Complexes of tin(IV) halides and diorganotin(IV) dihalides with 3,5-dimethyl-1-(2′-pyridyl)pyrazole

Article abstract of DOI:10.1016/S0020-1693(03)00240-8

3,5-Dimethyl-1-(2′-pyridyl)pyrazole (DMPP) reacts with SnX ₄ and R₂SnX₂ (X=Cl, Br, I; R=Me, Et, Bu, Ph) to yield adducts of types [SnX₄(DMPP)] and [SnR₂X ₂(DMPP)], respectively. The structure of [SnEt₂Br ₂(DMPP)] has been determined by X-ray diffractometry. The crystal consists of discrete [SnEt₂Br₂(DMPP)] molecules with the metal atom octahedrally coordinated to two Br atoms [Sn-Br=2.631(3), 2.703(3) ?; Br-Sn-Br=98.00(10)°], two ethyl carbons [Sn-C=2.11(3), 2.143(19) ?; C-Sn-C=172.3(11)°] and the two donor N atoms of the ligand [Sn-N=2.379(16), 2.387(16) ?; N-Sn-N=66.8(6)°]. The IR data and M?ssbauer parameters are consistent with all the organotin derivatives having, similar geometry whereas in the case of the [SnX₄(DMPP)] complexes the results of both techniques support the expectation of cis stereochemistry. The ¹H NMR data indicate significant dissociation in solution. The chlorobutyl derivative exhibited significant in vitro antitumour activity against the human carcinoma cell line KB.

Full text of DOI:10.1016/S0020-1693(03)00240-8

Inorganica Chimica Acta 353 (2003) 8ꢂ14
/
www.elsevier.com/locate/ica
Complexes of tin(IV) halides and diorganotin(IV) dihalides with
3,5-dimethyl-1-(2?-pyridyl)pyrazole
a
b
b
Pedro Alvarez-Boo , Jose´ S. Casas , Alfonso Castineiras , Mar´ıa D. Couce ,
a
´
˜
Eduardo Freijanes a, Ariella Furlani c, Umberto Russo d, Vito Scarcia c, Jose´ Sordo b,*,
Manuela Varela a
a Departamento de Qu´ımica Inorga´nica, Universidade de Vigo, Spain
b Departamento de Qu´ımica Inorga´nica, Universidade de Santiago de Compostela, Facultad de Farmacia, 15782 Santiago de Compostela, Galicia, Spain
c Dipartimento di Scienze Biomediche, Universita` degli Studi di Trieste, Italy
d Dipartimento di Chimica Inorganica, Metallorganica ed Analitica, Universita` di Padova, Italy
Received 28 June 2002; accepted 26 February 2003
Abstract
3,5-Dimethyl-1-(2?-pyridyl)pyrazole (DMPP) reacts with SnX4 and R2SnX2 (XÄ
/
Cl, Br, I; RꢀMe, Et, Bu, Ph) to yield adducts of
/
types [SnX4(DMPP)] and [SnR2X2(DMPP)], respectively. The structure of [SnEt2Br2(DMPP)] has been determined by X-ray
diffractometry. The crystal consists of discrete [SnEt2Br2(DMPP)] molecules with the metal atom octahedrally coordinated to two
˚
˚
Br atoms [SnÃ
/
Brꢀ
/
2.631(3), 2.703(3) A; BrÃ
/
SnÃ
/
Brꢀ
/
98.00(10)8], two ethyl carbons [SnÃ
/
Cꢀ
/
2.11(3), 2.143(19) A; CÃ
/
SnÃ
/
Cꢀ
/
˚
172.3(11)8] and the two donor N atoms of the ligand [SnÃ
Mossbauer parameters are consistent with all the organotin derivatives having, similar geometry whereas in the case of the
[SnX4(DMPP)] complexes the results of both techniques support the expectation of cis stereochemistry. The 1H NMR data indicate
significant dissociation in solution. The chlorobutyl derivative exhibited significant in vitro antitumour activity against the human
carcinoma cell line KB.
/
Nꢀ
/
2.379(16), 2.387(16) A; NÃSnÃ
/
/
Nꢀ66.8(6)8]. The IR data and
/
¨
# 2003 Elsevier B.V. All rights reserved.
Keywords: Crystal structures; Cytostatic activity; Mossbauer spectroscopy; Diorganotin(IV) dihalide complexes
¨
1. Introduction
inactive compounds, respectively [2]), which suggests
that dissociation of the ligand is a significant step in
their mechanism of action.
In previous work [3], we synthesized compounds of
this type either with the flexible ligand bis(1-methyl-2-
A considerable number of metal-based compounds,
including many organotin derivatives, have in recent
years been synthesized and characterized in the search
for compounds with greater antitumour activity and
lower toxicity than platinum complexes [1]. For com-
pounds [SnR2X2(LL)], where LL is an N,N?-didentate
imidazolylthio)methane as LL, in which case long SnÃ
/N
bonds resulted from the formation of an eight-mem-
bered ring; or with mepirizole [4-methoxy-2-(5-methoxy-
ligand, antitumour activity depends on the SnÃ
/
N
3-methyl-pyrazol-1-yl)-6-methylpyrimidine],
with substituents close to the donor N atoms that
hinder the formation of strong SnÃN bonds [4,5]. In
a
ligand
˚
distances (ꢀ
/
2.39 and B2.39 A for the active and
/
/
further pursuit of this second approach, we have now
used the ligand 3,5-dimethyl-1-(2?-pyridyl)pyrazole
(DMPP), a biologically active potentially N,N?-diden-
* Corresponding author. Tel.: ꢁ
912.
E-mail address: qijsordo@uscmail.usc.es (J. Sordo).
/
34-981-594 636; fax: ꢁ34-981-594
/
0020-1693/03/$ - see front matter # 2003 Elsevier B.V. All rights reserved.
doi:10.1016/S0020-1693(03)00240-8

´
P. Alvarez-Boo et al. / Inorganica Chimica Acta 353 (2003) 8ꢂ
/
14
9
tate compound [6], the coordination chemistry of which
has scarcely been studied [7].
2.2.2. [SnBr4(DMPP)] (2)
As above, from 0.438 g (1 mmol) of tin(IV) bromide
and 0.173 g (1 mmol) of ligand. Anal. Found: C, 19.4;
H, 1.7; N, 6.6. Calc. for C10H11Br4N3Sn: C, 19.6; H, 1.8;
N, 6.9%. Yield: 72%. M.p. 286 8C. Mossbauer: I.S. 0.87,
¨
Q.S. 0.30, G 0.79. IR (Raman) (cmꢃ1): 1604vs (1605m),
1575m (1574s), 1488vs (1485m), n(ring); 232s,b, 210m
1
(244m, 230w, 208s), n(SnÃ
/
Br). H NMR: 2.20 [s, C(3)Ã
/
CH3]; 6.11 [s, C(4)H]; 2.57 [s, C(5)Ã
/
CH3]; 7.29 [m,
C(3?)H]; 7.93 [m, C(4?)H]; 7.80 [m, C(5?)H]; 8.43 [m,
C(6?)H].
This paper describes the synthesis of the compounds
Cl, Br, I) and [SnR2X2(DMPP)]
Cl, Br), the crystal structure of
[SnEt2Br2(DMPP)] as determined by X-ray diffracto-
metry, and the in vitro cytostatic activities of the ethyl,
phenyl and butyl derivatives against the human carci-
noma cell line KB. The compounds [SnMe2Cl2(DMPP)],
[SnEt2Cl2(DMPP)] and [SnPh2Cl2(DMPP)] have been
described previously [7c,7d].
2.2.3. [SnI4(DMPP)] (3)
[SnX4(DMPP)] (Xꢀ
/
From 0.626 g (1 mmol) of tin(IV) iodide and 0.173 g
(1 mmol) of ligand. Anal. Found: C, 15.5; H, 1.3; N, 5.6.
Calc. for C10H11I4N3Sn: C, 15.0; H, 1.4; N, 5.3%. Yield:
(RꢀMe, Et, Bu, Ph; Xꢀ
/
/
53%. M.p. 216 8C. Mossbauer: I.S. 1.28, Q.S. 0.27, G
¨
0.96. IR (Raman) (cmꢃ1): 1602vs (1600w), 1573m
(1573m), 1484vs (1483w), n(ring); 188s, 177sh (193m,
182m, 167s), n(SnÃ
/
I). 1H NMR: 2.43 [s, C(3)Ã
CH3]; 7.79 [m, C(3?)H];
/CH3];
6.05 [s, C(4)H]; 2.67 [s, C(5)Ã
/
7.83 [m, C(4?)H]; 7.81 [m, C(5?)H]; 7.85 [m, C(6?)H].
2. Experimental
2.2.4. [SnMe2Cl2(DMPP)] (4)
From 0.217 g (1 mmol) of dichlorodimethyltin(IV)
and 0.173 g (1 mmol) of ligand. Anal. Found: C, 36.4;
H, 4.5; N, 10.0. Calc. for C12H17Cl2N3Sn: C, 36.8; H,
2.1. Materials
4.4; N, 10.7%. Yield: 60%. M.p. 124 8C. Mossbauer: I.S.
¨
All tin(IV) halides and diorganotin(IV) dihalides
except SnPh2Br2 were supplied by Ventron. SnPh2Br2
was prepared by reacting diphenyltin dichloride with
sodium bromide. DMPP was synthesized by condensa-
tion of acetylacetone with 2-hydrazynepyridine in 1:1
mole ratio [6]; the two reagents were mixed and stirred
until the reaction was practically complete and a bright
yellow liquid had formed (b.p. 74 8C, 0.4 mm of Hg).
1.62, Q.S. 3.97, G 0.79, A2/1 1.12. IR (Raman) (cmꢃ1):
1604vs (1604m), 1575m (1575s), 1488vs (1488m),
n(ring); 572m (570w), nas(SnÃ
C); 275s (270m), 247s,b (250m), n(SnÃ
2.35 [s, C(3)ÃCH3]; 6.03 [s, C(4)H]; 2.62 [s, C(5)Ã
7.20 [m, C(3?)H]; 7.82 [m, C(4?)H]; 7.77 [m, C(5?)H]; 8.56
/
C); 510w (508vs), ns(SnÃ
/
1
/
Cl). H NMR:
/
/CH3];
2
[m, C(6?)H]; 1.19 [s, (SnÃ
/
Ha), J(117/119SnÃ
/
1H)ꢀ
73.0/
.
/
76.4]. LM (MeCN, 10ꢃ3 M): 3.5 S cm2 molꢃ1
2.2. Synthesis of complexes
2.2.5. [SnMe2Br2(DMPP)] (5)
From 0.308 g (1 mmol) of dibromodimethyltin(IV)
and 0.173 g (1 mmol) of ligand. Anal. Found: C, 29.8;
H, 3.5; N, 8.6. Calc. for C12H17Br2N3Sn: C, 29.9; H, 3.5;
All complexes were synthesized by slow addition of a
solution of the donor in CH2Cl2 (10 ml) to a solution of
the acceptor in the same solvent (10 ml). After 24 h
stirring and another 24 h at low temperature, the solid
product was filtered out and dried in vacuo.
N, 8.7%. Yield: 84%. M.p. 115 8C. Mossbauer: I.S. 1.71,
¨
Q.S. 4.07, G 0.80, A2/1 1.00. IR (Raman) (cmꢃ1): 1603vs
(1603m), 1574m (1575m), 1487m (1487w), n(ring); 568m
(570w), nas(SnÃ
(200m), 188s,b (182m), n(SnÃ
C(3)ÃCH3]; 6.00 [s, C(4)H]; 2.64 [s, C(5)Ã
C(3?)H]; 7.82 [m, C(4?)H]; 7.77 [m, C(5?)H]; 8.44 [m,
/
C); 510w (502vs), ns(SnÃ
Br). 1H NMR: 2.31 [s,
CH3]; 7.15 [m,
/
C); 207m
2.2.1. [SnCl4(DMPP)] (1)
/
From 0.260 g (1 mmol) of tin(IV) chloride and 0.173 g
(1 mmol) of ligand. Anal. Found: C, 27.1; H, 2.5; N, 9.5.
Calc. for C10H11Cl4N3Sn: C, 27.7; H, 2.5; N, 9.7%.
/
/
2
C(6?)H]; 1.38 [s, (SnÃ
/
Ha), J(117/119SnÃ
/
1H)ꢀ
63.9/66.7].
/
Yield: 76%. M.p. 252 8C. Mossbauer: I.S. 0.59, Q.S.
LM (MeCN, 10ꢃ3 M): 7.2 S cm2 molꢃ1
.
¨
0.31, G 0.80. IR (Raman) (cmꢃ1): 1608vs (1606m),
1576m (1576s), 1489vs (1485m), n(ring); 328s,b, 284m
2.2.6. [SnEt2Cl2(DMPP)] (6)
1
(343s, 333s, 287s), n(SnÃ
/
Cl). H NMR: 2.31 [s, C(3)Ã
/
From 0.247 g (1 mmol) of dichlorodiethyltin(IV) and
0.173 g (1 mmol) of ligand. Anal. Found: C, 39.1; H, 5.5;
N, 9.7. Calc. for C14H21Cl2N3Sn: C, 40.0; H, 5.0; N,
CH3]; 6.21 [s, C(4)H]; 2.56 [s, C(5)Ã
C(3?)H]; 8.03 [m, C(4?)H]; 7.75 [m, C(5?)H]; 8.50 [m,
C(6?)H]. LM (MeCN, 10ꢃ3 M): 12.8 S cm2 molꢃ1
/
CH3]; 7.41 [m,
.
10.0%. Yield: 78%. M.p. 63 8C. Mossbauer: I.S. 1.79,
¨

´
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P. Alvarez-Boo et al. / Inorganica Chimica Acta 353 (2003) 8ꢂ
/
14
Q.S. 3.99, G 0.97, A2/1 0.95. IR (Raman) (cmꢃ1): 1603vs
(1603m), 1575m (1576s), 1483vs (1483m), n(ring); 535m
H, 4.1; N, 7.9. Calc. for C22H21Cl2N3Sn: C, 51.2; H, 4.1;
N, 8.1%. Yield: 50%. M.p. 154 8C. Mossbauer: I.S. 1.45,
¨
(534w), nas(SnÃ
(276m), 239s (236w), n(SnÃ
C(3)ÃCH3]; 6.14 [s, C(4)H]; 2.62 [s, C(5)Ã
[m, C(3?)H]; 7.99 [m, C(4?)H]; 7.67 [m, C(5?)H]; 8.90 [m,
/
C); 490m (486vs), ns(SnÃ
Cl). 1H NMR: 2.45 [s,
CH3]; 7.32
/
C); 267s,b
Q.S. 3.47, G 0.80, A2/1 1.04. IR (Raman) (cmꢃ1): 1604s
(1604m), 1573m (1574s), 1483vs (1486m), n(ring);
/
/
/
286s,b, n(SnÃ
Cl). 1H NMR: 2.31 [s, C(3)Ã
2.60 [s, C(5)ÃCH3]; 7.15 [m, C(3?)H]; 7.5ꢂ
/
C); 262s,b (270m), 230s (226w), n(SnÃ
CH3]; 6.02 [s, C(4)H];
7.8 [m,
/
/
C(6?)H]; 1.25 [t, (SnÃ
/
Hb)], 1.67 [q, (SnÃ
/
Ha)]. LM
/
/
(MeCN, 10ꢃ3 M): 9.7 S cm2 molꢃ1
.
C(4?)H, C(5?)H, SnÃPh]; 8.42 [m, C(6?)H]. LM
/
(MeCN, 10ꢃ3 M): 5.6 S cm2 molꢃ1
.
2.2.7. [SnEt2Br2(DMPP)] (7)
From 0.336 g (1 mmol) of dibromodiethyltin(IV) and
0.173 g (1 mmol) of ligand. Anal. Found: C, 32.7; H, 4.1;
N, 8.4. Calc. for C14H21Br2N3Sn: C, 33.0; H, 4.1; N,
2.2.11. [SnPh2Br2(DMPP)] (11)
From 0.432 g (1 mmol) of dibromodiphenyltin(IV)
and 0.173 g (1 mmol) of ligand. Anal. Found: C, 42.9;
H, 3.4; N, 6.9. Calc. for C22H21Br2N3Sn: C, 43.6; H, 3.5;
8.3%. Yield: 80%. M.p. 89 8C. Mossbauer: I.S. 1.83,
¨
Q.S. 4.00, G 0.79, A2/1 1.06. IR (Raman) (cmꢃ1): 1605s
(1609m), 1576m (1578s), 1483vs (1485m), n(ring); 526m,
N, 6.9%. Yield: 54%. M.p. 142 8C. Mossbauer: I.S. 1.56,
¨
Q.S. 3.57, G 0.80, A2/1 1.00. IR (Raman) (cmꢃ1): 1605s
(1604m), 1580sh (1579s), 1485vs (1485m), n(ring);
nas(SnÃ
n(SnÃ
Br). 1H NMR: 2.34 [s, C(3)Ã
2.63 [s, C(5)ÃCH3]; 7.18 [m, C(3?)H]; 7.78ꢂ
C(4?)H]; 7.78ꢂ7.83 [m, C(5?)H]; 8.53 [m, C(6?)H]; 1.38 [t,
/
C); 475m (476s), ns(SnÃ
/
C); 200sh, 170m (167m),
CH3]; 6.02 [s, C(4)H];
7.83 [m,
1
/
/
288s,b, n(SnÃ
2.31 [s, C(3)Ã
7.16 [m, C(3?)H]; 7.51ꢂ
SnÃ
Ph]. LM (MeCN, 10ꢃ3 M): 15.9 S cm2 molꢃ1
/
C); 162m,b (159m), n(SnÃ
/
Br). H NMR:
/
/
/
CH3]; 6.01 [s, C(4)H]; 2.64 [s, C(5)Ã
/CH3];
/
/
7.84 [m, C(4?)H, C(5?)H, C(6?)H,
(SnÃ
/
Hb)]; 1.84 [q, (SnÃ
/
Ha)]. LM (MeCN, 10ꢃ3 M): 12.0
/
.
S cm2 molꢃ1. A crystal suitable for X-ray diffraction
was grown from the mother liquor.
2.3. Physical measurements
2.2.8. [SnBu2Cl2(DMPP)] (8)
Elemental analyses were performed with a Carlo Erba
1108 apparatus. Melting points were measured on a
Gallenkamp apparatus. IR spectra were recorded in
Nujol mulls and Raman spectra in capillary tubes on a
Bruker IFS-66V FT-IR apparatus equipped with an
FRA-106 Raman module. Conductivities (10ꢃ3 M,
CH3CN) were measured in a CRISON micro CM
From 0.303 g (1 mmol) of dichlorodibutyltin(IV) and
0.173 g (1 mmol) of ligand. Anal. Found: C, 45.6; H, 6.6;
N, 8.9. Calc. for C16H25Cl2N3Sn: C, 45.4; H, 6.1; N,
8.8%. Yield: 87%. M.p. 87 8C. Mossbauer: I.S. 1.75,
¨
Q.S. 4.04, G 0.82, A2/1 1.00. IR (Raman) (cmꢃ1): 1606s
(1605m), 1578m (1578s), 1483vs (1483m), n(ring); 625w
(625w), nas(SnÃ
(244m), n(SnÃCl). H NMR: 2.30 [s, C(3)Ã
[s, C(4)H]; 2.63 [s, C(5)Ã
7.83 [m, C(4?)H]; 7.77ꢂ
C(6?)H]; 0.95 [t, (SnÃHd)]; 1.41 [m, (SnÃ
1.82 [m, (SnÃ
HaHb)]. LM (MeCN, 10ꢃ3 M): 10.1 S
cm2 molꢃ1
/
C); 590w (590vs), ns(SnÃ
/
C); 238b
2200 conductimeter. Mossbauer spectra were deter-
¨
1
/
/
CH3]; 6.00
mined at 80.0 K in a constant acceleration apparatus
with a Ca119mSnO3 source, with isomer shifts (I.S.)
referred to BaSnO3. 1H (250.13 MHz) NMR spectra
were recorded in CDCl3 at room temperature on a
Bruker WM-250 spectrometer, and were referred to
TMS.
/
CH3]; 7.15 [m, C(3?)H]; 7.77ꢂ
7.83 [m, C(5?)H]; 8.43 [m,
Hg)]; 1.62ꢂ
/
/
/
/
/
/
.
2.2.9. [SnBu2Br2(DMPP)] (9)
2.4. Determination of the structure of
[SnEt2Br2(DMPP)]
From 0.392 g (1 mmol) of dibromodibutyltin(IV) and
0.173 g (1 mmol) of ligand. Anal. Found: C, 38.1; H, 6.0;
N, 7.8. Calc. for C16H25Br2N3Sn: C, 38.2; H, 5.1; N,
A colourless prismatic crystal of the complex was
mounted on a glass fibre and used for data collection in
7.4%. Yield: 26%. M.p. 75 8C. Mossbauer: I.S. 1.83,
¨
Q.S. 3.98, G 0.83, A2/1 1.03. IR (Raman) (cmꢃ1): 1605s
(1606m), 1580m (1577s), 1483vs (1484m), n(ring); 632m
an EnrafꢂNonius MACH3 automatic diffractometer
/
[8]. Cell constants and an orientation matrix for data
collection were obtained by least-squares refinement of
the diffraction data from 25 reflections in the range
(632w), nas(SnÃ
(212m), n(SnÃBr). H NMR: 2.31 [s, C(3)Ã
[s, C(4)H]; 2.63 [s, C(5)Ã
7.83 [m, C(4?)H]; 7.75ꢂ
/
C); 588w (586vs), ns(SnÃ
/
C); 202m
CH3]; 6.00
1
/
/
/
CH3]; 7.15 [m, C(3?)H]; 7.75ꢂ
/
9.182B
Mo Ka radiation (lꢀ
/
u B12.9268. Data were collected at 293 K using
/
˚
/
7.83 [m, C(5?)H]; 8.44 [m,
/
0.71073 A) and the v ꢂ2u scan
/
C(6?)H]; 0.95 [t, (SnÃ
/
Hd)]; 1.42 [m, (SnÃ
/
Hg)]. LM
technique, and were corrected for Lorentz and polariza-
tion effects [9]. A semi-empirical absorption correction
was also made [10].
(MeCN, 10ꢃ3 M): 3.3 S cm2 molꢃ1
.
2.2.10. [SnPh2Cl2(DMPP)] (10)
From 0.343 g (1 mmol) of dichlorodiphenyltin(IV)
and 0.173 g (1 mmol) of ligand. Anal. Found: C, 51.6;
The structure was solved by direct methods [11],
which revealed the positions of all non-hydrogen atoms,
and was refined on F2 by a full-matrix least-squares

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P. Alvarez-Boo et al. / Inorganica Chimica Acta 353 (2003) 8ꢂ
/
14
11
procedure using anisotropic displacement parameters
were dissolved immediately before use in Me2SO and
these solutions were diluted with the growth medium to
the desired concentrations before addition to the wells.
At least five concentrations of each compound were
used, with eight cell culture wells for each concentration.
Each compound was assayed on at least three separate
occasions. Each assay included a blank containing
complete medium without cells.
[12]. All hydrogen atoms were located in their calculated
˚
0.93ꢂ0.97 A) and were refined using a
positions (CÃ
/
Hꢀ
/
/
riding model. Atomic scattering factors were taken from
International Tables for X-ray Crystallography [13].
Molecular graphics were obtained with PLATON-98 [14].
Table 1 summarizes the crystal data, experimental
details and refinement results.
The cells were incubated with the compounds to be
tested at 37 8C in an atmosphere that was 5% CO2 and
had a relative humidity of 100%. The incubation time
was 72 h, during which period the control cells showed
exponential growth.
Cell growth was terminated by in situ fixation and
followed by staining with the protein-binding dye
sulforhodamine B (SRB) [16]. Specifically, adherent
cell cultures were fixed in situ by addition of 250 ml of
cold 50% (wt/vol) trichloroacetic acid (TCA) and were
kept for 60 min at 4 8C. The supernatant was then
discarded and the plates were washed three times with
deionized water and dried. SRB solution (500 ml, 0.4%
wt/vol in 1% AcOH) was added to each well, and the
2.5. In vitro cytostatic activity
Cytostatic activity was assayed against the established
cell line KB, which derives from a human oral epider-
moid carcinoma. Stock cultures were grown in 25 cm3
flasks containing 10 ml of buffered Eagle’s Minimum
Essential Medium (MEM) supplemented with gluta-
mine, non-essential aminoacids (1%) and newborn calf
serum (10%), as previously described [15]. The cell
population doubling time was approximately 24 h. The
cells were dissociated with 0.05% trypsin solution, plated
at a density of 5ꢄ
105 cells per well in 24-well cell
/
culture clusters (Costar) containing 1.0 ml of MEM per
well, and preincubated for 24 h to allow adhesion to the
substrate. Subsequently, the compounds to be tested
cells were allowed to stain for 20ꢂ30 min at room
/
temperature. Unbound SRB was removed by washing
three times with 1% AcOH, and the plates were then air-
dried while bound stain was solubilized with unbuffered
Tris base [tris(hydroxymethyl)aminomethane]. Optical
Table 1
Crystal and structure refinement data for [SnEt2Br2(DMPP)]
densities at 565 nm were read on a Perkinꢂ/Elmer 550 SE
spectrophotometer.
Empirical formula
Formula weight
Temperature (K)
C14H21Br2N3Sn
509.85
293(2)
The SRB assay was also used to measure the cell
population density at time 0 (the time at which the test
compounds were added).
Cytostatic activity was evaluated from the inhibition
of cell growth in the treated cultures with respect to the
controls. IC50, the concentration of test compound at
which cell proliferation was 50% of that observed in
control cultures, was determined by linear regression
analysis. The statistical significance of these results was
˚
Wavelength (A)
0.71073
monoclinic
P21/c
Crystal system
Space group
Cell constants
˚
a (A)
8.197(7)
13.297(5)
16.797(7)
96.70(5)
1818.2(18)
4
˚
b (A)
˚
c (A)
b (8)
3
V (A )
˚
estimated by means of Student’s t-test (P B0.01).
/
Z
Dcalc (g cmꢃ3
)
1.863
5.795
984
Absorption coefficient (mmꢃ1
F(000)
)
3. Results and discussion
Theta range (8)
Crystal size (mm)
Index ranges
2.44ꢂ
0.20ꢄ
95h 5
05k 515,
195l 519
3144
/
24.19
0.15ꢄ
0,
/
/0.10
3.1. Description of the structure of [SnEt2Br2(DMPP)]
(7)
ꢃ
/
/
/
/
/
ꢃ/
/
/
Reflections collected
Fig. 1 shows the PLATON representation of the
molecular structure of the complex, together with the
atomic numbering scheme. Table 2 lists selected bond
lenghts and angles.
Unique reflections
2920 [Rint
Psi-Scans
ꢀ/0.1300]
Absorption correction
Max/min transmission factors
Refinement method
0.962, 0.916
full-matrix least-squares on F2
Data/restraints/parameters
Goodness-of-fit on F2
2920/0/185
0.978
The crystal consists of isolated SnEt2Br2(DMPP)
units. In each unit the coordination sphere around the
tin atom is formed by two donor N atoms, two mutually
trans ethyl carbon atoms and two cis Br atoms in a
Final R indices [I ꢀ
/
2s(I)]
R1ꢀ
R1ꢀ
0.892 and ꢃ
/
0.0605, wR2ꢀ
0.3206, wR2ꢀ
1.419
/
0.1330
R indices (all data)
/
/0.2108
Largest difference peak and hole
ꢃ3
/
˚
(e A
pseudo-octahedral distribution. Whereas the SnÃ
/
C dis-
˚
tances, 2.11(3) and 2.143(19) A, are slightly shorter than
)

´
12
P. Alvarez-Boo et al. / Inorganica Chimica Acta 353 (2003) 8ꢂ14
/
Table 2
˚
Selected bond lengths (A) and angles (8) in [SnEt2Br2(DMPP)], with
e.s.d.s in parentheses
(a) Tin environment
Bond lengths
Sn(1)Ã
Sn(1)Ã
Sn(1)Ã
/
C(21)
2.11(3)
2.379(16) Sn(1)Ã
2.631(3)
Sn(1)Ã
Sn(1)Ã
/
C(11)
2.143(19)
2.387(16)
2.703(3)
/N(1)
/N(3)
/Br(2)
/
Br(1)
Bond angles
C(21)ÃSn(1)Ã
C(11)ÃSn(1)Ã
C(21)ÃSn(1)Ã
N(1)ꢂSn(1)Ã
C(11)ÃSn(1)Ã
N(3)ÃSn(1)ÃBr(2)
C(11)ÃSn(1)ÃBr(1)
N(3)ÃSn(1)ÃBr(1)
C(12)ÃC(11)ÃSn(1)
/
/
C(11)
N(1)
N(3)
172.3(11) C(21)Ã
/
Sn(1)Ã
Sn(1)Ã
Sn(1)Ã
Sn(1)Ã
C(21)ÃSn(1)Ã
N(1)ÃSn(1)ÃBr(1)
Br(2)ÃSn(1)ÃBr(1)
C(22)ÃC(21)ÃSn(1)
/
N(1)
N(3)
Br(2)
85.6(10)
89.0(6)
/
/
87.1(7)
89.9(9)
66.8(6)
91.4(5)
89.7(4)
90.2(5)
172.3(4)
119.8(13)
C(11)Ã
C(21)Ã
N(1)Ã
/
/
/
/
/
/
96.1(11)
156.4(4)
89.8(8)
/
/
N(3)
/
/
Brl(2)
Br(1)
/
/Br(2)
/
/
/
/
/
/
105.5(4)
98.0(10)
131.0(3)
/
/
/
/
/
/
/
/
/
/
(b) DMPP ligand
Bond lengths
N(1)Ã
N(2)Ã
N(1)Ã
C(1)Ã
C(2)Ã
C(4)Ã
C(6)Ã
C(11)Ã
Bond angles
C(1)ÃN(1)Ã
N(2)ÃN(1)Ã
C(3)ÃN(2)Ã
C(8)ÃN(3)Ã
C(4)ÃN(3)Ã
N(1)ÃC(1)Ã
C(3)ÃC(2)Ã
N(2)ÃC(3)Ã
N(3)ÃC(4)Ã
N(2)ÃC(4)Ã
C(5)ÃC(6)Ã
N(3)ÃC(8)Ã
/
C(1)
C(3)
C(8)
1.32(3)
1.32(2)
1.32(2)
1.41(3)
1.41(3)
1.42(2)
1.37(3)
1.50(2)
N(1)Ã
N(2)Ã
N(3)Ã
C(1)Ã
C(3)Ã
C(5)Ã
C(7)Ã
C(21)Ã
/
N(2)
C(4)
C(4)
1.41(2)
1.41(2)
1.34(2)
1.56(3)
1.51(2)
1.33(2)
1.39(3)
1.24(4)
Fig. 1. The crystal structure of [SnEt2Br2(DMPP)], showing the
numbering scheme.
/
/
/
/
/
C(2)
C(3)
C(5)
C(7)
/
C(9)
C(10)
C(6)
C(8)
˚
/
/
the sum of the covalent radii (2.17 A) [17], the SnÃ
/
N
Br bonds are significantly longer than the
/
/
and SnÃ
/
/
/
˚
corresponding covalent radii sums (2.15 and 2.54 A,
/C(12)
/C(22)
˚
Nꢀ2.379(16) and 2.387(16) A,
and SnÃBrꢀ2.631(3) and 2.703(3) A. Although there
respectively [17]): SnÃ
/
/
˚
/
/
/
/
N(2)
100.1(18) C(1)Ã
114.9(12) C(3)Ã
115.3(17) C(4)Ã
116.1(17) C(8)Ã
118.3(13) N(1)Ã
122.0(2) C(1)Ã
C(2)Ã
103.6(19) N(2)ÃC(3)Ã
127.0(2) C(3)Ã
C(2)Ã
117.4(16) N(3)ÃC(4)Ã
C(5)Ã
C(7)Ã
/
N(1)Ã
N(2)Ã
N(2)Ã
N(3)Ã
C(1)Ã
/
Sn(1)
C(4)
N(1)
Sn(1)
C(2)
136.0(16)
131.7(17)
112.8(15)
125.6(13)
115.0(2)
123.0(2)
105.6(18)
127.0(2)
122.8(18)
117.0(2)
117.1(19)
/
/
Sn(1)
N(1)
C(4)
/
/
are no known trans-SnC2, cis-SnN2, cis-SnBr2 com-
plexes of SnEt2Br2 with which to compare 7, it may be
/
/
/
/
/
/
/
/
compared with [SnMe2Br2(M)] (Mꢀmepirizole) [5], in
/
/
/
Sn(1)
C(9)
/
/
which one of the two donor N atoms belongs to a
pyrimidine ring (cf. pyridine in DMPP), and the other,
as in DMPP, to a pyrazole ring with a methyl
substituent on a vicinal C atom. As in the mepirizole
complex, the pyrazole nitrogen is the more closely
/
/
/
/C(9)
/
/C(1)
/
/
C(2)
/
/
C(10)
N(2)
C(5)
/
/C(10)
/
/
/
/
C(5)
C(4)
C(8)
/
/
119.3(18) C(6)Ã
/
/
/
/C(7)
122.0(2)
C(6)Ã
/
/
bound to the Sn atom and lies trans to the longer SnÃ
Br bond, although both the SnÃN bonds are shorter and
both the SnÃBr bonds longer than in the mepirizole
complex.
Although some bond angles are close to the 908
proper to ideal octahedral geometry [C(11)ÃSn(1)Ã
N(1)ꢀ87.1(7); C(21)ÃSn(1)ÃN(3)ꢀ89.9(9); C(11)Ã
Sn(1)ÃBr(1)ꢀ90.2(5)8], Br(1)ÃSn(1)ÃBr(2) is wider
[98.00(10)8] because of the bulk of the Br atoms, and
N(3), is much narrower [66.8(6)8] because
/
/
/
C(7)
124.5(18)
/
/
the donor atoms, the bond lengths are only slightly
different: in the pyridine ring, for example, N(3)ÃC(4)ꢀ
1.34(2) A as against 1.32 A in the dimer, and N(3)Ã
/
/
˚
˚
/
/
/
˚ ˚
1.32(2) A as against 1.34 A; while in the pyrazole
C(8)ꢀ
ring: N(1)Ã
against 1.37ꢂ
Nor does coordination significantly change the C(8)Ã
N(3)ÃC(4) bond angle [116.2(1) and 115.9(1)8 in the
dimer, 116.1(17)8 in the complex], although coordina-
tion of the pyrazole N makes the C(1)ÃN(1)ÃN(2) angle
/
/
/
/
/
/
˚
/
N(2)ꢀ
/
1.41(2) and N(1)Ã
1.38 and 1.31 A, respectively in the dimer.
/
C(1)ꢀ1.32(3) A as
/
˚
/
/
/
/
/
/
N(1)Ã
/
Sn(1)Ã
/
/
of the rigidity of the bidentate ligand.
The pyridine and pyrazole rings of the ligand lie at an
angle of about 308 to each other, and the Sn atom lies
slightly out of the least-squares plane defined by the two
N and two Br atoms.
The structural parameters of the ligand rings differ
only slightly from those found by Phillips and Steel [18]
in free 2,2?-bis(3,5-dimethyl)-pyrazol-1-yl-4,4?-bipyri-
dine, a dimer consisting of two DMPP molecules linked
via the C(4) atoms of the pyridine rings. Even around
/
/
narrow from 103.9(4) or 104.9(4)8 in the dimer to
100.1(18)8 in the complex. In [Fe(DMPP)3](ClO4)2 and
[Ni(DMPP)3](BF4)2, the two DMPP compounds that
have been studied previously by X-ray diffractometry
[7b], the N(3)Ã
/
C(4), N(3)Ã
/
C(8), N(1)Ã
/
N(2) and N(1)Ã
/
C(1) bonds have mean lengths of 1.35, 1.34, 1.37 and
˚
1.28 A, respectively; the angles C(8)Ã
/
N(3)Ã
/
C(4) and
C(1)ÃN(1)ÃN(2) are respectively 114(1) and 108(1)8 in
/
/

´
P. Alvarez-Boo et al. / Inorganica Chimica Acta 353 (2003) 8ꢂ
/
14
13
the Ni compound and 115(1) and 107(2)8 in the Fe
compound (measured at 294 K); and the bite angles are
77.7(3) and 80.5(5)8 in the Ni and Fe compounds,
respectively.
less than half a linewidth means they have a large
relative error, the SnÃX bond lengths can be calculated,
using published formulae [25], as 2.43 and 2.60 A for the
chloride and bromide derivatives, respectively. The Q.S.
values for the [SnR2X2(DMPP)] derivatives are much
larger (around 4 mm sꢃ1), and are fully in keeping with
the trans arrangement of the R groups around the tin
/
˚
3.2. Infrared and Raman spectra
The DMPP ring bands at 1590vs (1592s), 1579vs
(1578s) and 1475vs (1479s) are shifted to similar extents
in the spectra of all the complexes, which suggests that
in all of them DMPP has the same N,N?-didentate
behaviour as was observed in 7 by X-ray diffractometry.
centre and with the CÃ
the ideal 1808, since values close to 2 mm sꢃ1 are
expected for cis CÃSnÃC [26] and the values calculated
/
SnÃ
/
C angles being quite close to
/
/
using the point charge formalism with the CÃ
/
SnÃ/C
angle observed for 7 are around 3.9 mm sꢃ1
.
In the 650ꢂ
C) stretching bands appear. None of the spectra of the
[SnX4(DMPP)] compounds show all the four n(SnÃX)
bands (2A1ꢁB1ꢁB2) that would be expected in both the
/
100 cmꢃ1 range the n(SnÃ
/
X) and the n(SnÃ
/
/
3.4. Conductimetric measurements
/
/
IR and Raman spectra if there were local C2V symmetry
around the metal atom, and neither do all the
[SnR2X2(DMPP)] spectra show the two IR and two
The molar conductivities of 10ꢃ3 M solutions of the
compounds in acetonitrile indicate that they are non-
ionogenic in this solvent [27].
Raman bands expected for a cis-(XÃ
/
SnÃ
/
X) fragment.
However, all the bands observed are very close to bands
found in systems with this fragment [7c,19,20]. For the
[SnR2X2(DMPP)] compounds, the number and activity
3.5. NMR spectroscopy
of the ns(SnÃ
Raman spectra are in keeping with the presence of a
bent trans CÃSnÃC fragment, as was found by X-ray
diffractometry in the case of the bromoethyl derivative.
/
C) and nas(SnÃ
/
C) bands in the IR and
1H NMR spectra of the complexes were recorded in
CDCl3. The DMPP signals at 2.30 [s, C(3)H3], 6.00 [s,
C(4)H], 2.63 [s, C(5)H3], 7.14 [m, C(3?)H], 7.82 [m,
C(4?)H], 7.77 [m, C(5?)H] and 8.42 [m, C(6?)H] ppm are
only slightly shifted upon coordination, particularly in
the SnR2X2 complexes. The 1H NMR data obtained for
these complexes are close to those of the free acceptors.
In the case of the methyl derivatives, for example,
/
/
3.3. Mossbauer spectra
¨
The Mossbauer spectra of all the compounds show
¨
singlets or doublets with narrow linewidths (0.79ꢂ0.96
/
mm sꢃ1) suggesting the existence of a single tin site. The
hyperfine parameters (isomer shift and quadrupole
splitting) are typical of [SnX4(LL)] and [SnR2X2(LL)]
complexes. The I.S. decrease as the electronegativity of
the ligands increases (from I to Cl and from alkyl to aryl
groups), in accordance with the expected trend in the
charge density in the s-orbital of the metal atom. The
dependence of the I.S. on the Mulliken electronegativity
of the halogen in the [SnX4(DMPP)] series is in fact
singlets are observed at 1.19 ppm (Xꢀ
ppm (XꢀBr), at the same or nearly the same positions
as for SnMe2Cl2 (1.21 ppm) and SnMe2Br2 (1.38 ppm),
/
Cl) and 1.38
/
respectively, and the values of J(117/119SnÃ
/
1H) (73.0/
2
76.4 Hz for XꢀCl; 63.9/66.7 Hz for XꢀBr) are also
/
/
close or almost identical to those reported previously
[28] for the free acceptors in the same solvent (65.7/68.7
and 63.2/66.1 Hz, respectively). These and the analogous
data for the Et, Bu and Ph derivatives suggest that the
chloride complexes are significantly dissociated in
CDCl3 and the bromide complexes almost completely,
as is found in similar systems [7c,29].
linear, as expected, but the slope (ꢃ0.94) is much
/
steeper than has been reported for similar compounds
[21,22]. This increase in slope may be due to the strong
asymmetry introduced in the structure by the small NÃ
/
SnÃN angle imposed by the ligand. It is also noteworthy
/
Table 3
Results of in vitro cytostatic assays against cell line KB
that the I.S. values themselves are somewhat higher than
expected [22,23], as is also the case for the organome-
tallic derivatives [24].
Compound
IC50 (mg mlꢃ1 medium)
IC50 (mM)
Quadrupole splitting (Q.S.) reflects the field gradient
generated around the tin nucleus by the s and p bonds
formed with the six donor atoms, and provides informa-
tion about the charge distribution arising from the
arrangement of the ligands around the metal. The
[SnX4(DMPP)] compounds have Q.S. values near zero,
as is expected for cis derivatives. Although their being
[SnEt2Cl2(DMPP)]
[SnEt2Br2(DMPP)]
[SnBu2Cl2(DMPP)]
[SnBu2Br2(DMPP)]
[SnPh2Cl2(DMPP)]
[SnPh2Br2(DMPP)]
cis-[PtCl2(NH3)2]
0.39
4.49
0.13
0.31
0.18
0.39
0.11
0.92
8.81
0.30
0.57
0.35
0.65
0.37

´
14
P. Alvarez-Boo et al. / Inorganica Chimica Acta 353 (2003) 8ꢂ14
/
[7] (a) N. Saha, S.K. Kar, J. Inorg. Nucl. Chem. 39 (1977) 1236;
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3.6. In vitro cytostatic activity
Table 3 lists the IC50 values of the compounds,
expressed in mM, together with that of cis-[PtCl2(NH3)2]
for comparison. The butyl derivatives were the most
active, and the ethyl derivatives the least. In particular,
[SnBu2Cl2(DMPP)] was even more active than cis-
[PtCl2(NH3)2]. However, all the [SnR2X2(DMPP)] com-
pounds except [SnEt2Cl2(DMPP)] were less active than
the corresponding complexes of mepirizole, which in
previous work were tested against the same cell line [4].
The bromide derivatives were less active than the
chlorides.
(c) R. Visalakshi, V.K. Jain, S.K. Kulshreshtha, G.S. Rao, Inorg.
Chim. Acta 118 (1986) 119;
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4. Supplementary material
[14] A.L. Spek: PLATON. A Multipurpose Crystallographic Tool.
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Complete crystallographic data for the structure
reported in this paper have been deposited at the
Cambridge Crystallographic Data Centre CCDC No.
187415. Copies of this data may be obtained free of
charge on application to The Director, CCDC, 12
[15] C. Rossi, A. Ambrogi, G. Grandolini, V. Scarcia, A. Furlani, J.
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Acknowledgements
Furlani, V. Scarcia, J. Sordo, U. Russo, M. Varela, Appl.
Organomet. Chem. 11 (1997) 963.
We thank the Xunta de Galicia, Spain, for financial
support of this work.
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