Diorganotin(IV) derivatives of N-methyl p-fluorobenzo-hydroxamic acid: Preparation, spectral characterization, X-ray diffraction studies and antitumor activity

Article abstract of DOI:10.3390/molecules18078696

Three diorganotin(IV) complexes of the general formula R2Sn[RcC(O)N(RN)O] (Rc = aryl, RN = Alkyl) have been synthesized by refluxing in toluene the corresponding diorganotin(IV) oxides with the free ligand N-methyl p-fluorobenzohydroxamic acid, using a Dean and Stark water separator. The ligand was derived from the reaction of the corresponding p-fluorobenzoyl chloride and N-methylhydroxylamine hydrochloride in the presence of sodium hydrogen carbonate. The isolated free ligand and its respective diorganotin compounds have been characterized by elemental analysis, IR and 1H-, 13C-, 119Sn-NMR spectroscopies. The crystal structures of the diorganotin complexes have been confirmed by single crystal X-ray diffraction methods. The investigations carried out on the diorganotin(IV) complexes of N-methyl p-fluorobenzohydroxamic acid confirmed a 1:2 stoichiometry. The complex formation took place through the O,O-coordination via the carbonyl oxygen and subsequent deprotonated hydroxyl group to the tin atom. The crystal structures of three diorganotin complexes were determined and were found to adopt six coordination geometries at the tin centre with coordination to two ligand moieties.

Full text of DOI:10.3390/molecules18078696

Molecules 2013, 18, 8696-8711; doi:10.3390/molecules18078696
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Diorganotin(IV) Derivatives of N-Methyl p-Fluorobenzo-
Hydroxamic Acid: Preparation, Spectral Characterization,
X-ray Diffraction Studies and Antitumor Activity
Naqeebullah 1,2, Yang Farina 1,*, Kok Meng Chan 3, Lo Kong Mun 4, Nor Fadilah Rajab 5 and
Theng Choon Ooi 5
1
School of Chemical Sciences and Food Technology, Faculty of Science & Technology,
Universiti Kebangsaan Malaysia, 43600 Bangi, Selangor Darul Ehsan, Malaysia
2
Department of Chemistry, Faculty of Basic Sciences, University of Balochistan,
87300 Sariab Road Quetta, Pakistan
3
Environmental Health Programme, Faculty of Allied Health Sciences, Universiti Kebangsaan Malaysia,
Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia
4
Department of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia
5
Biomedical Science Programme, Faculty of Health Sciences, Universiti Kebangsaan Malaysia,
Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia
* Author to whom correspondence should be addressed; E-Mail: farina@ukm.my;
Tel.: +601-3388-5492; Fax: +603-8921-5410.
Received: 23 May 2013; in revised form: 15 July 2013 / Accepted: 16 July 2013 /
Published: 22 July 2013
Abstract: Three diorganotin(IV) complexes of the general formula R2Sn[RcC(O)N(RN)O]
(Rc = aryl, RN = Alkyl) have been synthesized by refluxing in toluene the corresponding
diorganotin(IV) oxides with the free ligand N-methyl p-fluorobenzohydroxamic acid, using
a Dean and Stark water separator. The ligand was derived from the reaction of the
corresponding p-fluorobenzoyl chloride and N-methylhydroxylamine hydrochloride in the
presence of sodium hydrogen carbonate. The isolated free ligand and its respective
1
13
diorganotin compounds have been characterized by elemental analysis, IR and H-, C-,
119Sn-NMR spectroscopies. The crystal structures of the diorganotin complexes have been
confirmed by single crystal X-ray diffraction methods. The investigations carried out on
the diorganotin(IV) complexes of N-methyl p-fluorobenzohydroxamic acid confirmed a 1:2
stoichiometry. The complex formation took place through the O,O-coordination via the
carbonyl oxygen and subsequent deprotonated hydroxyl group to the tin atom. The crystal

Molecules 2013, 18
structures of three diorganotin complexes were determined and were found to adopt six
8697
coordination geometries at the tin centre with coordination to two ligand moieties.
Keywords: organotin; hydroxamic acid; X-ray diffraction; antitumor activity
1. Introduction
Hydroxamic acids [1], RcC(O)N(RN)OH (Rc = alkyl/aryl; RN = alkyl/aryl or H), have been the
source of much biochemical interest in recent years reflecting the fact that they demonstrate a wide
variety of biological activities. Much of their activities are due to their chelating properties with metal
ions, especially with transition metals, hence constituting a very important class of chelating agents
with versatile biological activities [2,3]. The principal coordination mode observed in metal-hydroxamic
acid complexes is the O,O-bidentate chelation in which the ligand is either singly deprotonated
(hydroxamato) or doubly (RN = H) deprotonated (hydroximato) [4]. A number of synthetic routes are
available for the preparation of hydroxamic acids [5–10], but some of them are tedious, time consuming
and also costly. The reasonable way of producing hydroxamic acid derivative is the reaction of
hydroxylamine with acid chlorides or esters [11]. Hydroxamic acids are capable of the inhibition of a
variety of enzymes, including ureases [12,13], peroxidases [14], and matrix metalloproteinases
(MMP) [15,16] and are also capable of competing as siderophores for iron-(III) [17,18]. These
compounds are used in the design of therapeutics targeting cancer [19,20], cardiovascular
diseases [21], HIV [22], Alzheimer’s [23], malaria [24,25], and allergic diseases [26].
Organotin(IV) complexes with bidentate O-donor ligands [27], including N-substituted hydroxamic
acids, are well known and have been a continuing subject of study in the recent years [28],
highlighting the synthesis of a number of complexes with interesting properties [29–31]. Moreover,
some of the diorganotin(IV) hydroxamates have been structurally characterized by X-ray diffraction
studies, which are well documented in the literature [32–34]. Organotin compounds are widely studied
class of organometallic compounds with, broad spectrum of applications, being used in antifouling
paints [35], as homogeneous catalysts [36] and in agriculture that give rise to ubiquitous environmental
contamination [37,38]. The biological activity of organotin compounds is predominantly determined
by the number and nature of organic groups linked to the central tin atom and generally decreases in
the following order: R3Sn+ > R2Sn2+ > RSn3+ [29,39–41]. In addition, the increasing interest in the
chemistry of organotin(IV) compounds has led to the extended studies against cancer [42,43].
The structural and biological diversity of organotin hydroxamates stirred our interest to further
illustrate the coordination chemistry and anti-proliferative activity of organotin compounds with
hydroxamic acid, herein we report the synthesis of a new ligand N-methyl p-fluorobenzohydroxamic
acid (LH) and its diorganotin(IV) derivatives (CH3)2SnL2, (C4H9)2SnL2 and (C6H5)2SnL2 with interesting
structural features to expand their scope.

Molecules 2013, 18
8698
2. Results and Discussion
2.1. Synthesis
The ligand was prepared by the reaction of p-fluorobenzoyl chloride with N-methyl-hydroxylamine
hydrochloride in the presence of sodium hydrogen carbonate as catalyst. All the reagents were in the
same ratio by weight (i). Diorganotin(IV) complexes were synthesized in 2:1 molar ratio, by refluxing
the free ligand with diorganotin(IV) oxides in hot toluene for 5–6 h with stirring and the water formed
was removed azeotropically using a Dean-Stark apparatus (ii), as summarized in Scheme 1. The
resulting solution was cooled and filtered and the solvent evaporated. The solid was precipitated by
adding petroleum ether (60–80 °C) and then recrystallized from ethanol. The purity of the ligand and
the diorganotin complexes were assured by TLC analysis using silica gel-G as adsorbent.
Scheme 1. A general reaction scheme of the free ligand (i) and its diorganotin(IV)
complexes (ii).
O
O
C
OH
C
Cl
N
NaHCO3
+
CH3NHOH.HCl
+
2HCl
CH3OH/ 0oC
CH3
F
F
N-methyl p-fluorobenzohydroxamic acid
(i)
+
R2SnO
Toluene
H3C
R
O
O
C
F
N
Sn
H2O
+
N
F
C
O
O
R
CH3
(ii)
R= CH3, C4H9 and C6H5
The newly synthesized ligand and its diorganotin complexes are white or colorless solids, stable in
air and soluble in common organic solvents. Tin was determined gravimetrically, by igniting a known
quantity of each complex. The calculated values were in a good agreement with the experimental values.
2.2. Infra-Red Spectroscopy
Solid state infrared spectra of the N-methyl p-fluorobenzohydroxamic acid and its complexes have
been recorded in the range 4,000–400 cm−1. The principal infrared absorption bands are those due to
ν(O-H), ν(C=O), ν(C-N) and ν(N-O) stretching vibrations of the hydroxamate group observed in the

Molecules 2013, 18
8699
spectrum of free hydroxamic acid at 3,175, 1,610, 1,432 and 908 respectively. The ν(O-H) band is
observed in the range 3,175 cm−1 appeared as a broad band indicating the presence of extensive
hydrogen bonding. The characteristic band ν(C=O) positioned within the range 1,610 cm−1 is notably,
below the usual ketonic ν(C=O) range of 1,650 cm−1 [44,45], indicates that in the solid state the ligand
exist in the keto form.
The IR spectra of the free ligand and its diorganotin(IV) complexes illustrated clear differences. In
all cases, (O-H) stretching modes were absent in the spectra of the complexes, thus suggesting the
deprotonation of the hydroxamate group on complexation, Similarly, the (C=O) group are shifted to
lower frequencies in the range 1,599–1,602 cm−1, indicating a further shift of (C=O) to lower energy
thus suggesting the predominance of the enolic form to give a five membered chelate rings at the tin
centre. Moreover, the (N-O) stretching vibrations occurring at 938–948 cm−1 in the diorganotin(IV)
hydroxamates, are shifted to higher frequencies, excluding the coordination via the nitrogen atom [46].
The occurrence of (Sn-O) in the range of 474–453 cm−1 indicates the chelation of the tin centre to the
enolate oxygen [45,47].
2.3. NMR Spectroscopy
1H-NMR spectra for the investigated ligand and their organotin(IV) complexes have been recorded
1
in CDCl3 solution and tetramethylsilane as internal standard at room temperature. In the H-NMR
spectra the free ligand show a signal at 10.34 ppm, which is due to the intramolecularly hydrogen
1
bonded hydroxyl proton. The peak disappeared in the H-NMR spectra of the complexes indicating,
thereby, the substitution of the hydroxyl proton and chelation of the oxygen to the tin atom. The proton
signals appearing in the region 3.40 ppm were attributed to methyl protons attached to the nitrogen
atom, which remained unchanged on chelation, supporting further, the non-involvement of this group
in complexation. In the dimethyltin(IV) derivative, the proton resonances appeared as a singlet in the
region 0.713 ppm, with well-defined satellites. The value of the two bond coupling constant 2J(119Sn-1H)
1
calculated from tin satellites in the H-NMR spectra of dimethyltin(IV) complex was found in the
region of 84.22 Hz, and the estimated C-Sn-C bond angle is 136.4°, based on the equation of Lockhart
and Manders [Equation (1)] [48], which fall in the region for six-coordinate tin [49]. In the dibutyltin(IV)
complex, the butyl protons were found as a multiplet and a triplet in the regions 1.36–1.84 ppm and
0.88 ppm due to -(CH2)3 and the terminal CH3 respectively. A complex multiplet found at 8.17–8.32 ppm
for the aromatic protons of the free ligand and all complexes, is due to the overlapping of the signals of
the aromatic protons of the ligand and phenyl group protons in diphenyltin(IV) complex [50,51].
θ(C-Sn-C) = 0.0161(2J Sn-H)2 – 1.32 (2J Sn-H) + 133.4
(1)
13C-NMR spectra for the investigated ligand and its organotin(IV) complexes have been recorded in
CDCl3 solution and tetramethylsilane as internal standard at room temperature. 13C-NMR chemical
shifts in every complex showed the expected resonances with appropriate multiplicities and intensities
and the spectra are generally in agreement with the results drawn from 1H-NMR signals. The carbonyl
(C=O) signal appeared at 165.0 ppm in free ligand and were shifted upfield in the corresponding
complexes (164.9–161.3ppm), indicating a decrease in electron density at the carbon atom when
oxygen atom is chelated to the tin atom. The methyl carbon attached to the nitrogen appears at

Molecules 2013, 18
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38.37–40.98 ppm. In dimethyltin (IV) complex, the methyl carbon attached to the tin appeared
1
at 6.57 ppm and the observed 119Sn satellites in 13C-NMR spectrum provide J(13C-119Sn) coupling
constant value 785.27 Hz, and the estimated C-Sn-C bond angle is 145.7°, based on the equation of
Lockhart and Manders [Equation (2)] [48], which is of the same order of magnitude of those observed
in hexa-coordinate organotin(IV) compounds. The butyl carbons attached to the tin in dibutyltin(IV)
complex appeared at 13.85, 26.63, 26.85 and 27.44 ppm. The signals appeared at 115–163 ppm, were
assigned to the aromatic carbons. By comparing the 13C-NMR spectra of the free ligand with its
diorganotin (IV) complexes, a slight upfield shift has been observed in the position of carbonyl signal,
suggesting the bidentate nature of hydroxamate group. One can notice that the oxygen chelated to metal ion
reduce the electron density at carbon atom, hence considered the cause for chemical shift [52,53].
(1J Sn-C) = 11.4 θ − 875
(2)
The 119Sn-NMR spectra of diorganotin(IV) complexes studied herein in DMSO, at room temperature.
The 119Sn-NMR chemical shifts of organotin(IV) compounds appear to depend not only on the
coordination number, on the other hand also on the alkyl groups bound to the metal ion and the types
of donor atoms [54]. The spectra show one sharp signal in dimethyl-, dibutyl- and diphenyltin
complexes at ꢀ = −407 ppm, −367 ppm and −205 ppm respectively, which strongly supports the six
coordination around tin in a distorted octahedral geometry [55–57]. In the later an associated structure
such as the stereoisomers specie is thus present in solution similar to spectra have reported by [56,58].
2.4. X-ray Crystallography
The crystal structure of compound (1), (2) and (3) are shown in Figures 1–3, respectively. Selected
bond angles and bond lengths are presented in Tables 1 and 2. The molecular structures of these
diorganotin complexes showed that the tin atom is bonded to two N-methyl-p-fluorobenzohydroxamic
acids via the hydroxyl oxygen and the carbonyl oxygen [30,59]. The two organic groups of the
diorganotin fragment complete the six coordination geometry at tin for the three complexes. It is
evident that the carbonyl oxygen are weakly coordinated to the tin compared to the covalent
Sn-Ohydroxyl bonds [compound (1): Sn-O1 2.0921(9), 2.0921(9) and Sn-O2 2.3778(9), 2.3778(9);
compound (2): Sn-O1: 2.117(3), 2.132(3) and Sn-O2 2.356(3), 2.407(3); compound (3): Sn-O1
2.110(2), 2.103(2) and Sn-O2 2.221(2), 2.183(2)]. The bond distances and angles of the three complexes
as given in Tables 1 and 2 revealed that the geometry of the crystals is distorted octahedral around the
six coordinated tin(IV) ion, similar to the diphenyltin(IV) bis(N-methyl p-bromobenzohydroxamate) [27]
and di-n-butyl-(4-chlorobenzo-hydroxamato)tin(IV) [60]. The distortion in the coordination sphere of
the metal ion from the ideal geometry may be due to the structural constraints imposed by the
hydroxamic acid ligand framework. The ligand bite angles O1-Sn-O2 at tin for the three complexes are
small with the values of 71.22(3)°, 71.23(3)° for (1), 70.36(9)°, 71.96(10)° for (2) and 73.26(8)°,
74.15(8)° for (3). Interestingly, the two alkyl substituents of the diorganotin fragment in compounds
(1) and (2) adopt the trans conformation [C-Sn-C angle of (1) and (2) is 143.98(8)° and 141.2(2)°,
respectively] whereas the two phenyl substituent in complex (3) adopts the cis conformation
[C-Sn-C angle is 104.2(1)°].

Molecules 2013, 18
Figure 1. Thermal ellipsoidal plot of C18 H20 F2 N2 O4 Sn (compound 1). Displacement
8701
ellipsoids are drawn at the 50% probability level, and H atoms are shown as spheres of
arbitrary radii. Symmetry transformation code i: −x + 1,y,−z + 3/2.
Figure 2. Thermal ellipsoidal plot of C24 H32 F2 N2 O4 Sn (compound 2). Displacement
ellipsoids are drawn at the 50% probability level, and H atoms are shown as spheres of
arbitrary radii.
Figure 3. Thermal ellipsoidal plot of C28 H24 F2 N2 O4 Sn (compound 3). Displacement
ellipsoids are drawn at the 50% probability level, and H atoms are shown as spheres of
arbitrary radii.

Molecules 2013, 18
8702
Table 1. Selected bond lengths (Å) of the complexes (1), (2) and (3).
(1)
(2)
(3)
N1 C1 1.326(4)
Sn1-O1
2.0921(9)
F1-C5 1.3583(15)
O1-N1 1.3807(13)
O2-C1 1.2696(15)
N1-C1 1.3192(16)
N1-C8 1.4558(16)
Sn1 O1 2.117(3)
Sn1 C21 2.125(4)
Sn1 O3 2.132(3)
Sn1 C17 2.143(4)
Sn1 O2 2.356(3)
Sn1 O4 2.407(3)
N1 C1 1.312(5)
N1 O1 1.385(4)
N1 C8 1.453(5)
N2 C9 1.321(5)
N2 O3 1.375(4)
O2 C1 1.262(5)
O4 C9 1.263(5)
Sn1 O3 2.103(2)
Sn1 O1 2.110(2)
Sn1 C17 2.144(3)
Sn1 C23 2.156(3)
Sn1 O4 2.183(2)
Sn1 O2 2.221(2)
F1 C5 1.353(4)
Sn1-O1 i 2.0921(9)
Sn1-C9 i 2.1184(13)
N1 O1 1.379(3)
N1 C8 1.452(4)
N2 C9 1.322(4)
N2 O3 1.380(3)
O2 C1 1.277(4)
O4 C9 1.285(4)
Sn1-C9
Sn1-O2
2.1184(13)
2.3778(9)
Sn1-O2 i 2.3778(9)
F1 C5
1.354(5)
Table 2. Selected bond angles (deg) of the complexes (1), (2) and (3).
(1)
(2)
(3)
O1-Sn1-O1i 76.58(5)
O1-Sn1-C9i 97.86(5)
O1i-Sn1-C9i 110.40(5)
O1-Sn1-C9 110.40(5)
O1i-Sn1-C9 97.86(5)
C9i-Sn1-C9 143.98(8)
C9i-Sn1-O2i 82.95(4)
O1 Sn1 C21 105.01(13)
O1 Sn1 O3 76.51(10)
C9 N2 O3 119.0(3)
O3 N2 C16 111.9(3)
N1 O1 Sn1 114.8(2)
C1 O2 Sn1 110.1(2)
C9 O4 Sn1 111.7(2)
N2 O3 Sn1 117.7(2)
C18 C17 Sn1 118.9(3)
Sn1 C17 H17A 107.6
Sn1 C17 H17B 107.6
C22 C21Sn1 117.2(3)
Sn1 C21 H21A 108.0
Sn1 C21 H21B 108.0
O2 C1 N1 121.1(4)
F1 C5 C6 118.9(4)
F1 C5 C4 117.7(4)
O4 C9 N2 120.1(3)
O4 C9 C10 119.2(3)
O3 Sn1 O1 158.08(9)
O3 Sn1 C17 89.96(10)
O1 Sn1 C17 103.49(10)
O3 Sn1 C23 105.08(10)
O1 Sn1 C23 88.55(10)
C17 Sn1C23 104.16(11)
C9 N2 O3 117.6(2)
O1 N1 C8 112.8(2)
O3 N2 C16 112.7(2)
C1 O2 Sn1 112.7(18)
N1 O1 Sn1 113.1(16)
N2 O3 Sn1 113.1(16)
C9 O4 Sn1 113.8(18)
C22 C17 Sn1 120.5(2)
C18 C17 Sn1 122.0(2)
C24 C23 Sn1 126.3(2)
C28 C23 Sn1 116.7(2)
O2 C1 N1 118.9(3)
C9-Sn1-O2i 85.64(4)
O2-Sn1-O2i 142.49(4)
N1-O1-Sn1 113.09(7)
C1-O2-Sn1 107.76(8)
C1-N1-O1 118.20(10)
C1-N1-C8 128.68(11)
O1-N1-C8 112.43(10)
O2-C1-N1 120.10(12)
O2-C1-C2 119.21(11)
N1-C1-C2 120.64(11)
F1-C5-C6 118.22(13)
C21 Sn1 O3 103.19(13)
O1 Sn1 C17 104.85(14)
C21 Sn1 C17 141.14(16)
O3 Sn1 C17 107.52(14)
O1-Sn1-O2
71.22(3)
O1 Sn1 O2
71.96(10)
O3 Sn1 O4
O1 Sn1 O4
74.15(8)
88.51(8)
O1i-Sn1-O2 145.75(3)
C9i-Sn1-O2 85.64(4)
C21 Sn1 O2 85.83(13)
O3 Sn1 O2 148.46(10)
C17 Sn1 O2 80.36(14)
O1 Sn1 O4 146.74(9)
C21 Sn1 O4 80.23(12)
O3 Sn1 O4 70.36(9)
C17 Sn1 O4 88.16(13)
O2 Sn1 O4 141.15(9)
C17 Sn1 O4 159.85(10)
C23 Sn1 O4 92.10(10)
O3 Sn1 O2 90.35(8)
O1 Sn1 O2 73.26(8)
C17 Sn1 O2 87.69(10)
C23 Sn1 O2 160.33(10)
O4 Sn1 O2 80.26(8)
C1 N1 O1 117.6(2)
C9-Sn1-O2
82.95(4)
O1-Sn1-O2i 145.75(3)
O1i-Sn1-O2i 71.23(3)
F1 C5 C6
118.8(3)
F1 C5 C4 118.1(3)
O4 C9 N2 118.8(3)
C1 N1 O1
118.8(3)
O1 N1 C8 111.7(3)
Symmetry transformation code for compound (1) i: −x + 1, y, −z + 3/2.

Molecules 2013, 18
8703
2.5. Antitumor Activity in vitro
The synthesized organotins were evaluated for the biological activity, specifically cytotoxicity on
HCT116 colorectal carcinoma cell line. All the tested organotins induced a concentration-dependent
anti-proliferative effect towards HCT116 cells upon treatment for 24 h. However, the cytotoxicity of
dibutyltin(IV)Bis[N-methyl p-fluorobenzohydroxamate] could not be assessed due to the lack of
solubility in DMSO at room temperature. Triphenyltin(IV) N-methyl p-fluorobenzohydroxamate was
the most potent organotin with IC50 value of 0.41 µM, follow by diphenyltin(IV)bis[N-methyl
p-fluorobenzohydroxamate] and dimethyltin(IV)bis[N-methyl p-fluorobenzohydroxamate] as shown in
Table 3. Our current data are in agreement with previous study, whereby the triphenyltin(IV)
complexes exhibit higher antiproliferative effects compare to diphenyltin(IV) complexes [61–63].
Similarily, it has also been demonstrated that triphenyltin(IV) complex possess the highest cytotoxic effect
whereas the dimethyltin(IV) complex have little or no cytotoxic effect on HCT116 cells upto 250 µM
treatment for 24 h [64]. Therefore, triphenyltin(IV) N-methyl p-fluorobenzohydroxamate has the
potential to be developed as an anti-tumor agent due to the potent cytotoxic effect at nano molar
concentration which warrant further mechanistic studies.
Table 3. IC50 values of organotins on HCT116 cells.
Compounds
IC50 values (µM)
dimethyltin(IV)bis[N-methyl p-fluorobenzohydroxamate]
diphenyltin(IV)bis[N-methyl p-fluorobenzohydroxamate]
dibutyltin(IV)bis[N-methyl p-fluorobenzohydroxamate]
triphenyltin(IV) N-methyl p-fluorobenzohydroxamate
>40
2.45
NA
0.41
3. Experimental
3.1. General
The chemicals were purchased from Aldrich and were used as received. All the chemicals were of
analytical grade. The triphenyltin(IV) N-methyl p-fluorobenzohydroxamate was success-fully prepared
according to a standard method reported in the literature [65]. The melting points were determined in
open capillary tubes using an Electrothermal 9300 digital melting point apparatus. The percentage
compositions of the elements (CHN) for the compounds were determined using an elemental analyzer
CHNS-O Model Fison EA 1108. Solid state infrared spectra of the compounds are recorded in the
range 4000–400 cm−1. The infrared spectra were recorded as potassium bromide discs using a
1
119
Perkin-Elmer spectrophotometer GX. The H-, 13C- and
Sn-nuclear magnetic resonance spectra
were recorded using the Bruker FT-NMR 600 MHz Cryo-Prob spectrometer and the JEOL JNM-ECP
400 spectrometer using DMSO/CDCl3 as a solvent and tetramethylsilane as an internal standard.
Crystals structures determination were carried out on a Bruker Smart APEX CCD area detector
diffractometer equipped with graphite mono-chromatised Mo-Kα (λ = 0.71073Å) radiation in each
case. All data collection was carried out at 100K. The program APEX2 (Bruker [66]) was used for
collecting frames of data, indexing of reflections and determination of lattice parameters, SAINT
(Bruker 2008) for absorption correction, and SHELX97 (Sheldrick [67]). HCT116 human colorectal

Molecules 2013, 18
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carcinoma cells were obtained from the American Type Culture Collection (Manassas, Virginia,
USA). The cells were grown in McCoy’s 5A medium (Invitrogen Cooperation, Paisley, UK)
supplemented with 10% FBS (PAA Laboratories, Morningside, QLD, Australia) and maintained at 37
°C with 5% CO2 in humidified incubator.
3.2. Synthesis of Ligand
p-Fluorobenzoyl chloride (0.01 mol) was poured down drop by drop to a stirred cold solution of
N-methylhydroxylamine hydrochloride (0.01 mol) containing sodium hydrogen carbonate (0.01 mol)
and was further stirred for 30 min below 4 °C. The solution was filtered and reduced to evaporate at
low pressure. The precipitate was then dissolved in boiling ethyl acetate to remove any undissolved
substance and then the filtrate is placed in the fridge overnight to obtain the crystals.
N-methyl p-fluorobenzohydroxamic acid. (HL): Colourless crystals. Yield: 84%. Melting point:
88–89 °C. 1H-NMR [DMSO-d6]: ꢀ (ppm) = 10.34 (s, br, 1H, O-H), 7.11–7.57 (m, 4H, C6H4), 3.40 (s, 3H,
13
N-CH3). C-NMR [DMSO-d6]: ꢀ (ppm) = 165.0 (CO); 163–115 (C aromatic); 38.37 (C aliphatic). IR
(KBr pellets, cm−1): 3175(s, br, ν O-H), 1610 (s, ν C=O), 1432 (s, ν C-N) and 908 (s, ν N-O).
Elemental Analysis: Calcd. (%) for H8C8NO2F (molecular weight: 169.06): C, 56.80; H, 8.28; N, 4.73.
Found (%): C, 57.08; H, 8.36; N, 5.14.
3.3. Synthesis of Complexes
Diorganotin(IV) complexes were synthesized by 2:1 molar ratio, dissolving the free ligand
(0.005 mol) in hot toluene and then added the diorganotin(IV) oxides (0.0025 mol) to the solution. The
solution was refluxed for 5–6 h with magnetic stirrer and the water formed during the course of
reaction was removed azeotropically using a Dean-Stark apparatus. The solution was then cooled and
filtered. The filtrate was placed under vacuum to evaporate the solvent and the solid was precipitated
by adding petroleum ether (60–80 °C) and then recrystallized in ethanol.
Dimethyltin(IV)Bis[N-methyl p-fluorobenzohydroxamate] (1). Colourless crystals. Yield: 71%.
1
Melting point: 115–116 °C. H-NMR [DMSO-d6]: ꢀ (ppm) = 7.11–7.77 (m, 4H, C6H4), 3.41 (s, 3H,
13
N-CH3), 0.71 (s, 3H, Sn-CH3), C-NMR [DMSO-d6]: ꢀ (ppm) = 161.3 (CO), 124–131 (C aromatic),
39.29 (N-C), 6.57 (Sn-C). 119 Sn-NMR [DMSO-d6]: ꢀ (ppm) = −407. IR (KBr pellets, cm−1): 1600 (s, ν
C=O), 1432 (s, ν C-N), 938 (s, ν N-O), 439 (s, ν Sn-O) and 576 (s, ν Sn-C). Elemental Analysis:
Calcd. (%) for H20C18N2O4F2Sn (molecular weight: 485.16): C, 44.53; H, 4.13; N, 5.77; Sn, 24.53.
Found (%): C, 43.74; H, 5.78; N, 5.00; Sn, 22.05.
Dibutyltin(IV)Bis[N-methyl p-fluorobenzohydroxamate] (2). Colourless crystals. Yield: 77%. Melting
1
point: 103–104°C. H-NMR [DMSO-d6]: ꢀ (ppm) = 7.11–7.44 (m, 4H, C6H4), 3.45 (s, 3H, N-CH3),
1.36–1.84 (m, 6H, Sn-CH2-CH2-CH2), 0.88 (t, 3H, -CH3). 13C-NMR [DMSO-d6]: ꢀ (ppm) = 164.5
(CO), 115–129 (C aromatic), 40.98 (N-C), 13.85–27.44 (Sn-C). 119Sn-NMR [DMSO-d6]: ꢀ (ppm) = −367.
IR (KBr pellets, cm−1): 1600 (s, ν C=O), 1530 (s, ν C-N), 953 (s, ν N-O), 474 (s, ν Sn-O) and 562 (s, ν
Sn-C). Elemental Analysis: Calcd. (%) for H32C24N2O4F2 Sn (molecular weight: 569.26): C, 50.59; H,
5.85; N, 4.92; Sn, 20.90. Found (%): C, 50.16; H, 4.91; N, 5.85; Sn, 19.21.

Molecules 2013, 18
8705
Diphenyltin(IV)Bis[N-methyl p-fluorobenzohydroxamate] (3). White crystals. Yield: 82%. Melting
1
point: 203–204 °C. H-NMR [DMSO-d6]: ꢀ (ppm) = 8.17–8.32 (m, 9H, C6H4, C6H5), 3.46 (s, 3H,
N-CH3). 13C-NMR [DMSO-d6]: ꢀ (ppm) = 164.9 (C=O), 123–150 (C aromatic), 38.86 (N-C).
119 Sn-NMR [DMSO-d6]: ꢀ (ppm) = −205. IR (KBr pellets, cm−1): 1599 (s, ν C=O), 1454 (s, ν C-N),
948 (s, ν N-O), 453 (s, ν Sn-O) and 563 (s, ν Sn-C). Elemental Analysis: Calcd. (%) for
H24C28N2O4F2Sn (molecular weight: 609.19): C, 55.16; H, 3.97; N, 4.60; Sn, 19.54. Found (%): C,
55.64; H, 4.74; N, 4.02; Sn, 18.60.
3.4. X-ray Crystallography
The single crystals of dimethyltin, dibutyltin and diphenyltin complexes of N-methyl
p-fluorobenzohydroxamic acid of suitable quality were each mounted on a fine glass capillary and
aligned on the Bruker SMART APEX2 diffractometer, equipped with graphite monochromated
Mo-Kα radiation source (λ = 0.71073 Å). The range of theta for data collections together with other
crystallographic information are given in Table 4. All calculations were performed using the
SHELXTL-97 package [68]. Crystallographic data for the compounds (1), (2) and (3) have been
deposited with the Cambridge Crystallographic Data Centre, CCDC reference numbers (924068,
933217, 924061). This information may be obtained free of charge from: the Director, CCDC, 12
Union Road, Cambridge, CB2 1EZ, UK (fax: +44-1223-336033; e-mail:deposit@ccdc.cam.ac.uk;
website: http://www.ccdc.cam.ac.uk).
Table 4. Crystallographic parameter for the diorganotin compounds (1), (2) and (3).
Compound
Gross formula
M
(1)
(2)
(3)
C18 H20 F2 N2 O4 Sn C24 H32F2 N2 O4 Sn C28 H24 F2 N2 O4 Sn
485.05
569.21
609.15
Crystal system, space group Monoclinic, C2/c
Triclinic, P-1
Block
Triclinic, P-1
Block
Crystal shape
Colour
a, Ǻ
Block
Colourless
21.7581(2)
11.2694(1)
7.8964(1)
90
Colourless
11.0271(7)
11.1155(7)
11.1404(7)
75.948(3)
82.636(3)
77.919(3)
1290.99(14)
2
White
8.8999(2)
12.3601(3)
12.4362(3)
109.600(1)
99.770(1)
98.015(1)
1241.34(5)
2
b, Ǻ
c, Ǻ
ꢁ, deg
ꢂ, deg
ꢃ, deg
V, Ǻ 3
94.357
90
1930.58(3)
4
Z
dc, g/cm-3
F(000)
Μ, mm-1
T , K
1.669
1.464
1.37
968
580
612
1.368
1.035
1.083
100(2)
100(2)
100(2)
Crystal size, mm
T min
0.24× 0.29× 0.35
0.6415
0.7457
0.40× 0.15× 0.05
0.6824
0.10×0.05× 0.05
0.8995
T max
0.9501
0.9479

Molecules 2013, 18
8706
Table 4. Cont.
(2)
Compound
(1)
(3)
measured reflections
8979
2221
2191
0.0114
27.5
10517
10184
4581
4231
0.0219
25.5
independent reflections
5056
reflections with I > 2s(I)
4593
Rint
0.1236
26
θ max
θ min
1.88
1.89
1.79
Completeness to theta
0.998
−28 28
−14 14
−10 10
0.0136
0.0367
1.146
2221
125
0.998
−12 13
−13 13
−13 13
0.0539
0.1444
1.096
5056
0.993
−10 10
−14 14
−15 15
0.0239
0.0654
1.19
h
k
l
R[F2 > 2s(F2)]
wR(F2)
S
reflections
parameters
restraints
4581
336
302
0
0
0
ρ
max e Ǻ−3
0.261
−0.450
1.538
−3.311
0.532
−0.571
∆ρmin e Ǻ−3
w = 1/[σ2 (Fo ) + (0.0717P)2 + 0.215P] where P = (Fo2 + 2Fc2)/3 for compound (1);
2
w = 1/[σ2(Fo ) + (0.0921P)2 + 0.0000P] where P = (Fo2 + 2Fc2)/3 for compound (2);
2
w = 1/[σ2(Fo ) + (0.0454P)2 + 0.5345P] where P = (Fo2 + 2Fc2)/3 for compound (3).
2
3.5. MTT Cytotoxicity Assay
The antitumor activity against carcinoma cells was assayed by the MTT method [69]. Cells were
seeded in 96-well plate at a density of 5 × 104 cells per well in a volume of 200 mL and were treated
with various concentrations of the compounds for 24 h. After treatment, 20 µL of 5 mg/mL MTT
(Sigma-Alrich, St. Louis, MO, US) was added to each treated cells and further incubated for 4 h at 37
°C. Subsequently the medium was discarded from each well before adding 200 µL DMSO (Fisher
Scientific, Loughborough, UK). For complete dissolution, the plate was incubated for 15 min followed
with gentle shaking for 5 min. The cytotoxic effect of the organotins on HCT116 cells was assessed by
measuring the absorbance of each well at 570 nm. Mean absorbance for each concentration was
expressed as a percentage of vehicle control absorbance and plotted versus compound concentration.
4. Conclusions
In this work, we have successfully synthesized a novel ligand and its three diorganotin(IV)
hydroxamates, which gave fairly sharp melting points indicating that the compounds were pure and
were characterized by elemental analyses, IR, NMR and X-ray single-crystal diffraction. The structural
analyses of complexes 1–3 reveal that the coordination mode observed in metal-hydroxamic acid
complexes is the O,O-bidentate chelation and a five membered chelated ring was assembled. The
NMR and X-ray studies were in full concurrent with the IR spectral evidences. The crystal structures
of the three diorganotin complexes adopted a six coordination geometry at tin which is coordinated to

Molecules 2013, 18
8707
the carbonyl oxygen and hydroxyl oxygen of two benzohydroxamic acid ligands and the two organic
substituent of the diorganotin(IV) fragment. The diphenyltin(IV) and triphenyltin(IV) complexes
demonstrated promising antiproliferative activities whereas dimethyltin(IV) shows very little cytotoxic
effect at μM concentration on human HCT116 cells.
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/18/7/8696/s1.
Acknowledgments
This work was supported by grant UKM-ST-06-FRGS 112-2009, UKM-GUP-NBT-08-27-112,
GUP-2012-022 and UKM-GGPM-TKP-052-2010 and we gratefully acknowledge the School of
Chemical Sciences and Food Technology, Universiti Kebangsaan Malaysia, for providing the essential
laboratory facilities. We would also like to thank the Faculty Development Programme, University of
Balochistan Quetta, Pakistan for their financial support.
Conflict of Interest
The authors declare no conflict of interest.
References
1. Nandurkar, N.S.; Petersen, R.; Qvortrup, K.; Komnatnyy, V.V.; Taveras, K.M.; Le Quement, S.T.;
Frauenlob, R.; Givskov, M.; Nielsena, T.E. A convenient procedure for the solid-phase synthesis
of hydroxamic acids on PEGA resins. Tetrahedron Lett. 2011, 52, 7121–7124.
2. Farkas, E.; Csoka, H.; Gama, S.; Santos, M.A. Dihydroxamate based siderophore model,
piperazine-1,4-bis-(N-methyl-acetohydroxamic acid (PIPDMAHA), as a chelating agent of
molybdenum(VI). Talanta 2002, 57, 935–943.
3. Jain, R.; Sundram, A.; Lopez, S.; Neckermann, G.; Wu, C.; Hackbarth, C.; Chen, D.; Wang, W.;
Ryder, NS.; Weidmann, B.; et al. α-Substituted hydroxamic acids as novel bacterial deformylase
inhibitor-based antibacterial agents. Bioorg. Med. Chem. Lett. 2003, 13, 4223–4228.
4. Farkas, E.; Enyedy, E.A.; Micera, G.; Garribba, E. Coordination modes of hydroxamic acids in
copper(II), nickel(II) and zinc(II) mixed-ligand complexes in aqueous solution. Polyhedron 2000,
19, 1727–1736.
5. Sibi, M.P.; Hasegawa, H.; Ghorpade, S.R. A Convenient Method for the Conversion of
N-Acyloxazolidinones to Hydroxamic Acids. Org. Lett. 2002, 4, 3343–3346.
6. Giacomelli G.; Porcheddu, A.; Salaris, M. Simple One-Flask Method for the Preparation of
Hydroxamic Acids. Org. Lett. 2003, 5, 2715–2717.
7. Porcheddu. A.; Giacomelli, G. Angeli—Rimini’s Reaction on solid support: A new approach to
hydroxamic acids. J. Org. Chem. 2006, 71, 7057–7059.
8. Reddy, A.S.; Kumar, M.S.; Reddy. G.R. A convenient method for the preparation of hydroxamic
acids. Tetrahedron Lett. 2000, 41, 6285–6288.

Molecules 2013, 18
8708
9. Volonterio, A.; Bellosta, A.S.; Bravo, P.; Canavesi, M.; Corradi, E.; Meille, S.V.; Monetti, M.;
Moussier, N.; Zanda, M. Solution/Solid-Phase synthesis of partially modified Retro- and
Retro-Inverso-ψ[NHCH (CF3)]-Peptidyl hydroxamates and their evaluation as MMP-9 inhibitors,
Eur. J. Org. Chem. 2002, 2002, 428–438.
10. Price, S.; Osbourn, S.E. Solid-Phase Synthesis of N-Formylhydroxylamines (Reverse/Retro
Hydroxamates). Org. Lett. 2005, 7, 3761–3763.
11. Codd, R. Traversing the coordination chemistry and chemical biology of hydroxamic acids.
Coord. Chem. Rev. 2008, 252, 1387–1408.
12. Mishra, H.; Parrill, A.L.; Williamsom, J.S. Three-dimensional quantitative structure-activity
relationship and comparative molecular field analysis of dipeptide hydroxamic acid. Antimicrob.
Agents Chemother. 2002, 46, 2613–2618.
13. Zhang, Y.; Li, D.; Houtman, J.C.; Witiak, D.T.; Seltzer, J.; Bertics, P.J.; Lauhon, C.T. Design,
combinatorial chemical synthesis and in vitro characterization of novel urea based gelatinase
inhibitors. Bioorg. Med. Chem. Lett. 1999, 9, 2823–2826.
14. Tsukamoto, K.; Itakura, H.; Sato, K.; Fukuyama, K.; Miura, S.; Takahashi, S.; Ikezawa, H.; Hosoya,
T. Binding of salicylhydroxamic acid and several aromatic donor molecules to Arthromyces ramosus
peroxidase, investigated by X-ray crystallography, Optical difference spectroscopy, NMR relaxation,
molecular dynamics, and kinetics. Biochemistry 1999, 38, 12558–12568.
15. Leung, D.; Abbenante, G.; Fairlie, D.P. Protease inhibitors: current status and future prospects.
J. Med. Chem. 2000, 43, 305–341.
16. Hidalgo, M.; Eckhardt, S.G. Development of matrix metalloproteinase inhibitors in cancer
Therapy. J. Natl. Cancer Inst. 2001, 93, 178–193.
17. Albrecht-Gary, A.M.; Libman, J.; Shanzer, A. Biomimetic iron(l11) trishydroxamate complexes
and triple stranded diferric helices. Pure Appl. Chem. 1996, 68, 1243–1247.
18. Hara, Y.; Shen, L.; Tsubouchi, A.; Akiyama, M.; Umemoto, K. Tripodal peptide hydroxamates as
siderophore models. iron(III) binding with ligands containing H-(Alanyl)n-β-(N-hydroxy)alanyl
strands (n = 1−3) anchored by nitrilotriacetic acid. Inorg. Chem. 2000, 39, 5074–5082.
19. Munster, P.N.; Troso-Sandoval, T.; Rosen, N.; Rifkind, R.; Marks, P.A.; Richon, V.M. The
histone deacetylase inhibitor suberoylanilide hydroxamic acid induces differentiation of human
breast cancer cells. Cancer Res. 2001, 61, 8492–8497.
20. Steward, W.P.; Thomas, A.L. Marimastat: the clinical development of a matrix metallopro-teinase
inhibitor. Expert Opin. Invest. Drugs 2000, 9, 2913–2922.
21. Jeng, A.Y.; De Lombaert, S. Endothelin converting enzyme inhibitors. Curr. Pharm. Des. 1997,
3, 597–614.
22. Torres, G. Hydroxyurea, a potential new anti-HIV agent. GMHC Treatment Issues 1995, 9, 7–9.
23. Parvathy, S.; Hussain, I.; Karran, E.H.; Turner, A.J.; Hooper, N.M. Alzheimer's Amyloid Precursor
Protein α-Secretase Is Inhibited by Hydroxamic Acid-Based Zinc Metalloprotease Inhibitors:
Similarities to the Angiotensin Converting Enzyme Secretase. Biochem. 1998, 37, 1680–1685.
24. Cabantchik, Z.I. Iron Chelators as antimalarials: the biochemical basis of selective cytotoxicity.
Parasitol. Today 1995, 11, 74–78.

Molecules 2013, 18
8709
25. Tsafack, A.; Golenser, J.; Libman, J.; Shanzer, A.; Cabantchik, Z.I. Mode of action of iron(III)
chelators as antimalarials. III. Over additive effects in the combined action of hydroxamate-based
agents on in vitro growth of Plasmodium falciparum. Mol. Pharmacol. 1995, 47, 403–409.
26. Valapour, M.; Gou, J.; Schroeder, J.T.; Keen, J.; Cianferoni, A.; Casolaro, V.; Georas, S.N.
Histone deacetylation inhibits IL-4 gene expression in T cells. J. Allergy Clin. Immunol. 2002,
109, 238–245.
27. Drovetskaia, T.V.; Yashina, N.S.; Leonova, T.V.; Petrosyan, V.S.; Lorberth, J.; Wocadlo, S.;
Massa, W.; Pebler, J. Synthesis and structure of some Diethyl and Diphenyltin Bis-Hydroxamates.
J. Organomet. Chem. 1996, 507, 201–205.
28. Smith, F.E.; Khoo, L.E.; Goh, N.K.; Hynes, R.C.; Eng, G. The synthesis, and molecular and
crystal structure of diphenyl(2-oxidonaphthylmethyl-iminoacetato)tin(lV).Can. J. Chem. 1996,
74, 2041–2047.
29. Pellerito, L.; Nagy, L. Organotin(IV) complexes formed with biologically active ligands: Equilibrium
and structural studies and some biological aspects. Chem. Rev. 2002, 224, 111–150.
30. Gielen, M. Organotin compounds and their therapeutic potential: a report from the
Organo-metallic Chemistry Department of the Free University of Brussels. Appl. Organomet. Chem.
2002, 16, 481–494.
31. Nath, M.; Pokharia, S.; Yadav, R. Organotin(IV) complexes of amino acids and peptides, Coord.
Chem. Rev. 2001, 215, 99–149.
32. Petrosyan, V.S.; Yashina, N.S.; Ponomarev, S.V. Syntheses, Structures and biological activites of
Organogermaniun and Organotin derivatives of hydroxamic acids. Met. Based Drugs 1998, 5,
237–244.
33. Shang, X.M.; Wu, J.Z.; Li, Q.S. New Coordination Modes of Substituted Benzohydroxa-mic Acid
with Dialkyltin(IV): Structural diversity through Ligand Isomerization. Eur. J. Inorg. Chem.
2006, 2006, 4143–4150.
34. Harrison, P.G.; King, T.J.; Phillips, R.C. Structural studies in main-group chemistry. Part XVI.
Crystal and molecular structures of bis(N-acetylhydroxylamino)dimethyltin(IV) and its
monohydrate. J. Chem. Soc. Dalton Trans. 1976, 22, 2317–2321.
35. Omae, I. Organotin antifouling paints and their alternatives. App. Organomet. Chem. 2003, 17,
81–105.
36. Otera, J. Transesterification. Chem. Rev. 1993, 93, 1449–1470.
37. Jensen, K.G.; Andersen, O.; Ronne, M. Organotin compounds induce aneuploidy in human
peripheral lymphocytes in vitro. Mutat. Res. 1999, 246, 109–112.
38. Choa, J.S.; Wei, L.Y.; Huang, M.C.; Liang, S.C.; Chen, H.H.C. Genotoxic effects of triphenyltin acetate
and triphenyltin hydroxide on mammalian cells in vitro and in vivo. Mutat. Res. 1999, 444, 167–174.
39. White, J.S.; Tobin, J.M.; Cooney, J.J. Organotin compounds and their interactions with
microorganisms. Can. J. Microbiol. 1999, 45, 541–554.
40. Wong, P.T.S.; Chau, Y.K.; Kramar, O.; Bengert, G.A. Structure–toxicity relationship of tin
compounds on Algae. Can. J. Fish. Aquat. Sci. 1982, 39, 483–488.
41. Berg, M.; Arnold, C.G.; Muller, S.R.; Muhlemann, J.; Schwarzenbach, R.P. Sorption and
desorption behavior of organotin compounds in sediment−pore water systems. Environ. Sci.
Technol. 2001, 35, 3151–3157.

Molecules 2013, 18
8710
42. Gielen, M. Tin-Based Antitumour Drugs. Coord. Chem. Rev. 1996, 151, 41–51.
43. Gielen, M.; Biesemans, M.; Willem, R. Organotin compounds: from kinetics to stereo-chemistry
and antitumour activities. Appl. Organomet. Chem. 2005, 19, 440–450.
44. Baul, T.; Masharing, C.; Ruisi, G.; Jirasko, R.; Holcapek, M.; De Vos, D.; Wolstenholme, D.;
Linden, A. Self-assembly of extended Schiff base amino acetate keletons,2-{[(2Z)-(3-hydroxy-1-
Methyl-2-butenylidene)]amino}Phenylpropio-nate and 2-{[(E)-1-(2-hydroxy-aryl) alkylidene]
amino} Phenyl-propionate skeletons incorporating organotin(IV) moieties: Synthesis, spectroscopic
characterization, crystal structures, and in vitro cytotoxic activity. J. Organomet. Chem. 2007, 692,
4849–4862.
45. Saad, E.; Farina, Y.; Baba, I.; Othman, H. Synthesis and characterization of some diorganotin(IV)
bis(N-methyl o-nitrobenzohydroxamate). Sains Malays. 2003, 32, 79–86.
46. Shahid, S.; Ali, S.; Hussain, M.; Mazhar, M.; Mahmood, S.; Rehman, S. Synthesis,
characterization and thermal analysis of organotin(IV) derivatives of 4-(N-Maleoyl) butanoate.
Turk. J. Chem. 2002, 26, 589–597.
47. Li, Q.S.; Guedes da Silva, M.F.C.; Zhao J.H.; Pombeiro, A.J.L. Diorganotin(IV) derivatives of
arylhydroxamic acids: Synthesis, Properties and antitumor activity. J. Organomet. Chem. 2004,
689, 4584–4591.
48. Lockhart, T.P.; Manders, W.F. Structural determination by NMR spectroscopy. Dependence of
[2J(119Sn,1H)] on the Me-Sn-Me angle in methyltin (IV) compounds. Inorg. Chem. 1986, 25,
892–895.
49. Nadvornik, M.; Holeček, J.; Handlir, K.; Lycka, A. The [13]C and [119]Sn NMR spectra of Some
four- and five-coordinate tri-n-butyltin (IV) compounds. J. Organomet. Chem. 1984, 275, 43–51.
50. Mohammad, M.; Khadija, S.; Sohail, M.; Saqib, A.; Moazzam, B. Synthesis, Spectral
Characterization and Biological Applications of Tri- and Diorganotin(IV) Derivatives of
2[N-(2,6- Dichloro-3-methyl phenyl)amino]benzoic acid. Turk. J. Chem. 2004, 28, 17–26.
51. Das, M.K.; Nath, M.; Zuckermann, J.J. Di- And Triorganotin (IV) Derivatives of
N, N-Substituted hydroxylamines. Inorg. Chem. Acta 1983, 71, 49–59.
52. Ahmed, F.; Ali, S.; Parvez, M.; Munir, A.; Mazhar, M.; Shah, T.A. Synthesis, Characterization
and biological studies of tri- and diorganotin (IV) complexes with 2,4-difluoro-4-hydroxy-[1,1]-
biphenyle-3-carbolic acid: Crystal structure of [(CH3)3Sn(C13H7O3F2)]. Heteroatom. Chem. 2002,
13, 638–642.
53. Ali, S.; Ahmad, F.; Mazhar, M.; Munir, A.; Masood, M.T. Synthesis and spectral studies of
di- and triorganotin (IV) complexes with 2-(6-methoxynaphthyl) propionic acid (Naproxen).
Synth. React. Inorg. Met-Org. Chem. 2001, 32, 357–372.
54. Yoder, C.H.; Margolis, L.A.; Horne, J.M. A Tin-119 NMR investigation of phosphine and
phosphine oxide adducts of organotin chlorides. J. Organomet. Chem. 2001, 633, 33–38.
55. Holecek, J.; Nadvornik, M.; Handlír, K.; Lycka, A. 13C and 119Sn NMR spectra of
di-n-butyltin(IV) compounds. J. Organomet. Chem. 1986, 315, 299–308.
56. Choudhary, M.A.; Mazhar, M.; Ali, S.; Song, X.; Eng, G. Synthesis, characterization and
biological activity of dimethyltin dicarboxylates containing germanium. Met. Based Drugs 2002,
8, 275–281.

Molecules 2013, 18
8711
57. Harrison, P.G. Chemistry of Tin; Harrison, P.G, Ed.; Chapman and Hall: New York, NY, USA,
1989; p.76 and references therein.
58. Nath, M.; Yadav, R.; Gielen, M.; Dalil, H.; de Vos, D.; Eng, G. Synthesis, Characteristic spectral
studies and in vitro antimicrobial and antitumour activities of organotin (IV) complexes of Schiff
bases derived from amino acids. App. Organomet. Chem. 1997, 11, 727–736.
59. Harrison, P.G.; King, T.J.; Richards, J.A. Structural studies in main group chemistry. Part VIII.
The crystal and molecular structure of Bis(N-methyl acetylhydroxylamino) dimethyltin(IV).
J. Chem. Soc. Dalton Trans. 1975, 9, 826–830.
60. Shang, X.M.; Li, Q.S.; Wu, J.Z. Synthesis and crystal structure of a mixed-ligand compound
di-n-butyl-(4-chlorobenzohydroxamato)tin(IV). J. Organomet. Chem. 2005, 17, 3997–4000.
61. Gomez-Ruiz, S.; Kaluderovic, G.N.; Prashar, S.; Hey-Hawkins, E.; Eric, A.; Zizak , Z.; Juranic,
Z.D. Study of the cytotoxic activity of di and triphenyltin(IV) carboxylate complexes. J. Inorg.
Biochem. 2008, 102, 2087–2096.
62. Gielen, M.; Handlir, K.; Hollein, M.; De Vos, D. Synthesis, characterization and anti-tumour
activity of some butyltin (IV) cysteaminates and N,N-dimethyl-cysteaminates. Met. Based Drugs
2000, 7, 233–236.
63. Gielen, M.; Biesemans, M.; De Vos, D.; Willem, R. Synthesis, characterization and in vitro
antitumor activity of di- and triorganotin derivatives of polyoxa- and biologically relevant
carboxylic acids. J. Inorg. Biochem. 2000, 79, 139–145.
64. Xanthopoulou, M.N.; Hadjikakou, S.K.; Hadjiliadis, N.; Schurmann, M.; Jurkschat, K.; Michaelides,
A.; Skoulika, S.; Bakas, T.; Binolis, J.; Karkabounas, S.; et al. Synthesis, Structural characterization
and in vitro cytotoxicity of organotin(IV) derivatives of heterocyclic thioamides,
2-mercaptobenzothiazole, 5-chloro-2-mercaptobenzothiazole, 3- methyl-2-mercaptobenzothiazole and
2-mercaptonicotinic acid. J. Inorg. Biochem. 2003, 96, 425–434.
65. Sharma, N.; Puneet, P.; Sharma, V.; Bhatt S.S.; Chaudhary, S.C. Synthesis, characterization and
thermal study of di- and triphenyltin(IV) complexes of p-chloro and p-nitro and benzohydroxamic
acid. Synth. Reactiv. Inorg. Metal-Org. C 1997, 27, 1381–1397.
66. APEX2 and SAINT; Bruker AXS Inc.: Madison, WI, USA, 2008.
67. Sheldrick, G.M. A short history of SHELX. Acta Cryst. 2008, A64, 112–122.
68. Sheldrick, G.M. SHELXS-97, Program for Crystal Structure Determination; University of
Göttingen: Göttingen, Germany, 1997.
69. Denizot, F.; Lang, R. Rapid colorimetric assay for cell growth and survival Modifications to the
tetrazolium dye procedure giving improved sensitivity and reliability. J. Immunol. Meth. 1986, 89,
271–277.
Sample Availability: Samples of the ligand and complexes are available from the authors.
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