds, the activity
generally increases with the length of the carbon chain of the alkyl ligand, being higher for the complexes with benzohydroxamato
ligands bearing an electron-acceptor substituent (X = NO2 or F). No structure-activity relationship based on the HammettÕs rp con-
stant, or related ones, has been recognized.
ꢀ 2004 Elsevier B.V. All rights reserved.
Keywords: Diorganotin; Hydroxamate ligands; Antitumor activity
1. Introduction
in analytical chemistry [4]. In particular, arylhydroxamic
acids are nucleoside reductase inhibitors [5] and thus ex-
hibit some antitumor activity [6].
Organotin(IV) complexes with bidentate O-donor lig-
ands [7–15], including N-substituted hydroxamic acids,
are well known and some of them exhibit antitumor
activity against the MCF-7 mammary tumor and the
WiDr colon tumor [16–18] but they are inactive against
most of other tumors.
Hydroxamic acids constitute a very important class
of chelating agents with versatile biological activity
[1,2]. The research on their coordination properties is
mostly oriented towards modeling the biological func-
tion such as microbial transportation of iron [2] and
inhibition of urease activity [3], although they also have
been extensively used as detectors for many metal ions
In previous studies of the interactions between dior-
ganotin(IV) acceptors and benzohydroxamic acid and
its derivatives [19,20], a synergic effect was recognized
and most of this type of compounds showed promising
in vitro activity against a series of human tumor cell
lines and, in some cases, they even exhibited in vivo
*
Corresponding author. Tel.: +351 2184 19237; fax: +351 2184
64455.
E-mail addresses: qingshanl@yahoo.com (Q. Li), fatima.guedes
@ist.utl.pt (M. Fa´tima C. Guedes da Silva), pombeiro@ist.utl.pt
(A.J.L. Pombeiro).
0022-328X/$ - see front matter ꢀ 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2004.08.025

Q. Li et al. / Journal of Organometallic Chemistry 689 (2004) 4584–4591
4585
activity against gastrointestinal tumors, with the dibu-
tyltin(IV) benzohydroxamate monomeric complexes
being the lead compounds [20].
The first synthetic method for the mononuclear com-
pounds is more convenient than the second one which
uses diorganotin oxide compounds as starting materials
in solvent refluxing conditions and which was applied
[21,22] to the preparation of other dialkyltin(IV) com-
plexes. Complexes 1c1 and 1c2, prepared from the corre-
sponding diorganotin oxide, were published elsewhere
[22a], but their synthesis (in the latter case by the advan-
tageous procedure we indicate herein that starts from
[(nBu)2SnCl2]) and characterization are also included
for comparative purposes.
Diorganotin 5-coordinate complexes with oxo-
bridges are known namely diorganodicarboxylatodis-
tannoxanes {[XC6H3(OH-2)COOSn(nBu)2]2O}2 (X =
Me-3, OMe-3, OMe-4, OMe-5, NH2-4) [24] which are
dimeric with the oxo ligand bridging three metals. How-
ever, a related dimeric structure for our complexes is ru-
led out by the detection of a single 119Sn resonance (see
below).
The dinuclear hydroxamate [R2Sn{ONHC(O)C6H4-
X}]2O (R = Et, nBu; X = H, OH-2, OH-4) complexes
related to those of this study have been prepared by a
distinct and more complex route, involving the reaction
of [R2SnCl2(1,10-phenanthroline)] with hydroxamic
acids [25].
All the complexes are stable in air and sparingly sol-
uble in common organic solvents and in hydroalcoholic
solutions. The fluoro- and the amino-substituted com-
plexes tend to exhibit a higher solubility in water than
the other ones.
In this paper, we extend the study of diorganotin(IV)
complexes to those with different substituted 4-X-ben-
zohydroxamic acids, HL = HL1 (X = NH2), HL2
(X = NO2) or HL3 (X = F), presenting X substituents
with electron donor/acceptor properties span over quite
a wide range, thus investigating their influence on the
antitumor activity of the complexes, and searching for
a better solubility in organic solvents, in alcohols and/
or even in water, an important property in view of their
possible biological application. The preparation of the
mononuclear [R2SnL2] (R = Me, Et, nBu, Ph; L = L1,
L2 or L3) and the dinuclear [R2SnL]2O compounds
and a study of their spectroscopic features are thus re-
ported, as well as their antitumor in vitro activity.
The in vitro activity, against various tumors, was also
detected in some other dialkyltin(IV) complexes with
diacyl or monoacyl heterocyclic derivatives of hydroxa-
mic acids [21,22], and in some triorganotin(IV) com-
pounds with basic forms of terebic, benzoic or salycilic
acids [23].
3
2
O
1
X
4
N
H
OH
HL
X = NH2 (HL1), NO2 (HL2) or F (HL3)
2.1. Spectroscopic data
By comparing the IR spectra of the free HL1, HL2
and HL3 with those of the corresponding complexes,
one notes the disappearance of the strong and broad
band centered at 2700 cmꢁ1 in the former, what is
indicative of the loss of the proton in the CO–NHOH
group upon coordination, thus resulting in the elimina-
tion of the O–Hꢂ ꢂ ꢂO intramolecular stretch. The IR
spectra of all the compounds show evidence for the
coordination of the hydroxamate ligand via both oxy-
gen atoms of the CONHOꢁ group. In fact, ligation
through the carbonyl oxygen is indicated by the
m(C@O) shift to a lower frequency, i.e. from ca. 1650
cmꢁ1 in the free species to 1620 cmꢁ1 in the chelated
one. Moreover, the shift towards higher frequency of
the N–O stretching vibration (from 849–897 to 910–
1060 cmꢁ1) excludes the coordination via the nitrogen
atom [26,27]. The observed strong absorptions of com-
plexes [R2SnL]2O in the 535–400 cmꢁ1 region are due
to m(Sn–O) [28] and the presence of more than one
stretching vibration probably reflects different Sn–O
bond distances in the solid state [29–31]. Strong bands
in the 611–635 cmꢁ1 region are assigned to Sn–O–Sn
bond vibrations [25,32].
2. Results and discussion
Complexes [R2SnL2] were synthesized by reaction (Eq.
(1)) of [R2SnCl2] with HL and KOH (both in a twofold
molar amount relatively to the tin complex) in undried
methanol at room temperature [L = L1, R = Me (1a1),
Et (1b1); L = L2, R = Me (1a2), Et (1b2), nBu (1c2)] or
by reaction (Eq. (2)) of [R2SnO] with HL (twofold molar
ratio) in a refluxing 1:3 mixture of benzene/methanol
[L = L1, R = nBu (1c1), Ph (1d1); L = L2, R = Ph (1d2);
L = L3, R = Me (1a3), nBu (1c3), Ph (1d3)]. The dinu-
clear complexes [R2SnL]2O [L = L1, R = Me (2a1), nBu
(2c1), Ph (2d1); L = L3, R = Me (2a3), nBu (2c3), Ph
(2d3)] were obtained similarly from [R2SnO] but by using
a stoichiometric amount of HL (Eq. (3)).
½R2SnCl2ꢀ þ 2HL þ 2KOH
! ½R2SnL2ꢀ þ 2KCl þ 2H2O
ð1Þ
ð2Þ
ð3Þ
½R2SnOꢀ þ 2HL ! ½R2SnL2ꢀ þ H2O
2½R2SnOꢀ þ 2HL ! ½R2SnLꢀ O þ H2O
2

4586
Q. Li et al. / Journal of Organometallic Chemistry 689 (2004) 4584–4591
In the 1H and 13C–{1H} NMR spectra the assignment
2.2. Antitumor activity in vitro
of phenyl protons and carbons were based on theoretical
predictions [33]. The measured 2JSn–H coupling constant
for 1a3 and 2a3 (83.0 and 78.6 Hz, respectively) enabled
the estimate, based on the equation of Lockhart and
Manders (Eq. (4)) [34], of the values of the h(C–Sn–C)
angles for these compounds: 135ꢁ (1a3) and 129ꢁ (2a3)
(the lower solubility of the other organotin complexes
The antitumor activity in vitro was tested on various
human tumor cell lines [immature granulocyte leukemia
(HL-60) as well as nasopharyngeal (KB), hepatocellular
(Bel-7402), ovarian (Hela) and colon (HCT-8) carcino-
mas] and mouse tumor cell lines (lymphocyte carcino-
mas B and T). The results are summarized in Tables 1
and 2. As observed in a previous study [20], both the
organoligand R and the para-phenyl (X) substituent of
the hydroxamate ligand appear to play an important
role. Indeed, the dibutyltin(IV) complexes, with the
longest alkyl chain, exhibit the strongest antitumor
activity in each series of complexes, which is identical
or even more potent than that of cisplatin, the clinically
widely used drug. In contrast, the dimethyltin(IV) deriv-
atives usually exhibit the weakest activity. The other
organo-derivatives follow an order that is also depend-
ent on the type of tumor and on the arylhydroxamate
ligand. Hence, for [R2Sn(L2)2], the activity follows the
order nBu > Ph, Et > Me for nearly all the tumor cells,
with the diphenyl complex (1d2) being more active than
the diethyl one (1b2) for the Bel-7402 and Hela tumors.
Similar trends were also found in diorganotin(IV) carb-
oxylates [24]. However, in our study the reverse is ob-
served for the KB and T cases (for the HL-60 and B
tumors, both complexes have comparable activities).
The electronic influence of the X substituent also af-
fects the antitumor activity of the complexes as expected
in view of its influence on the electron-donor character
of the ligand. Thus, the complexes with L2 and L3 which
have the electron-withdrawing NO2 and F substituents
tend to show better activities than those with L1 with
the electron-releasing NH2 group. The strongest activ-
ity, however, in the cases of the Bel-7402 and KB carci-
2
precluded the measurement of JSn–H). These h values
are compatible [20,34–37] with a distorted octahedral
structure and a distorted trigonal–bipyramidal structure
[h commonly in the 115–130ꢁ range for pentacoordinate
dimethyltin(IV) complexes] [34] for the monomer and
the dinuclear complexes, respectively. Such deforma-
tions, which occur frequently in diorganotin(IV) com-
pounds, are known [35,37] to be determined not only
by the tin coordination number but also by electronic
and stereochemical factors.
2
2
2
hðC–Sn–CÞ ¼ 0:0161ð JSn–HÞ ꢁ 1:32ð JSn–HÞ þ 133:4:
ð4Þ
The 119Sn NMR resonances of the mononuclear com-
plexes occur at chemical shifts (from ꢁ287 to ꢁ489
ppm) that fall within the range of hexacoordinate ti-
n(IV) complexes whereas the lower field chemical shift
(ꢁ196.36 ppm) of 2a1 is in accord with the pentacoordi-
nation of this dinuclear complex. However, the other
dinuclear compounds reveal d(119Sn) outside the values
characteristic of pentacoordinated Sn complexes falling
in the common range of 6-coordinate compounds
[35,38,39]. Hence, we cannot rule out the possibility of
a pseudo-octahedral environment around the tin atoms
in solutions of the dinuclear complexes in a coordinating
solvent such as DMSO, methanol or acetone.
The FAB+ mass spectra of most of the compounds
show the respective molecular ions [M]+ and/or frag-
ments formed upon sequential loss of ligands.
nomas, is shown by
complex, 1c3, although the F-substituent is a much
a
fluorobenzohydroxamato
Table 1
Inhibition (%) of diorganotin(IV) complexesa against human and mouse tumor cell lines
Compound
No.
HL-60
KB
Bel-7402
Hela
HCT-8
B
T
X
R
1a1
1b1
1c1
1d1
NH2
Me
Et
19.0
13.0
70.4
19.9
9.6
16.5
88.2
19.5
20.6
24.2
71.2
15.9
–
34.5
20.8
39.4
9.7
10.0
35.8
70.6
23.5
1.3
70.9
3.2
nBu
Ph
1a2
1b2
1c2
1d2
NO2
Me
Et
16.0
64.9
83.3
66.5
8.5
86.5
98.6
63.4
4.2
42.0
98.2
80.8
–
27.5
71.3
67.1
69.0
31.1
66.0
68.9
53.2
43.8
97.5
73.6
nBu
Ph
1c3
1d3
2c3
2d3
a
F
nBu
Ph
79.8
71.8
71.4
68.3
95.5
66.5
86.8
69.1
91.7
81.2
75.8
83.7
nBu
Ph
Dose level of 10 lM (X = NH2, NO2) or 5 lg/mL (X = F).

Q. Li et al. / Journal of Organometallic Chemistry 689 (2004) 4584–4591
4587
Table 2
Summary of the screening data for the in vitro antitumor activitya
Compound
HL-60
KB
Bel-7420
Hela
HCT-8
B
T
1a1
1b1
1c1
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
+
++
ꢁ
++
ꢁ
++
ꢁ
++
ꢁ
+
++
ꢁ
1d1
1a2
1b2
1c2
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
++
++
++
++
+++
++
+++
++
+
+
++
++
++
++
++
++
++
++
+++
++
++
++
1d2
1c3
+++
++
Cisplatin
a
++
++
++
++
IC50 > 1 · 10ꢁ4 mol/L (–, inactivity); IC50 6 1 · 10ꢁ4 mol/L (+, weak activity); IC50 6 1 · 10ꢁ5 mol/L (++, medium activity); IC50 6 1 · 10ꢁ6
mol/L (+++, strong activity).
weaker electron-acceptor than NO2, conceivably on ac-
count of the higher solubility in aqueous medium of the
former complex. The higher water-solubility of fluorine-
substituted organotin complexes with antitumor activ-
ity, relatively to related non-fluorinated compounds,
has already been reported [24]. Other strategies to in-
crease the solubility in water of bioactive organotin
complexes have been applied and in particular some
water-soluble polyoxaalkylcarboxylate tin complexes
display rather promising anti-tumor activity [24,40–42].
was achieved using CsI. Melting points were measured
on a Kofler-table (Leica Galen III).
HONHC(O)C6H4NH2-4 (HL1). White powder. Ele-
mental Analysis Calcd. (%) for H8C7N2O2: C, 55.25; H,
5.31; N, 18.41; Found: C, 55.30; H, 5.37; N, 18.50%. IR:
3334s, 3279s m(N–H); 2700s, br m(O–H); 1648s, 1599s,
1537s and 1507s m(C'O)/m(N'C); 897s m(N–O). 1H
NMR [(CD3)2CO]: d 10.55 [s, br, 1H, NH]; 8.18 [s, br,
3
3
1H, OH]; 7.74 [d, J = 9.0, 2H, H(2)]; 6.81 [d, J = 9.0,
2H, H(3)]; 5.35 [s, br, 2H, NH2]. 13C{1H} [(CD3)2CO]
d 166.10 (CO); 152.67 [C(4)], 131.83 [C(1)], 137.00
[C(2)], 124.51 [C(3)]. Yield 54%.
3. Experimental section
HONHC(O)C6H4NO2-4 (HL2). White powder. Ele-
mental Analysis Calcd. (%) for H6C7N2O4: C, 46.15; H,
3.31; N, 15.38; Found: C, 46.07; H, 3.40; N, 15.49%. IR:
3249s, m(N–H); 2700s, br m(O–H); 1652s, 1599s, 1561w
and 1515s m(C'O)/m(N'C); 898s m(N–O). 1H NMR
[(CD3)2CO]: d 9.94 [s, br, 2H, NH and OH]; 8.23 [d,
3J = 9.0, 2H, H(2)]; 8.48 [d, 3J = 9.0, 2H, H(3)].
13C{1H} [(CD3)2CO]: d 166.29 (CO); 150.44 [C(4)],
138.95 [C(1)], 129.13 [C(2)], 124.41 [C(3)]. Yield 49%.
HONHC(O)C6H4F-4 (HL3). White powder. Ele-
mental Analysis Calcd. (%) for H6C7N1O2 F1: C,
54.19; H, 3.87; N, 9.03; Found: C, 54.23; H, 3.83; N,
8.98%. IR: 3297m m(N–H); 2700s, br m(O–H); 1642s
3.1. General
The diorganotin(IV) chloride and oxide and the
methylbenzoate derivatives were purchased from Alfa
or Aldrich and used as received. All the other chemicals
were of analytical grade. The substituted benzohydroxa-
mic acids HL1, HL2 and HL3, were prepared according
to a known [43] general procedure.
The samples for microanalyses were dried in vacuo to
constant weight (20 ꢁC, ca. 0.1 Torr) and the analyses
were carried out either by the Microanalytical Service
1
´
of the Instituto Superior Tecnico in Lisbon or by the
m(C'O)/m(N'C); 849s m(N–O). H NMR [CD3OD]: d
3
Analytical Laboratory of Shanxi University, China.
Infrared spectra were recorded on a Bio-Rad FTS
3000MX FT-IR spectrometer in KBr pellets (4000–400
7.07 [t, JHH = 3JFH = 9.0, 2H, H(3)]; 7.69 [dd,
4
3JHH = 9.0, JFH = 5.4, 2H, H(2)]. 13C{1H} [CD3OD]:
d 166.19 [1JCF = 250.6, C(4)], 116.51 [2JCF = 22.3,
C(3)], 130.66 [3JCF = 8.7, C(2)], 129.88 [C(1)]. 19F
[CD3OD]: ꢁ110.10. Yield 65%.
1
cmꢁ1). H, 13C, 19F and 119Sn NMR spectra were re-
corded on a Varian Unity 300 spectrometer (300.0
1
MHz for H, 75.5 MHz for 13C, 282.2 MHz for 19F
and 111.9 MHz for 119Sn) at ambient temperature [d val-
3.2. Syntheses of the complexes
ues in ppm relative to SiMe4 (1H, 13C), CFCl3 (19F) or
SnMe4
(
119Sn)]. The fast-atom bombardment (FAB)
3.2.1. Mononuclear bis(4-X-benzohydroxamato)dialkyl-
tin(IV), [R2SnL2] [L = L1, R = Me (1a1), Et (1b1);
L = L2, R = Me (1a2), Et (1b2), nBu (1c2)]
Dialkyltin(IV) dichloride (0.220 g, 1 mmol) was
added to a methanolic solution (20 mL) of HL (2 mmol)
and KOH (0.112 g, 2 mmol). A precipitate formed
mass spectrometric measurements were performed on
a Trio 2000 instrument and the positive-ion FAB spectra
were obtained by bombarding 3-nitrobenzyl alcohol
(NOBA) matrixes of the samples with 8 keV xenon
atoms. Mass calibration for the data acquisition system

4588
Q. Li et al. / Journal of Organometallic Chemistry 689 (2004) 4584–4591
gradually and the mixture was stirred for 48 h at room
temperature under N2. The precipitate was then filtered
off, washed with cold methanol, recrystallized from
chloroform/light petroleum (or methanol/diethylether
for 1a1) and dried to constant weight.
[nBu2Sn{ONHC(O)C6H4NH2-4}2] (1c1). Light yel-
low; m.p.: 168–169 ꢁC. Elemental Analysis Calcd. (%)
for H32C22O4N4Sn: C, 49.36; H, 6.04; N, 10.47; Found:
C, 45.96; H, 6.11; N, 9.97%. IR: 3352s and 3219s m(N–
H); 1607s, 1562w and 1534w m(C'O)/m(N'C); 915s
m(N–O); 515m m(Sn–O); 629s and 557w m(Sn–C). 1H
NMR [(CD3)2SO]: d 12.15 [br, 2H, NH], 7.69 [d,
3.2.2. Mononuclear bis(4-X-benzohydroxamato)dialkyl-
tin(IV), [R2SnL2] [L = L1, R = nBu (1c1), Ph (1d1);
L = L2, R = Ph (1d2); L = L3, R = Me, (1a3), nBu
(1c3), Ph (1d3)]
Dialkyltin oxide (1 mmol) was added to a dry meth-
anol:benzene (1:3 v/v) solution of HL (2 mmol) which
was refluxed for 6 h under N2. The solvent was then
evaporated to dryness. The precipitate thus formed
was recrystallized from methanol/light petroleum, chlo-
roform (1a3), n-hexane (1c3) or ethanol (1d3) and dried
to constant weight.
3
3JHH = 8.1, 4H, H(2)]; 6.80 [d, JHH = 8.1, 4H, H(3)];
5.46 [br, 2H, NH2], 5.28 [br, 2H, NH2]; 3.55–3.05,
2.16–0.96 [m, R-Sn]. 13C{1H} [(CD3)2SO]: d 163.36
(CO); 153.25 [C(4)], 116.32 [C(1)], 128.76 [C(2)], 114.36
[C(3)]; 28.02–13.33 (m, R-Sn). 119Sn [(CD3)2SO:CDCl3]:
d ꢁ356.96. Yield 34%.
[Ph2Sn{ONHC(O)C6H4NH2-4}2] (1d1). White;
m.p.: 162–164 ꢁC. Elemental Analysis Calcd. (%) for
H32C26O4N4Sn: C, 54.28; H, 4.21; N, 9.74; Found: C,
55.08; H, 4.22; N, 9.82%. IR: 3323s and 3240s m(N–H);
1607s, 1562w and 1534w m(C'O)/m(N'C); 915s m(N–
1
3.2.3. Dinuclear bis(4-X-benzohydroxamato)dialkyl-
tin(IV) [R2SnL]2O [L = L1, R = Me (2a1), nBu
(2c1), Ph (2d1); L = L3, R = Me (2a3), nBu (2c3),
Ph (2d3)]
Dialkyltin oxide (1 mmol) was added to a metha-
nol:benzene (1:3 v/v) solution of HL (1 mmol) and the
mixture was refluxed for 6 h under N2 whereafter the
solvent was evaporated to dryness. The precipitate thus
formed was filtered off, recrystallized from dry ethanol
(L = L1), methanol (2a3), cyclohexane (2c3) or benzene
(2d3) and dried to constant weight.
O); 515m m(Sn–O); 629s and 557w m(Sn–C). H NMR
3
[(CD3)2CO]: d 12.03 [br, 2H, NH], 7.37[d, JHH = 6.0,
3
4H, H(2)]; 6.79 [d, JHH = 6.0, 4H, H(3)]; 5.37 [br, 2H,
NH2]; 7.85–7.50 [m, R-Sn]. 13C{1H} [(CD3)2CO]:
163.44 (CO); 152.68 [C(4)], 137.63–127.49 [m, C(1),
C(2), C(3), R-Sn). 119Sn [(CD3)2CO]: d ꢁ357.01. Yield
80%.
[Me2Sn{ONHC(O)C6H4NO2-4}2] (1a2). Light yel-
low; m.p.: >300 ꢁC. Elemental Analysis Calcd. (%) for
H16C16O8N4Sn: C, 37.60; H, 3.16; N, 10.97; Found:
C, 37.32; H, 3.61; N, 10.89%. IR: 3113s m(N–H);
1626m, 1596m, 1573s and 1225s m(C'O)/m(N'C);
1015m m(N–O); 525m and 491s m(Sn–O); 643s and
571w m(Sn–C). 1H NMR [(CD3)2CO]: d 8.45 [d,
[Me2Sn{ONHC(O)C6H4NH2-4}2] (1a1). White;
m.p.: 252 ꢁC (dec.). Elemental Analysis Calcd. (%) for
H20C16O4N4Sn: C, 42.60; H, 4.48; N, 12.42; Found: C,
42.35; H, 4.70; N, 12.34%. IR: 3360s, 3230s m(N–H);
1610s, 1561w and 1538w m(C'O)/m(N'C); 916s m(N–
O); 521m m(Sn–O); 598s m(Sn–C). 1H NMR [(CD3)2CO]:
d 7.73 [s, br, 4H, H(2)]; 6.84 [br, 4H, H(3)]; 5.43 [br, 4H,
NH2]; 0.96 [s, br, 6H, CH3, R-Sn]. 13C{1H} [(CD3)2SO]:
d 164.13 (CO); 152.73 [C(4)], 129.69 [C(1)], 127.58
[C(2)], 115.23 [C(3)]; 5.54 (CH3, R-Sn). 119Sn
[(CD3)2CO]: d ꢁ448.69. FAB+-MS: m/z 452 [M]+, 437
[M ꢁ R]+, 301 [M ꢁ L]+, 286 [M ꢁ R ꢁ L]+, 150
[M ꢁ 2L]+, 135 [M ꢁ R ꢁ 2L]+, 120 (Sn+). Yield 38%.
[Et2Sn{ONHC(O)C6H4NH2-4}2] (1b1). Light yel-
low; m.p.: 158–159 ꢁC. Elemental Analysis Calcd. (%)
for H24C18O4N4Sn: C, 45.12; H, 5.06; N, 11.70; Found:
C, 45.89; H, 5.27; N, 11.43%. IR: 3348s and 3216s m(N–
H); 1605s, 1558w and 1539w m(C'O)/m(N'C); 915s
m(N–O); 512m m(Sn–O); 627s and 561w m(Sn–C). 1H
NMR [(CD3)2SO:CDCl3]: d 11.40 [br, 2H, NH] 7.01
[s, br, 4H, H(2)]; 6.09 [br, 4H, H(3)]; 4.54 [br, 2H,
NH2], 4.32 [br, 2H, NH2]; 2.79 [s, br, CH2, R-Sn, par-
tially buried under DMSO ressonance]; 0.72 [s, br, 6H,
CH3, R-Sn]. 13C{1H} [(CD3)2SO:CDCl3]: d 160.86
(CO); 149.90 [C(4)], 129.70 [C(1)], 126.93 [C(2)], 112.56
[C(3)]; 17.02 (CH2, R-Sn); 9.03 (CH3, R-Sn). 119Sn
[(CD3)2SO:CDCl3): d ꢁ355.69. Yield 40%.
3
3J = 8.8, 4H, H(2)]; 8.22 [d, J = 8.8, 4H, H(3)]; 0.91
[s, br, 6H, CH3, R-Sn]. 119Sn [(CD3)2CO]: d ꢁ449.14.
Yield 30%.
[Et2Sn{ONHC(O)C6H4NO2-4}2] (1b2). Light yel-
low; m.p.: 212–215 ꢁC. Elemental Analysis Calcd. (%)
for H20C18O8N4Sn: C, 40.10; H, 3.75; N, 10.39; Found:
C, 40.65; H, 3.69; N, 10.43%. IR: 3192s m(N–H); 1620m,
1581s and 1519s m(C'O)/m(N'C); 962m m(N–O); 520m
and 498w m(Sn–O); 567w m(Sn–C). 1H NMR
[(CD3)2CO]: d 8.40–8.20 [m, 8H, H(2), H(3)]; 1.43–1.75
[m, 10H, R-Sn]. 13C{1H} [(CD3)2CO]: d 162.95 (CO);
151.72 [C(4)], 137.29 [C(1)], 132.18 [C(2)], 124.52
[C(3)]; 27.56–13.93 (m, R-Sn). 119Sn [(CD3)2CO]: d
ꢁ287.09. Yield 55%.
[nBu2Sn{ONHC(O)C6H4NO2-4}2] (1c2). Light yel-
low; m.p.: 243–245 ꢁC. Elemental Analysis Calcd. (%)
for H28C22O8N4Sn: C, 44.39; H, 4.75; N, 9.41; Found:
C, 44.23; H, 4.80; N, 9.36%. IR: 3115s m(N–H);
1598m, 1585s, 1526s and 1525s m(C'O)/m(N'C);
1016m m(N–O); 530m and 501w m(Sn–O); 581s m(Sn–
1
3
C). H NMR [(CD3)2CO]: d 8.40 [d, JHH = 8.8, 4H,
H(2)]; 8.20 [d, JHH = 8.8, 4H, H(3)]; 0.98–1.87 [m,
3
18H, R-Sn]. 13C{1H} [(CD3)2CO]: d 172.22 (CO);
151.67 [C(4)], 137.29 [C(1)], 132.18 [C(2)], 124.52

Q. Li et al. / Journal of Organometallic Chemistry 689 (2004) 4584–4591
4589
[C(3)]; 27.56–13.93 (m, R-Sn). 119Sn [(CD3)2CO]: d
ꢁ380.44. Yield 58%.
m(N–H); 1625s, 1587s, 1552s and 1514m m(C'O)/
m(N'C); 911s m(N–O); 625s and 571s m(Sn–O–Sn) and
m(Sn–C); 527m, 499w and 422m m(Sn–O);. 1H NMR
[(CD3)2CO]: d 12.24 [s, br, 4H, NH2]; 7.37 [d,
[Ph2Sn{ONHC(O)C6H4NO2-4}2] (1d2). Yellow;
m.p.: 250 ꢁC (dec). Elemental Analysis Calcd. (%) for
H28C26O8N4Sn: C, 49.16; H, 3.18; N, 8.82; Found: C,
49.31; H, 3.37; N, 8.52%. IR: 3202s m(N–H); 1597s and
1529s (C'O)/m(N'C); 918s m(N–O); 517m and 448m
3
3JHH = 6.9, 4H, H(2)]; 6.50 [d, JHH = 6.9, 4H, H(3)];
5.65 [br, 2H, NH2], 5.24 [br, 2H, NH2]; 0.63–0.18 [m,
12H, CH3, R-Sn]. 13C{1H} [(CD3)2CO]: d 161.75 (CO);
151.65 [C(4)], 116.15 [C(1)], 127.50 [C(2)], 112.91
[C(3)]; 8.71, 6.97, 5.26 (CH3, R-Sn). 119Sn [(CD3)2CO]:
d ꢁ196.36. Yield 46%.
1
m(Sn–O); 559w m(Sn–C). H NMR [(CD3)2CO]: d 8.37–
7.22 [m, 18H, H(2), H(3), R-Sn]. 13C{1H} [(CD3)2CO]:
161.36 (CO); 150.43 [C(4)], 137.49–123.59 [m, C(1),
C(2), C(3), R-Sn). 119Sn [(CD3)2CO]: d ꢁ344.46. Yield
44%.
[nBu2Sn{ONHC(O)C6H4NH2-4}]2O (2c1). Light
yellow; m.p.: 160–161 ꢁC. Elemental Analysis Calcd.
(%) for H26C18O5N4Sn: C, 45.95; H, 6.38; N, 7.15;
Found: C, 45.32; H, 6.28; N, 7.23%. IR: 3216s and
3354s m(N–H); 1607s, 1527w and 1514m m(C'O)/
m(N'C); 910s m(N–O); 627s m(Sn–O–Sn) and m(Sn–C);
595s m(Sn–C); 525m and 515s m(Sn–O). 1H NMR
[Me2Sn{ONHC(O)C6H4F-4}2] (1a3). White; m.p.:
>300 ꢁC. Elemental Analysis Calcd. (%) for
H16C16N2O4F2Sn: C, 42.01; H, 3.50; N, 6.13; Found:
C, 41.97; H, 3.58; N, 6.03%. IR: 3474w and 3222 m(N–
H); 1613s (C'O)/m(N'C); 910s m(N–O); 490m (Sn–
1
3
3
O). H NMR [CD3OD]: d 7.18 [t, JHH = 3JHF = 8.8,
[(CD3)2CO]: d 7.71 [d, JHH = 8.0, 4H, H(2)]; 6.73 [d,
3
4
4H, H(3)]; 7.78 [dd, JHH = 8.8, JHF = 5.4, 4H, H(2)];
4.95 [s, br, 2H, NH]; 0.59 [s, JSnH = 83.0]. 13C{1H}
3JHH = 8.0, 4H, H(3)]; 5.36 [br, 4H, NH2]; 1.80–0.95
[m, 36H, R-Sn]. 13C{1H} [(CD3)2CO]: d 163.21 (CO);
152.78 [C(4)], 128.86 [C(2)], 114.35 [C(3)]; 15.12, 13.46
(R-Sn). 119Sn [(CD3)2CO]: d ꢁ443.58. Yield 58%.
2
1
[CD3OD]: d 166.17 [d, JCF = 250.5, C(4)], 116.63 [d,
2JCF = 22.3, C(3)]; 130.36 [d, JCF = 9.3 C(2)], 130.50
3
[C(1)]. 119Sn [CD3OD]: d ꢁ488.30. 19F [CD3OD]: d
ꢁ109.80. FAB+-MS: m/z 443 [M ꢁ R]+, 304 [M ꢁ L]+,
274 [M ꢁ 2R ꢁ L]+. Yield 42%.
[Me2Sn{ONHC(O)C6H4F-4}]2O (2a3). White;
m.p.: >300 ꢁC. Elemental Analysis Calcd. (%) for
H22C18N2O5F2Sn2: C, 34.73; H, 3.54; N, 4.50; Found:
C, 34.69; H, 3.51; N, 4.58%. IR: 3436w m(N–H); 1607s
m(C'O)/m(N'C); 902s m(N–O); 634s and 625s m(Sn–
O–Sn) and m(Sn–C); 521m m(Sn–C). 1H NMR
[nBu2Sn{ONHC(O)C6H4F-4}2] (1c3). White; m.p.:
140–143 ꢁC. Elemental Analysis Calcd. (%) for
H28C22N2O4F2Sn: C, 48.80; H, 5.18; N, 5.18; Found:
C, 48.92; H, 5.15; N, 5.12%. IR: 3211m (N–H); 1611s
3
[(CD3)2SO]: d 6.27 [d, JHH = 3JHF = 8.7, 4H, H(3)];
3
6.90 [dd, JHH = 8.7, JHF = 6.0, 4H, H(2)]; 1.65 [s, br,
4
m(C'O)/m(N'C); 915s (N–O); 512m m(Sn–C); 467m
3
2
m(Sn–O). 1H NMR [CD3OD]: d 7.18 [t, JHH
=
2H, NH]; ꢁ0.30 [s, JSnH = 78.6]. 119Sn [(CD3)2SO]: d
3JHF = 8.7, 4H, H(3)]; 7.79 [dd, JHH = 8.7, JHF = 5.4,
4H, H(2)]; 1.69–1.59, 1.43–1.30 [m, 14H, CH3CH2CH2];
0.85 [t, 3JHH = 7.2, –CH2Sn]; 1.65 [s, 2H, NH]. 13C{1H}
ꢁ488.31. 19F [(CD3)2SO]: d ꢁ112.86. Yield 48%.
3
4
[nBu2Sn{ONHC(O)C6H4F-4}]2O (2c3). White;
m.p.: 180–182 ꢁC. Elemental Analysis Calcd. (%) for
H46C30N2O5F2Sn2: C, 45.57; H, 5.82; N, 3.54; Found:
C, 45.45; H, 5.79; N, 3.66%. IR: 3500w m(N–H);
1606s m(C'O)/m(N'C); 912s and 900s m(N–O); 635s,
br and 611s, br m(Sn–O–Sn) and m(Sn–C); 517m m(Sn–
1
[CD3OD]: d 166.37 [d, JCF = 250.5, C(4)], 117.00 [d,
2JCF = 22.5, C(3)]; 130.42 [d, JCF = 8.7, C(2)]; 128.40
3
1
[C(1)]; 28.74 [s, JSnC = 36.7, Sn–C]; 27.92, 27.34, 14.42
[Sn-R]. 119Sn [CD3OD]: d ꢁ488.30. 19F [CD3OD]: d
ꢁ109.94. FAB+-MS: m/z 485 [M ꢁ R]+, 388 [M ꢁ L]+,
274 [M ꢁ 2R ꢁ L]+. Yield 55%.
1
C); 503m m(Sn–O). H NMR (CDCl3): d 14.44 [s, br,
NH]; 7.08–7.54 [m, 4H, H(3)]; 7.86–7.54 [m, H(2)];
[Ph2Sn{ONHC(O)C6H4F-4}2] (1d3). White; m.p.:
235 ꢁC (dec.). Elemental Analysis Calcd. (%) for
H20C26N2O4F2Sn: C, 53.52; H, 3.77; N, 4.80; Found:
C, 53.62; H, 3.90; N, 4.78%. IR: 3200m m(N–H); 1606s
1.47–1.34, 1.80–1.70, 0.95 [m, 36H, SnR]. 13C{1H}
(CDCl3):
1JCF = 242.9], 163.41 [d, JCF = 241.7] [C(4)]; 114.82
d
164.6 and 161.8 [CO]; 164.49 [d,
1
2
[d, JCF = 21.0], 115.60 [d, JCF = 22.0] [C(3)]; 128.59
2
1
3
3
m(C'O)/m(N'C); 915s m(N–O). H NMR [CD3OD]: d
[d, JCF = 8.2], 129.09 [d, JCF = 8.7] [C(2)]; 130.15
and 126.31 [C(1)]; 28.7–26.2 and 13.9–13.6 [m, Sn-R].
Yield 64 %.
6.47–6.31 and 6.99–6.75 [m, 18H, H(3), H(2), RSn];
10.35 [s, 2H, NH]. 13C{1H} [(CD3)2SO] (unstable in
solution): d 159.6 [CO]; 135.03, 129.0–127.3, 115.4
[C(3), C(2), C(1), Sn-R]. 119Sn [(CD3)2SO]: d ꢁ488.31
and ꢁ429.04. 19F [(CD3)2SO]: d ꢁ108.01 and ꢁ107.45.
FAB+-MS: m/z 581 [M]+, 505 [M ꢁ L]+, 737 [M + L]+,
1028 [2M ꢁ 2R + O]+. Yield 41%.
[Ph2Sn{ONHC(O)C6H4F-4}]2O (2d3). White;
m.p.: >300 ꢁC. Elemental Analysis Calcd. (%) for
H30C38N2O5F2Sn2: C, 52.17; H, 3.89; N, 3.20; Found:
C, 51.14; H, 3.93; N, 3.18%. IR: 3364m m(N–H);
1607s m(C'O)/m(N'C); 916s m(N–O); 625s m(Sn–O–
1
[Me2Sn{ONHC(O)C6H4NH2-4}]2O (2a1). Light
yellow; m.p.: 260 ꢁC (dec.). Elemental Analysis Calcd.
(%) for H26C18O5N4Sn: C, 35.10; H, 4.22; N, 9.10;
Found: C, 34.98; H, 4.03; N, 9.54%. IR: 3219s, 3340s
Sn) and m(Sn–C); 446m m(Sn–O). H NMR [(CD3)2SO]:
d 12.55 [s, br, 2H, NH]; 6.47–6.39 and 6.99–6.67 [m,
28H, H(3), H(2), SnR]. 13C{1H} [(CD3)2SO]: d 159.6
[CO]; 148.18 [d, JCF = 265.5, C(4)]; 115.46 [d,
1

4590
Q. Li et al. / Journal of Organometallic Chemistry 689 (2004) 4584–4591
3
2JCF = 21.7, C(3)]; 135.10 [d, JCF = 6.2, C(2)]; 128.95
[C(1)]; 135.43, 128.17, 127.76 [Sn-R]. 119Sn [(CD3)2SO]:
d ꢁ427.95. 19F [(CD3)2SO]: d ꢁ106.73. FAB+-MS: m/z
505 [SnLR2]+, 425 [SnL2]+, 366 [SnLRO]+, 347
[SnLPh]+. Yield 65%.
However, no general trend could be found between
the antitumor activity of the complexes and the rp or
any other constant (like rþp , rI, Taft polar constant,
etc. [45]) that measures the electronic effects (either the
inductive, the resonance or the overall one) of the X-
substituent.
3.3. Antitumor activity in vitro
In other series of diorganotin(IV) complexes with
carboxylate ligands [24], the most active ones were the
n-butyl derivatives, as in our case, and similarly no rela-
tionship between the activity and the substituent
HammettÕs rp constant was recognized.
Although for the dialkyl complexes the antitumor
activity tends to increase with the electron withdrawing
ability of the substituent from X = NH2 up to X = Cl, a
further increase of the latter character does not result in
an additional enhancement of that activity, i.e. the
strongest acceptor, NO2, does not lead to the highest
activity. The solubility of the complexes also plays a
role, and the upper activity of the fluoro-substituted
complexes, relative to the nitro-substituted ones, may re-
sult from the higher solubility in water of the former.
The use of dinuclear complexes does not improve the
activity.
Hence, the antitumor activity appears to be deter-
mined by a complex combination of effects of the vari-
ous ligands and the establishment of structure-activity
relationships with considerable generality still requires
further investigation. Nevertheless, the best combination
appears to be provided by the mononuclear dibutyl-
tin(IV) (R = nBu) complexes, i.e. with the organo-lig-
ands having the longest carbon chain, in particular
those with hydroxamate ligands presenting an elec-
tron-acceptor X substituent (a halo-atom or the nitro
group).
The antitumor activity against tumor cell lines was
assayed by the MTT method [44] in the State Key Lab-
oratory of Natural and Mimic Drugs, Beijing Medical
University, China. The following cell lines were used
for screening: human immature granulocyte leukemia
(HL-60) as well as nasopharyngeal (KB), hepatocellular
(Bel-7402), ovarian (Hela) and colon (HCT-8) carcino-
mas, along with mouse lymphocyte carcinomas B and
T. Aliquots of log-phase cells were incubated for 72 h
at 37 ꢁC with three dose levels of each diorganotin(IV)
compounds in triplicate. About 50 lL of 0.1% MTT
was added to each well. After 4 h incubation, the culture
medium was removed, and the blue formazan in the cells
was dissolved with 2-propanol by vigorous shaking. The
absorbance of each well was measured at 570 nm.
The antitumor activity was determined by expressing
the mean absorbance for drug-treated cells at each con-
centration as a percentage of that for untreated cells.
The dose causing 50% inhibition of cell growth (IC50)
was determined from the curve of inhibiting percentage
versus dose.
4. Final comments
We have prepared series of diorganotin(IV) com-
plexes with different organo and substituted arylhydr-
oxamate ligands and shown that they display in vitro
antitumor activity which is markedly ligand dependent.
A first conclusion is that the mononuclear dibutyltin
complexes, i.e. those with the organo-ligands having the
longest carbon chain, exhibit the highest activity, as
known [24] to occur for other diorganotin(IV)
complexes.
Concerning the X substituents, one can compare,
over a wide range of electronic properties, their effects
on the antitumor activities by considering the results ob-
tained in this work and those in our previous study [20],
i.e. for the series of p-substituted benzohydroxamate
complexes of the type [R2SnL2] (R = Me, Et, nBu, Ph;
L = ONHC(O)C6H4X-4 with X = NO2, Cl [20], F,
OMe [20], NH2). In fact, the electron withdrawing/do-
nor character of X varies drastically from the very
strong acceptor NO2 group to the quite effective donor
NH2 substituent, in the following order (with the values
of the HammettÕs rp constant [45] given in parentheses):
NO2 (0.778) > Cl (0.227) > F (0.062) > OMe (ꢁ0.268) >
NH2 (ꢁ0.66).
Acknowledgements
ˆ
The financial supports from the Fundac¸a˜o para a Cien-
cia e a Tecnologia, the PRAXIS (fellowship PRAXIS
XXI/BPD/20138/99) and POCTI (Project POCTI/QUI/
43415/2001) (FEDER-funded) programs (Portugal),
from the National Natural Science Foundation of China
(No. 39900185), the State Commission of Science and
Technology of China (No. 96-901-06-38), from the State
Commission of Education of China and the Marie Curie
RTN Programme (project AQUACHEM contract
MRTN-CT-2003-503864) are gratefully acknowledged.
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