close

Вход

Забыли?

вход по аккаунту

?

Structural studies of diethyltin(IV) derivatives and their biological aspects as potential antitumor agents against Agrobacterium tumefacien cells.

код для вставкиСкачать
Full Paper
Received: 29 May 2010
Revised: 25 November 2010
Accepted: 25 November 2010
Published online in Wiley Online Library: 14 April 2011
(wileyonlinelibrary.com) DOI 10.1002/aoc.1777
Structural studies of diethyltin(IV) derivatives
and their biological aspects as potential
antitumor agents against Agrobacterium
tumefacien cells
Mukhtiar Hussaina , Zia-ur-Rehman a , Muhammad Hanifa ,
Muhammad Altafb , Aziz-ur-Rehman a , Saqib Alia∗
and Kingsley J. Cavellc
A series of new diethyltin(IV) derivatives of substituted phenyl acrylates have been synthesized and characterized by elemental
analysis, IR, multinuclear NMR (1 H, 13 C, 19 F and 119 Sn) and X-ray single crystal analysis. X-ray single crystal diffraction study
of complex 8 has shown the formation of secondary O· · ·Sn, F· · ·H and H· · ·O intermolecular interactions. These complexes
proved to be good antitumor agents. The antitumor properties are presumably due to the intercalative mode of interaction of
c 2011 John Wiley & Sons, Ltd.
these complexes with the tumor cells’ DNA. Copyright Supporting information may be found in the online version of this article.
Keywords: diethyltin(IV) derivatives; substituted phenylacrylates; multinuclear NMR; Agrobacterium tumefacien cells; X-ray structure
412
Introduction
Experimental
Cancer and tumor growth in humans and plants are prime challenges for chemists. In the search for alternatives and effective
metallo-organic anticancer and antitumor drugs, organotin carboxylates have received considerable attention on account of
their potential biological applications.[1 – 7] Our research group
has also contributed towards extensive research on the evaluation of organotin(IV) compounds as potent tumor inhibitors.[8 – 15]
Organotin(IV) compounds are eco-toxicants whose action depends upon their structure. Owing to higher activity and lower
toxicity of diorganotin derivatives,[16] the compounds of the type
[(RCOOSnR2 )2 O]2 and (RCOO)2 SnR2 have been extensively studied for their antitumor activity against tumor cell lines.[3] Our
recent investigations[13 – 15] showed that these compounds interact with DNA in intercalative fashion by making secondary
contacts with the bases, culminating in its structural machinery.
The outcome is that the compounds have the ability to form
strong noncovalent interactions with DNA and should be good
antitumor agents. In order to pursue this idea, and keeping in
view the antitumor potential of diorganotins, we designed nine
new carboxylate ligands with the capability to form secondary
interactions, e.g. hydrogen bonding, π –H and O–H bonding, and
coupled them with diethyltin(IV) moiety. These compounds were
tested against plant tumors and proved effective. Antitumour
studies were carried out against Agrobacterium tumefacien cells.
These are Gram-negative bacteria and infect the plants through
their Ti plasmids. This study is a continuation of our previous
work[12 – 18] and will be helpful in designing new organotins of
pharmaceutical value.
The reagents, phenyl acetic acids, aldehydes and acetic anhydride,
were purchased from commercial sources (Aldrich, USA) and
were used without further purification. The solvents were
dried prior to use by standard procedures.[19] Melting points
were determined with Gallenkemp (UK) apparatus and were
uncorrected. Elemental analyses were carried out using a Leco
CHNS-932 analyzer USA. Infrared spectra were recorded as
KBr pellets on Bio-Rad Excalibur FT-IR, model FTS 300 MX
spectrophotometer, in the frequency range of 4000–400 cm−1 . 1 H,
13 19
C, F and 119 Sn NMR spectra in solution were recorded on Bruker
ARX 300 MHz, 400 MHZ and 500 MHz FT-NMR spectrometers,
respectively. Chemical shifts are reported in ppm relative to
the external references, tetramethylsilane (TMS) for 1 H, 13 C
NMR, trichlorofluoromethane for 19 F and tetramethyltin for 119 Sn
chemical shifts. X-ray single crystal analysis was made on a Nonius
Kappa CCD diffractometer with graphite monochromated MoKα
radiation.
Appl. Organometal. Chem. 2011, 25, 412–419
∗
Correspondence to: Saqib Ali, Department of Chemistry, Quaid-i-Azam
University Islamabad-45320, Pakistan. E-mail: drsa54@yahoo.com
a Department of Chemistry, Quaid-i-Azam University Islamabad-45320, Pakistan
b Institute of Microtechnology, University of Neuchátel, Rue Emile-Argand 11,
CH-2009 Neuchátel, Switzerland
c School of Chemistry, Cardiff University, Main Building Park Place Cardiff C10
3AT, UK
c 2011 John Wiley & Sons, Ltd.
Copyright Structural studies of diethyltin(IV) derivatives
3-(2,3-Methylenedioxyphenyl)-2-(4-methyoxyphenyl) acrylic acid
(HL5 )
13
C NMR δ (ppm): 173.2 (1-C), 160.7 (7-C), 148.5 (13-C), 147.4 (12-C),
138.3 (3-C), 132.3 (2-C), 131.8 (4-C), 125.4 (5, 5 -C), 124.8 (6, 6 -C),
120.7 (9-C), 120.3 (10-C), 114.7 (8-C), 109.6 (11-C), 103.1(14-C), 54.3
(15-C).
Scheme 1. Preparation of o-piperonal.
Synthesis of 2,3-Methylenedioxy Benzaldehyde (o-Piperonal)
and Substituted Phenylacrylic Acids
3-(4-Trifluoromethylphenyl)-2-(4-fluorophenyl) acrylic acid (HL6 )
13
C NMR δ (ppm): 172.6 (1-C), 164.4 (7-C), 1 J[13 C, 19 F] 245 Hz, 141.0
(3-C), 137.6 (8-C), 133.0 (2-C), 131.7 (4-C), 131.2, 130.8, 130.4 (9, 10,
11, 12, 13-C), 126.5 (5, 5 -C 3 J[13 C, 19 F] 7 Hz, 124.3 (14-C), 116.2 (6,
6 -C) 2 J[13 C, 19 F] 24 Hz.
The o-piperonal and substituted phenylacrylic acids were synthesized by reported methods[20,21] as shown in Schemes 1 and 2,
respectively. Ligand acids were synthesized by dissolving phenyl
acetic acids and aromatic aldehydes (1 : 1) in 10 ml of acetic anhydride. The mixture was gently heated for 2–3 h. To the cooled
solution, potassium carbonate (0.18–0.25 g, 1.3–1.8 mmol) was
added as basic medium. Neutralization of this solution by hydrochloric acid provided the final product as precipitates. It was
purified by washing with water three times.
NMR δ (ppm): 172.8 (1-C), 141.8 (3-C), 137.9 (8-C), 135.8 (7-C),
133.6 (13-C), 132.1 (2-C), 131.5 (4-C), 130.7, 129.7 (5, 5 , 6, 6 -C),
127.4, 126.8, 125.5, 124. 8 (9, 10, 11, 12-C), 15.8 (14-C).
3-(2, 3-Methylenedioxyphenyl)-2-(4-fluorophenyl) acrylic acid (HL1 )
3-(2-Methylphenyl)-2-(4-fluorophenyl) acrylic acid (HL8 )
13 C NMR
δ (ppm): 167.5 (1-C),
244 Hz, 147.9
(13-C), 147.6 (12-C), 140.6 (3-C), 132.1 (2-C), 131.7 (4-C), 126.2 (5,
5 -C) 3 J[13 C, 19 F] 8 Hz, 121.3 (9-C), 121.1 (10-C), 117.0 (8-C), 115.1
(6, 6 -C) 2 J[13 C, 19 F] 23 Hz, 107.4 (11-C), 106.3 (14-C).
13 C NMR δ (ppm): 173.1 (1-C), 163.7 (7-C) 1 J[13 C, 19 F] 244 Hz, 141.8
(3-C), 137.9 (8-C), 133.6 (13-C), 132.1 (2-C), 131.5 (4-C), 126.4 (5,
5 -C) 2 J[13 C, 19 F] 8 Hz, 127.2, 126.1, 125.5, 124.9 (9, 10, (11, 12-C),
15.8 (14-C), 115.8 (6, 6 -C) 2 J[13 C, 19 F] 24 Hz.
3-(2, 3-Methylenedioxyphenyl)-2-(2-fluorophenyl) acrylic acid (HL2 )
3-(4-Trifluoromethylphenyl)-2-(3-methylphenyl) acrylic acid (HL9 )
13 C NMR
13 CNMR δ (ppm): 172.8 (1-C), 140.3 (3-C), 138.6 (8-C), 137.8 (6, 6 -C),
132.2 (2-C), 131.5 (4-C), 130.8, 130.0, 129.3 (9, 10, 11, 12, 13-C),
128.8, 126.7, 125.6, 124.7 (5, 5 , 6, 7-C), 122.0 (14-C), 21.4 (15-C).
162.1 (7-C) 1 J[13 C, 19 F]
158.9 (5-C) 1 J[13 C, 19 F]
δ (ppm): 168.9 (1-C),
245 Hz, 147.5
(13-C), 147.4 (12-C), 136.6 (3-C), 132.4 (2-C), 130.3 (4-C), 126.3 (7-C)
3 J[13 C, 19 F] 8 Hz, 124.2 (5, 5 -C) 3 J[13 C, 19 F] 4 Hz, 123.4 (6-C), 121.3
(9-C), 121.1 (10-C), 116.3 (8-C), 115.9 (6 -C) 2 J[13 C, 19 F] 23 Hz, 109.6
(11-C), 101.3 (14-C).
3-(2, 3-Methylenedioxyphenyl)-2-(4-chlorophenyl) acrylic acid (HL3 )
13 CNMR δ
(ppm): 172.3 (1-C), 147.5 (13-C), 147.4 (12-C), 139.6 (3-C),
135.6 (7-C), 132.5 (2-C), 131.9 (6, 6 -C), 131.4 (4-C), 129.4 (5, 5 -C),
121.3 (9-C), 121.2 (10-C), 116.8 (8-C), 108.9 (11-C), 101.4 (14-C).
3-(2, 3-Methylenedioxyphenyl)-2-(4-bromophenyl) acrylic acid (HL4 )
13 C NMR δ (ppm): 167.1 (1-C), 147.7 (13-C), 147.2 (12-C), 140.3 (3-C),
135.4 (6, 6 -C), 134.1 (5, 5 -C), 133.6 (2-C), 131.3 (4-C), 128.8 (7-C),
121.7 (9-C), 121.3 (10-C), 116.5 (8-C), 109.5 (11-C), 101.3 (14-C).
3-(2-Methylphenyl)-2-(4-chlorophenyl) acrylic acid (HL7 )
13 C
Synthesis of Diethyltin(IV) Derivatives (1–9)
For synthesis of ethyltin(IV) derivatives, sodium salts of HL1 – 5
and triethylammonium salts of HL6 – 9 were prepared as reported
earlier.[10,11,17,18] Triethyl ammonium salts were prepared in situ
by reaction of ligand acids and triethylamine (022–0.27 ml,
1.6–1.95 mmol) in 1 : 1 ratio using toluene as solvent. Diethyltin(IV)
dichloride in toluene (70 ml) was added in stoichiometric amounts
(1 : 2) to suspension of sodium–triethyl ammonium salt of ligands
in toluene. The mixture was refluxed for 6–7 h with constant
stirring. Byproducts (NaCl/triethyl ammonium chloride) were
removed by filtration and clear filtrate was evaporated under
reduced pressure, yielding a solid product (Scheme 3).
413
Scheme 2. Preparation of substituted phenylacrylic acids HL1 –HL9 .
Appl. Organometal. Chem. 2011, 25, 412–419
c 2011 John Wiley & Sons, Ltd.
Copyright wileyonlinelibrary.com/journal/aoc
M. Hussain et al.
Scheme 3. Preparation of diethyltin(IV) esters of phenylacrylic acids 1–9.
Diethyltin(IV) bis-[3-(2,3-methylenedioxyphenyl)-2-(4-fluorophenyl)
acrylate] (1)
Diethyltin(IV) bis-[3-(4-trifluoromethylyphenyl)-2-(4-fluorophenyl)
acrylate] (6)
13 C NMR
13
δ (ppm): 176.7 (1-C), 164.1 (7-C) 1 J[13 C, 19 F] 245 Hz, 147.5
(13-C), 147.0 (12-C), 135.8 (3-C), 132.0 (2-C), 131.6 (4-C), 126.7 (5,
5 -C) 3 J[13 C, 19 F] 8 Hz, 121.8 (9-C), 121.2 (10-C), 117.1 (8-C), 115.4
(6, 6 -C),2 J[13 C, 19 F] 24 Hz, 109.1 (11-C), 101.1 (14-C), 17.8 (α-C,
SnCH2 CH3 ), 1 J[119 Sn, 13 C] 778 Hz, (C-Sn-C) angle (deg) 145, 9.1
(β-C, Sn-CH2 CH3 ). 119 Sn NMR δ (ppm): −235.4. 19 F NMR δ (ppm):
−114.3.
C NMR δ (ppm): 176.3 (1-C), 164.3 (7-C) 1 J[13 C, 19 F] 247 Hz, 140.0
(3-C), 138.1 (8-C), 133.6 (2-C), 131.6 (4-C), 131.1, 130.5, 129.6 (9, 10,
11, 12, 13-C), 125.8 (5, 5 -C) 3 J[13 C, 19 F] 8 Hz, 116.1 (6, 6 -C) 2 J[13 C,
19 F] 22 Hz, 124.2 (14-C), 17.9 (α-C, SnCH CH ) 1 J[119 Sn, 13 C] 595 Hz,
2
3
(C-Sn-C) angle (deg) 129, 9.1 (β-C, SnCH2 CH3 ). 119 Sn NMR δ (ppm):
−95. 19 F NMR δ (ppm): −63.8 (C-F3 ), −114.0 (C-F).
Diethyltin(IV) bis [3-(2-methylphenyl)-2-(4-chlorophenyl) acrylate] (7)
Diethyltin(IV) bis-[3-(2,3-methylenedioxyphenyl)-2-(2-fluorophenyl)
acrylate] (2)
13
C NMR δ (ppm): 176.1 (1-C), 161.8 (5-C) 1 J[13 C, 19 F] 246 Hz, 147.4
(13-C), 147.0 (12-C), 135.7 (3-C), 132.9 (2-C), 130.1 (4-C), 126.1 (7-C)
3 13 19
J[ C, F] 8 Hz, 125.3 (5, 5 -C) 3 J[13 C, 19 F] 6 Hz 124.2 (6, 6 -C), 121.3
(9-C), 121.2 (10-C), 117.1 (8-C), 115.9 (6-C),2 J[13 C, 19 F] 21 Hz, 109.2
(11-C), 101.1 (14-C), 17.9 (α-C, Sn-CH2 CH3 ), 1 J[119 Sn, 13 C] 561 Hz,
(C-Sn-C) angle (deg) 126, 8.9 (β-C, SnCH2 CH3 ). 119 Sn NMR δ (ppm):
−75.0. 19 F NMR δ (ppm): −114.05.
Diethyltin(IV) bis-[3-(2,3-methylenedioxyphenyl)-2-(4-chlorophenyl)
acrylate] (3)
13 C NMR δ (ppm): 176.1 (1-C), 147.4 (13-C), 146.9 (12-C), 137.0 (3-C),
134.9 (7-C), 133.4 (2-C), 131.7 (6, 6 -C), 131.2 (4-C), 128.6 (5, 5 -C),
121.8 (9-C), 121.2 (10-C), 117.2 (8-C), 108.9 (11-C), 101.1 (14-C), 18.0
(α-C, SnCH2 CH3 ), 1 J[119 Sn, 13 C] 504 Hz, (C-Sn-C) angle (deg) 121,
8.7 (β-C, SnCH2 CH3 ). 119 Sn NMR δ (ppm): −165.8.
Diethyltin(IV) bis-[3-(2,3-methylenedioxyphenyl)-2-(4-bromophenyl)
acrylate] (4)
13
C NMR δ (ppm): 173.1 (1-C), 141.0 (3-C), 136.7 (8-C), 135.6 (7-C),
134.8 (13-C), 132.7 (2-C), 131.4 (4-C), 130.6, 129.2 (5, 5 , 6, 6 -C),
127.4, 126.2, 125.4, 124.5 (9, 10, 11, 12-C), 19.1 (14-C), 17.1 (α-C,
SnCH2 CH3 ), 8.2 (β-C, SnCH2 CH3 ). 119 Sn NMR δ (ppm): −147.1.
Diethyltin(IV) bis [3-(2-methylphenyl)-2-(4-fluorophenyl) acrylate] (8)
13
C NMR δ (ppm): 177.1 (1-C), 163.8 (7-C), 1 J[13 C, 19 F] 245 Hz, 141.1
(3-C), 137.6 (8-C), 134.2 (13-C), 132.1 (2-C), 131.5 (4-C), 126.2 (5, 5-C)
3 13 19
J[ C, F] 8 Hz, 129.6, 128.6, 125.4, 124.8 (9, 10, 11, 12-C), 115.4 (6,
6 -C) 2 J[13 C, 19 F] 21 Hz, 20.2 (14-C), 17.9 (α-C, SnCH2 CH3 ), 1 J[119 Sn,
13 C] 539 Hz, (C-Sn-C) angle (deg) 124, 9.2 (β-C, SnCH CH ). 119 Sn
2
3
NMR δ (ppm): −163.6. 19 F NMR δ (ppm): −114.
Diethyltin(IV) bis [3-(4-trifluoromethylphenyl)-2-(3-methyl) acrylate]
(9)
13
C NMR δ (ppm): 175.2 (1-C), 141.3 (3-C), 137.9 (8-C), 135.4 (6,
6 -C), 132.2 (2-C), 131.4 (4-C), 130.5, 129.6, 128.7 (9, 10, 11, 12,
13-C), 127.6, 126.3, 125.6, 124.9 (5, 5 , 6, 7-C,), 123.2 (14-C), 20.5
(15-C), 16.9 (α-C, SnCH2 CH3 ) 1 J[119 Sn, 13 C] 504 Hz, (C-Sn-C) angle
(deg) 122, 8.0 (β-C, SnCH2 CH3 ). 119 Sn NMR δ (ppm): −166.7. 19 F
NMR δ (ppm): −63.4.
13
C NMR δ (ppm): 176.6 (1-C), 146.9 (13-C), 147.5 (12-C), 138.4 (3-C),
136.0 (6, 6 -C), 134.7 (5, 5 -C), 132.6 (2-C), 131.6 (4-C), 129.5 (7-C),
122.1 (9-C), 121.8 (10-C), 116.9 (8-C), 109.2 (11-C), 101.2 (14-C), 17.9
(α-C, SnCH2 CH3 ), 1 J[119 Sn, 13 C] 584 Hz, (C-Sn-C) angle (deg) 128,
9.1 (β-C, SnCH2 CH3 ). 119 Sn NMR δ (ppm): −75.0.
Results and Discussion
Physical data of ligand acids (HL1 –HL9 ) and diethyltin(IV)
complexes (1–9) is given in Table 1.
Infrared Spectroscopy
Diethyltin(IV) bis-[3-(2,3-methylenedioxyphenyl)-2(4-methoxyphenyl) acrylate] (5)
414
13 C NMR δ (ppm): 177.4 (1-C), 160.3 (7-C), 147.7 (13-C), 147.2 (12-C),
136.7 (3-C), 132.9 (2-C), 131.3 (4-C), 124.9 (5, 5 -C), 122.2 (6, 6 -C),
121.4 (9-C), 121.3 (10-C), 114.3 (8-C), 109.2 (11-C), 101.4 (14-C), 55.3
(15-C), 18.2 (α-C, SnCH2 CH3 ,), 1 J[119 Sn, 13 C] 527 Hz, (C-Sn-C) angle
(deg) 123, 9.5 (β-C, SnCH2 CH3 ). 119 Sn NMR δ (ppm): −125.
wileyonlinelibrary.com/journal/aoc
In the IR spectra of all complexes (Table 2), the appearance of a
new Sn· · ·O vibration in the region 436–478 cm−1 indicated the
deprotonation of the ligand upon coordination with diethyltin(IV)
moiety via two oxygen atoms of the COO group.[16] The difference
between asymmetric and symmetric stretching frequencies (ν)
is an excellent indicator to assess the mode of coordination of the
ligand. The calculated ν values lie in the range 170–188 cm−1 ,
c 2011 John Wiley & Sons, Ltd.
Copyright Appl. Organometal. Chem. 2011, 25, 412–419
Structural studies of diethyltin(IV) derivatives
Table 1. Physical data of ligand acids (HL1 –HL9 ) and complexes 1–9
Reactants
HL/complex Phenyl acetic acid
1
HL
HL2
HL3
HL4
HL5
HL6
HL7
HL8
HL9
Complex 1
Complex 2
Complex 3
Complex 4
Complex 5
Complex 6
Complex 7
Complex 8
Complex 9
Molecular
formula
Aldehyde
4-Fluoro (0.5 g, 3.25 mmol)
2-Fluoro (0.5 g, 3.25 mmol)
4-Chloro (0.5 g, 2.93 mmol)
4-Bromo (0.5 g, 2.3 mmol)
4-Methoxy (0.5 g, 3.0 mmol)
4-Fluoro (0.5 g, 3.25 mmol)
4-Chloro (0.5 g, 2.93 mmol)
4-Fluoro (0.5 g, 3.25 mmol)
3-Methyl (0.5 g, 3.33 mmol)
Ligand (NaL1 – 5 /HL6 – 9 )
NaL1 (0.31g, 1.0 mmol)
NaL2 (0.31g, 1.0 mmol)
NaL3 (0.32g, 1.0 mmol)
NaL4 (0.37g, 1.0 mmol)
NaL5 (0.32g, 1.0 mmol)
HL6 (0.5g, 1.6 mmol)
HL7 (0.5g, 1.8 mmol)
HL6 (0.5g, 1.95 mmol)
HL6 (0.5g, 1.6 mmol)
o-Piperonal (0.49 g, 3.25 mmol)
C16 H11 O4 F
o-Piperonal (0.49 g, 3.25 mmol)
C16 H11 O4 F
o-Piperonal (0.44 g, 2.93 mmol)
C16 H11 O4 Cl
o-Piperonal (0.35 g, 2.3 mmol)
C16 H11 O4 Br
o-Piperonal (0.45 g, 3.0 mmol)
C17 H14 O5
4-CF3 benzaldehyde (0.56 g, 3.25 mmol)
C16 H10 O2 F4
o-Tolualdehyde (0.35 g, 2.93 mmol)
C16 H13 O2 Cl
o-Tolualdehyde (0.39 g, 3.25 mmol)
C16 H13 O2 F
4-CF3 benzaldehyde (0.58 g, 3.33 mmol)
C17 H13 O2 F3
Diethyltin(IV) dichloride
(C2 H5 )2 SnCl2 (0.5 g, 2.0 mmol)
C36 H30 O8 F2 Sn
(C2 H5 )2 SnCl2 (0.5 g, 2.0 mmol)
C36 H30 O8 F2 Sn
(C2 H5 )2 SnCl2 (0.5 g, 2.0 mmol)
C36 H30 O8 Cl2 Sn
(C2 H5 )2 SnCl2 (0.5 g, 2.0 mmol)
C36 H30 O8 Br2 Sn
(C2 H5 )2 SnCl2 (0.5 g, 2.0 mmol)
C38 H36 O10 Sn
(C2 H5 )2 SnCl2 (0.8 g, 3.2 mmol)
C36 H28 O4 F8 Sn
(C2 H5 )2 SnCl2 (0.9 g, 3.6 mmol)
C36 H34 O4 Cl2 Sn
(C2 H5 )2 SnCl2 (0.97 g, 3.9 mmol)
C36 H34 O4 F2 Sn
(C2 H5 )2 SnCl2 (0.8 g, 3.2 mmol)
C38 H34 O4 F6 Sn
Melting Yield
point (◦ C) (%)
Elemental analysis
%C calcd %H calcd
(found)
(found)
203–205
173–176
186–188
213–215
229–231
163–166
175–177
170–172
185–188
83
88
75
78
65
78
81
82
76
67.1 (67.6)
67.1 (66.4)
63.5 (64.0)
55.3 (55.7)
68.5 (67.8)
61.9 (62.3)
70.4 (70.0)
75.0 (75.4)
66.6 (67.1)
3.8 (4.2)
3.8 (3.2)
3.6 (4.0)
3.2 (3.7)
4.7 (4.1)
3.2 (3.8)
4.8 (4.1)
5.0 (5.5)
4.2 (4.8)
160–163
170–172
115–120
172–176
199–201
134–138
174–176
138–143
157–161
85
84
71
80
74
74
68
79
78
57.9 (57.2)
57.9 (57.3)
55.4 (55.6)
49.7 (49.0)
59.2 (58.6)
54.4 (55.3)
60.0 (60.4)
62.9 (63.0)
58.0 (58.3)
4.0 (4.7)
4.0 (4.7)
3.9 (4.3)
3.5 (3.6)
4.7 (5.4)
3.6 (4.1)
4.8 (4.9)
5.0 (4.7)
4.4 (4.9)
Table 2. Infrared data of ligand acids (HL1 –HL9 ) and complexes 1–9
ν(COO)
HL/complex
ν(C–H)
ν(OH)
νAsym
νSym
ν
ν(O–CH2 –O)
ν(Sn–C)
ν(Sn–O)
HL1
HL2
HL3
HL4
HL5
HL6
HL7
HL8
HL9
Complex 1
Complex 2
Complex 3
Complex 4
Complex 5
Complex 6
Complex 7
Complex 8
Complex 9
3063
3110
3134
3105
3141
3150
3132
3144
3150
3138
3134
3139
3130
3149
3154
3138
3150
3153
2900–2512
2908–2516
2880–2540
2916–2538
2946–2532
3033–2506
3041–2506
3015–2514
3020–2524
–
–
–
–
–
–
–
–
–
1669
1677
1667
1656
1671
1679
1671
1670
1679
1630
1638
1628
1630
1620
1629
1620
1622
1620
1420
1425
1412
1406
1431
1416
1419
1422
1422
1460
1452
1442
1451
1441
1450
1432
1446
1440
249
255
255
250
240
263
252
248
252
170
186
186
179
179
179
188
176
180
930
928
931
930
929
–
–
–
–
923
930
927
929
933
–
–
–
–
–
–
–
–
–
–
–
–
–
538
538
556
539
544
536
562
537
553
–
–
–
–
–
–
–
–
–
436
467
462
456
430
456
478
430
470
which is a shift of ∼80 cm−1 towards lower energies than ligand
acids (249–255 cm−1 ). This further supports ligand coordination
with the Sn center in bidentate fashion, thus rendering octahedral
geometry to these compounds in the solid state.[17] The band
associated with ν(Sn–C) vibration was located in the region
538–562 cm−1 .[18]
NMR Spectroscopy
Appl. Organometal. Chem. 2011, 25, 412–419
c 2011 John Wiley & Sons, Ltd.
Copyright wileyonlinelibrary.com/journal/aoc
415
The 1 H NMR resonances were assigned on the basis of chemical
shifts, multiplicities and coupling constants. 1 H NMR data is
given in Table 3. The total numbers of protons calculated were
in agreement with the expected molecular composition. The
resonances have been assigned for all protons, as shown in
Scheme 4. However, multiplets are observed in some cases. In
compounds 1–5, the protons of the aromatic ring having 2,3methylenedioxy group appeared as two doublets (6.26–6.34 and
6.62–6.74 ppm) and a triplet (6.47–6.58 ppm). Methylene protons
of OCH2 O resonate as singlets at downfield (5.90–5.92 ppm) with
no 119 Sn, 1 H coupling satellites that confirmed noncoordination of
this site to tin atom. In ligands with flouro groups directly attached
M. Hussain et al.
Table 3.
1
H NMR data of ligand acids (HL1 –HL9 ) and complexes 1–9
H
HL1
HL2
HL3
HL4
HL5
HL6
HL7
HL8
HL9
3
5
5
6
6
7
9
10
11
12
13
14
15
1H
3
5
5
6
6
7
9
10
11
12
13
14
15
α
10.12 (s)
7.33 (s)
7.19 d(8.0)
7.19 d(8.0)
7.30 dd(8.1)
7.30 dd(8.1)
–
6.77 d(7.2)
6.54 t(8.1)
6.34 d(8.1)
–
–
6.0 (s)
–
Complex 1
8.10 (s)
7.10 d(8.5)
7.10 d(8.5)
7.30 dd(8.1)
7.30 dd(8.1)
–
6.73 d(7.5)
6.58 t(8.1)
6.26 d(8.1)
–
–
5.92 (s)
–
1.75 q(7.9) [92]
1.37 t(8.0)
9.98 (s)
8.05 (s)
7.23 d(8.4)
7.23 d(8.4)
7.38 d(8.4)
7.38 d(8.4)
–
6.74 d(7.8)
6.58 t(8.1)
6.27 d(8.1)
–
–
5.95 (s)
–
Complex 3
8.02 (s)
7.23 d(8.4)
7.23 d(8.4)
7.34 d(8.4)
7.34 d(8.4)
–
6.71 d(7.6)
6.54 t(8.0)
6.30 d(8.1)
–
–
5.90 (s)
–
1.73 q(8.1)
[67]
1.39 t(8.0)
11.2 (s)
7.95 (s)
7.25 d(8.4)
7.25 d(8.4)
7.59 d(8.7)
7.59 d(8.7)
–
6.79 d(9.0)
6.59 t(8.1)
6.29 d(8.1)
–
–
6.01 (s)
–
Complex 4
8.08 (s)
7.18 d(8.1)
7.18 d(8.1)
7.52 d(8.4)
7.52 d(8.4)
–
6.74 d(7.5)
6.57 t(8.1)
6.32 d(8.1)
–
–
5.92 (s)
–
1.73 q(7.8)
[76]
1.36 t(8.0)
10.76 (s)
8.01 (s)
7.17 d(8.0)
7.17 d(8.0)
6.97 d(7.5)
6.97 d(7.5)
–
6.83 d(8.1)
6.77 t(7.8)
6.44 d(7.6)
–
–
6.01 (s)
3.73 (s)
Complex 5
7.95 (s)
7.13 d(8.7)
7.13 d(8.7)
6.77 d(7.7)
6.77 d(7.7)
–
6.62 d(7.7)
6.47 t(8.0)
6.26 d(8.2)
–
–
5.91 (s)
3.76 (s)
1.63 q(7.9)
β
9.98 (s)
8.15 (s)
–
7.14–7.41 (m)
7.14–7.41 (m)
7.14–7.41 (m)
7.14–7.41 (m)
6.55 d(7.5)
6.30 t(8.0)
6.28 t(8.1)
–
–
5.92 (s)
–
Complex 2
8.14 (s)
–
7.01–7.37 (m)
7.01–7.37 (m)
7.01–7.37 (m)
7.01–7.37 (m)
6.70 d(7.5)
6.55 t(8.0)
6.34 t(8.1)
–
–
5.92 (s)
–
1.75 q(8.0)
[76]
1.37 t(7.8)
10.36 (s)
7.98 (s)
7.14 d(8.4)
7.14 d(8.4)
7.49 dd(8.7)
7.49 dd(8.7)
–
7.18–7.28 (m)
7.18–7.28 (m)
–
7.18–7.28 (m)
7.18–7.28 (m)
–
–
Complex 6
8.02 (s)
7.10 d(8.4)
7.10 d(8.4)
7.48 dd(8.7)
7.48 dd(8.7)
–
7.18–7.26 (m)
7.18–7.26 (m)
–
7.18–7.26 (m)
7.18–7.26 (m)
–
–
1.78 q(8.1)
[79]
1.39 t(8.1)
–
8.16 (s)
6.90 d(8.1)
6.90 d(8.1)
6.76 d(7.8)
6.76 d(7.8)
–
7.01–7.24 (m)
7.01–7.24 (m)
7.01–7.24 (m)
7.01–7.24 (m)
–
2.18 (s)
–
Complex 7
8.01 (s)
6.80 d(8.0)
6.80 d(8.0)
6.70 d(7.6)
6.70 d(7.6)
–
7.01–7.16 (m)
7.01–7.16 (m)
7.01–7.16 (m)
7.01–7.16 (m)
–
2.29 (s)
–
1.72 q(8.0)
[72]
1.32 t(8.0)
10.48 (s)
8.19 (s)
6.79 d(7.5)
6.79 d(7.5
6.94 dd(6.0)
6.94 dd(6.0)
–
7.15–7.21 (m)
7.15–7.21 (m)
7.15–7.21 (m)
7.15–7.21 (m)
–
2.41 (s)
–
Complex 8
8.21 (s)
6.99 d(7.5)
6.99 d(7.5)
6.81 dd(8.7)
6.81 dd(8.7)
–
7.12–7.22 (m)
7.12–7.22 (m)
7.12–7.22 (m)
7.12–7.22 (m)
–
2.29 (s)
–
1.82 q(8.7)
[71]
1.45 t(7.9)
9.30
7.94 (s)
7.0–7.28 (m)
7.0–7.28 (m)
7.0–7.28 (m)
–
7.0–7.28 (m)
7.32 d(7.5)
7.46 d(8.4)
–
7.46 d(8.4)
7.32 d(7.5)
–
2.36 (s)
Complex 9
7.88 (s)
6.69–7.11 (m)
6.69–7.11 (m)
6.69–7.11 (m)
–
6.69–7.11 (m)
7.19 d(7.4)
7.35 d(8.2)
–
7.35 d(8.2)
7.19 d(7.4)
–
2.24 (s)
1.60 q(7.5)
[68]
1.18 t(7.2)
1.27 t(7.9)
Scheme 4. Numbering scheme of ligand acids (HL1 –HL9 ) and compounds 1–9.
416
to the aromatic ring, doublets of doublets were observed but in
compounds 1, 6 and 8, the protons of the aromatic ring close
to the flouro group demonstrated a doublet of doublet owing to
participation of the fluoro group in coupling as well. The proton
chemical shift values for diethyl moieties were straightforward
from the multiplicity pattern and 2 J(119 Sn-1 H) coupling constant
values. The CSnC angles (148.2–117◦ ) calculated by Lockhart’s
equation[22] supports a five-coordinate environment around Sn
wileyonlinelibrary.com/journal/aoc
in complexes 2–4 and 6–9.[23] The tendency of going from sixcoordination to five may be due to the fluxional behavior as shown
in Scheme 5. Compound 1 maintained its solid-state octahedral
geometry even in solution, as evident from the 2 J [119 Sn, 1 H]
coupling value.[16]
13 C NMR spectral data in CDCl solution resolved the resonances
3
corresponding to the magnetically nonequivalent carbon atoms.
The aromatic carbon resonances were assigned by the comparison
c 2011 John Wiley & Sons, Ltd.
Copyright Appl. Organometal. Chem. 2011, 25, 412–419
Structural studies of diethyltin(IV) derivatives
Scheme 5. Fluxional behavior of compounds 2–4 and 6–9.
Figure 1. Ortep diagram of compound (8) with numbering scheme and secondary interactions.
of experimental chemical shifts with those calculated from the
incremental method.[24] In order to gain further information
about the possible coordination geometries in solution, a close
examination of the 1 J[119 Sn,13 C] was undertaken. On the basis of
the calculated 1 J[119 Sn,13 C] values, a skew trapezoidal geometry
was assignable to compound 1, whereas compounds 2–9
exhibited a five-coordinated environment around the Sn atom
[23].
In 119 Sn NMR spectra, the presence of a single peak for
all compounds confirmed the formation of single species.
In compounds 2–9 the 119 Sn value ranged from −75 to
−166.7 ppm authenticated penta-coordinated Sn atom.[16,23] The
119 Sn resonance for 1 at −235.4 ppm, matched well with bidentate
coordination of the two ligands which in turn rendered octahedral
geometry around Sn.[23] These values strongly depend upon the
nature and the orientation of organic groups bonded to tin.
The shifts observed in the tested compounds can be explained
quantitatively in terms of an increase in electron density on the tin
atom as the coordination number increases.
The 13 C chemical shift data elucidated fluoro substituent
chemical shift values in the aromatic system studied in our
work. In compounds 1, 2 and 6, the aromatic carbons appeared
further downfield (161.8–164.3 ppm) than expected owing to the
presence of electron-withdrawing fluoro group. Moreover, 1 J[19 F,
13 C], 2 J[19 F, 13 C] and 3 J[19 F, 13 C] coupling values were in the ranges
245–247, 21–22 and 7–8 Hz, respectively, in these compounds.[25]
In 19 F NMR, compounds 1, 2, 6 and 8 fluorine resonance were
observed in the range −114.0 to −114.3 ppm and fluoro groups
of CF3 group appeared at −63.4 ppm (6 and 9).
X-ray Crystallography
Appl. Organometal. Chem. 2011, 25, 412–419
C36 H34 Cl2 O4 Sn1
Empirical formula
Formula weight
Crystal system
Space group
Unit cell dimensions
A (Å)
B (Å)
C (Å)
α (deg)
β (deg)
γ (deg)
V (Å 3 )
Z
Dc (g cm−3 )
Crystal size (mm)
F(000)
Total reflections
Independent reflections
R indices (all data)
Final R indices [I > 2σ (I)]
Goodness-of-fit
Theta range for data collection (deg)
720.26
Triclinic
P−1
11.101(2)
11.247(2)
13.805(3)
73.054(5)
74.136(6)
80.308(10)
1578.57(5)
2
1.52
0.20 × 0.25 × 0.38
732
13 572
7227
R1 = 0.084, wR2 = 0.214
R1 = 0.074, wR2 = 0.198
0.963
3.176–27.494
C–Sn–C angle is 141.78(14)◦ . The four oxygen atoms occupy
the corners of the trapezoidal plan coordinated with the Sn
atom in an anisobidentate fashion with two shorter and two
longer tin–oxygen bonds [Sn–O = 2.135(18) Å and Sn· · ·O =
2.462(18) Å; and Sn–O = 2.120(18) Å and Sn· · ·O = 2.540(18) Å)].
The short Sn–O bonds are close to the covalent radii of tin
and oxygen atoms but the longer Sn–O bonds are significantly
smaller than the sum of van der Waals radii of the two atoms
(3.68 Å). These Sn–O and Sn· · ·O values agree well with early
reports.[22] Asymmetric coordination of the two ligands is also
reflected in C–O bonds; the oxygen with the longer Sn–O bond
c 2011 John Wiley & Sons, Ltd.
Copyright wileyonlinelibrary.com/journal/aoc
417
The molecular structure of 8 is shown in Fig. 1. The most
relevant crystallographic data and selected geometric parameters
are summarized in Tables 4 and 5. The Sn center is hexacoordinate having a skew-trapezoidal geometry, in which the
axial positions are occupied by two ethyl groups and four
oxygen atoms of the carboxylic group are at the plan positions.
Owing to steric reasons and electronic repulsion, ethyl groups
cannot occupy the exact trans positions to one another and the
Table 4. Crystal data and structure refinement parameters for
complex 8
M. Hussain et al.
Table 5. Selected bond lengths (Å) and bond angles (deg) of complex
8
Bond lengths (Å)
Sn1–O4
Sn1–O5
Sn1–O8
Sn1–O10
O4–C13
Sn1–C25
Sn1–C32
F2–C35
O8–C13
O5–C9
2.135(18)
2.540(18)
2.462(18)
2.120(18)
1.303(3)
2.122(3)
2.124(3)
1.367(3)
1.239(3)
1.240(3)
Bond angles (deg)
O4–Sn1–O5
O4–Sn1–O8
O5–Sn1–O8
O4–Sn1–C9
C9–O5–Sn1
C13–O8–Sn1
C13–O4–Sn1
C9–O5–Sn1
C9–O10–Sn1
C25–Sn1–O5
136.43(7)
56.29(7)
167.16(7)
110.12(12)
83.64(15)
85.72(15)
99.20(16)
83.64(15)
101.28
83.87(9)
Table 6. Antitumor activities of diethyltin(IV) esters of potential
ligandsa
Test agents
1
2
3
4
5
6
Vincristine
DMSO
Average number
of tumors ± SE
3.9 ± 0.56
2.8 ± 2.77
2.3
0.0
6.3
0.0
0.0 ± 0.0
7.6 ± 0.686
Percentage inhibition
of tumors
80.1
73.4
66.6
100
10.0
100
100
–
Potato disk antitumor assay, concentration: 1000 µg ml−1 in DMSO.
More than 20% tumor inhibition is significant. Data represent mean
value of 15 replicates.
a
418
is associated with the shorter C–O bond and vice versa. The
molecular structure of compound 8 is mediated by intermolecular
Sn· · ·O and F· · ·H interactions. The presence of intermolecular
Sn· · ·O interactions presumably has three causes: (a) the presence
of small ethyl groups allows close contact of the molecules; (b) the
ethyl groups are bent towards one side of the octahedral plan,
which provides enough room for oxygen atoms to interact with
Sn; and (c) the electron-withdrawing oxygen atoms make the Sn
electron deficient. It can be observed from the structure that ligand
in the title compound exists in E configuration, in agreement with
earlier reports.[26,27] This can be confidently interpreted for all
ligands and complexes.
wileyonlinelibrary.com/journal/aoc
Biological Studies
Antitumor Assay
For antitumor activity, Crown gall tumor inhibition assay[28] was
performed for all these synthesized compounds (1–5). In this
assay, potato disks (0.5 cm thickness) were obtained from surfacesterilized potatoes using a metallic cork borer and special cutter
under completely aseptic conditions. These potato disks were
then transferred to Petri plates each containing 25 ml of 1.5% agar
solution. Then 0.5 ml of stock (10 mg ml−1 ) of the test sample was
added to 2 ml of a broth culture of Agrobacterium tumefaciens
strain At-10 (48 h culture containing 5 × 109 cells ml−1 ) and 2.5 ml
of autoclaved distilled water was added to make 1000 ppm final
concentration. One drop of these cultures was poured on each
potato disk. The Petri plates were incubated at 28 ◦ C. After 21 days
incubation, the number of tumors was counted with the aid of
a dissecting microscope after staining with Lugol’s solution (10%
KI, 5% iodine). the following formula was used to determine the
percentage inhibition of each concentration:
percentage inhibition = 100
− [no. of tumors with sample/no. of tumors with control
× 100]
The antitumor potato disk assay was performed for diethyltin(IV)
derivatives of substituted phenylacrylic acids using Agrobacterium
tumefacien (At-10) and results are summarized in Table 6. The
activity decreased in the sequence: 4 ≈ 6 > 1 > 2 >
3 > 5. These complexes exert their toxic action presumably
by interacting with the DNA in intercalative mode. In such
interactions the compound makes noncovalent contacts with
DNA bases that cause unwinding of the local structure of
DNA and thus culminates in the damage of the DNA storage,
transcription and genetic transformation machinery.[12] The
proposition of such kind of mechanism is based on the capability
of these compounds to form noncovalent interactions (Fig. 2)
and our recent investigations on the mechanism of organotin(IV)
derivatives by cyclic voltammetry.[13] The high activity for 4 may
be due to the highly polarizable bromo group whereas the high
activity for 6 can be attributed to the presence of four fluoro groups
that can make strong hydrogen bonds with the DNA bases. The
lower activity of 2 than 1 can be explained by the steric effect of
the closely associated COO group which partially masks the fluoro
group involved in hydrogen bonding. The higher activity of 3 than
5 is presumably due to the presence of the chloro group, which
can interact strongly with the DNA bases as compared with the
methoxy group.
Conclusions
The antitumor activities of the complexes are, in broader terms,
excellent and far exceed the level for free ligands. The influence of
the metal is clearly visible. The activity is maximized for complexes
4 and 6, although all organotin complexes have reasonable activity.
This study provides a further step in designing potent plant tumor
inhibitors.
Acknowledgments
Thanks to the Higher Education Commission of Pakistan (HEC) for
financial support.
c 2011 John Wiley & Sons, Ltd.
Copyright Appl. Organometal. Chem. 2011, 25, 412–419
Structural studies of diethyltin(IV) derivatives
Figure 2. Closed packing diagram of compound (7).
Supplementary Information
Supporting information can be found in the online version of
this article. Crystallographic data for the structural analysis have
been deposited with the Cambridge Crystallographic Data Centre,
CCDC no. 699543 for complex 8. Copies of these information
may be obtained on request from the Director, CCDC, 12 Union
Road, Cambridge CBZ 1EZ, UK (Fax: +44-1223-336033; email:
deposit@ccdc.cam.ac.uk or www: http://www.ccdc.cam.ac.uk).
References
[1] M. Gielen, Appl. Organomet. Chem. 2002, 16, 481.
[2] M. Gielen, M. Biesemans, D. De Vos, R. Willem, J. Inorg. Biochem.
2000, 79, 139.
[3] a) M. Gielen, M. Biesemans, R. Willem, Appl. Organomet. Chem. 2005,
19, 440; b) V. I. Bregadze, S. A. Glazun, P. V. Petrovskii, Z. A. Starikova,
V. Y. Rochev, H. Dalil, M. Biesemans, R. Willem, M. Gielen, D. de Vos,
Appl. Organomet. Chem. 2003, 17, 453.
[4] M. Gielen, E. R. T. Tiekink, in Metallotherapeutic Drug and Metalbased Diagnostic Agents: 50 Sn Tin Compounds and Their Therapeutic
Potential (Eds.: M. Gielen, E. R. T. Tiekink), Wiley: Chichester, 2005,
p. 421.
[5] M. Gielen, A. G. Davies, K. Pannell, E. R. T. Tiekink (Eds.), Tin Chemistry:
Fundamentals, Frontiers and Applications, Wiley: Chichester, 2008,
p. 413.
[6] M. Hanif, M. Hussain, S. Ali, M. H. Bhatti, M. S. Ahmad, B. Mirza,
H.S. Evans, Polyhedron 2010, 29, 613.
[7] M. S. Ahmad, M. Hussain, M. Hanif, S. Ali, M. Qayyum, B. Mirza, Chem.
Biol. Drug Des. 2008, 71, 568.
[8] M. S. Ahmad, B. Mirza, M. Hussain, M. Hanif, S. Ali, M. J. Walsh,
F. L. Martin, PMC Biophysics 2008, 1(3), 1.
[9] M. Hanif, M. Hussain, S. Ali, M. H. Bhatti, M. S. Ahmad, B. Mirza,
H. S. Evans, Turk J. Chem. 2007, 31, 349.
[10] M. Hussain, M. S. Ahmad, A. Siddique, M. Hanif, S. Ali, B. Mirza, Chem.
Biol. Drug Des. 2009, 74, 183.
[11] M. S. Ahmad, M. Hussain, M. Hanif, S. Ali, B. Mirza, Molecules 2007,
12, 2348.
[12] Zia-ur Rehman , A. Shah, N. Muhammad, S. Ali, R. Qureshi,
A. Meetsma, I. S. Butler, Eur. J. Med. Chem. 2009, 44, 3986.
[13] Zia-ur-Rehman , A. Shah, N. Muhammad, S. Ali, R. Qureshi,
I. S. Butler, J. Organomet. Chem. 2009, 694, 1998.
[14] N. Muhammad, Zia-ur-Rehman , S. Ali, A. Meetsma, F. Shaheen,
Inorg. Chim. Acta 2009, 362, 2842.
[15] N. Muhammad, A. Shah, Zia-ur-Rehman , S. Shuja, S. Ali, R. Qureshi,
A. Meetsma, M. N. Tahir, J. Organomet. Chem. 2009, 694, 3431.
[16] C. Pettina, M. Pellei, F. Marchetti, C. Santina, M. Miliani, Polyhedron
1998, 17, 561.
[17] M. Hussain, M. Zaman, M. Hanif, S. Ali, M. Danish, J. Serb. Chem. Soc.
2008, 73(2), 179.
[18] M. Hussain, M. Hanif, S. Ali, S. Shahzadi, M. S. Ahmad, B. Mirza,
H. S. Evans, J. Coord. Chem. 2009, 62(13), 2229.
[19] W. L. F. Armarego, C. L. L. Chai, Purification of Laboratory Chemicals,
6th edn, Butterworth-Heinemann: London, 2008, p. 61.
[20] P. L. Chen, C. C. Cheng, J. Med. Chem. 1970, 13, 867.
[21] D. E. Nicholas, W. K. Brewster, M. P. Johnson, R. Oberlender, R. M.
Riggs, J. Med. Chem. 1990, 33, 703.
[22] T. P. Lockhart, W. F. Manders, E. M. Holt, J. Am. Chem. Soc. 1986, 108,
6611.
[23] Imtiaz-ud-Din , M. Mazhar, K. C. Molloy, K. M. Khan, J. Organomet.
Chem. 2006, 691, 1643.
[24] H. O. Kalinowski, S. Berger, S. Braun. 13 C-NMR-Spektroskopie, Georg
Thieme: Stuttgart 1984, p. 283.
[25] M. Gielen, A. El Khloufi, M. Biesemans, F. Kayser, R. Willem, Appl.
Organomet. Chem. 1993, 7, 201.
[26] M. Hussain, S. Ali, T. Zahur, M. Hanif, H. S. Evans, Acta Crystallogr. E
2006, E62, o4618.
[27] M. Hussain, M. Hanif, S. Ali, M. Altaf, H.S. Evans, Acta Crystallogr. E
2006, E62, o5020.
[28] A. Rehman, M. I. Choudhary, W. J. Thomsen, Bioassay Techniques for
Drug Development, Harwood Academic: Amsterdam, 2001, p. 62.
419
Appl. Organometal. Chem. 2011, 25, 412–419
c 2011 John Wiley & Sons, Ltd.
Copyright wileyonlinelibrary.com/journal/aoc
Документ
Категория
Без категории
Просмотров
0
Размер файла
282 Кб
Теги
potential, structure, tumefaciens, aspects, biological, agenti, diethyltin, agrobacterium, studies, derivatives, antitumor, cells
1/--страниц
Пожаловаться на содержимое документа