Homoleptic tin(IV) compounds containing tridentate ONS dithiocarbazate Schiff bases: Synthesis, X-ray crystallography, DFT and cytotoxicity studies

Article abstract of DOI:10.1016/j.molstruc.2019.127635

Six new tin(IV) compounds derived from tridentate dinegatively charged ONS dithiocarbazate Schiff bases derived from 2-hydroxy-3-methoxybenzaldehyde (H₂L1, H₂L2 and H₂L3) and 2,3-dihydroxybenzaldehyde (H₂L4, H₂L5 and H₂L6) (where H₂Ln = di-acids of Schiff base) are reported. The compounds were characterised by elemental analysis, FT-IR and multinuclear NMR (¹H, ¹³C and ¹¹⁹Sn) spectroscopy. The crystal structures of tin(IV) [S-4-methybenzyl-β-N-(2-hydroxy-3-methoxybenzylmethylene)dithiocarbazate] (2) and tin(IV) [S-benzyl-β-N-(2-hydroxy-3-methoxy benzylmethylene)dithiocarbazate] (3) were determined by X-ray single crystal diffraction analysis. X-ray crystallography showed the molecular geometries in homoleptic 2 and 3 to be quite similar in which the dinegative tridentate ligand coordinated the tin atoms via thiolate-S, phenoxide-O and imine-N atoms. The coordination geometries are based on an octahedron with like-atoms mutually trans. The experimental findings were validated by density functional theory (DFT) calculations at the B3LYP/LanL2DZ/6-311G(d,p) level of theory. All the tin(IV) compounds, except the insoluble compound 2 were screened for their in vitro cytotoxicity against a panel ten of cancer cell lines and one normal breast cell line (MCF-10 A) by MTT assay. Interestingly, the cytotoxicity of five tin(IV) compounds against HT29, MCF7 and MIA was higher than the reference drug, cisplatin.

Full text of DOI:10.1016/j.molstruc.2019.127635

Journal Pre-proof
Homoleptic tin(IV) compounds containing tridentate ONS dithiocarbazate Schiff
bases: Synthesis, X-ray crystallography, DFT and cytotoxicity studies
Enis Nadia Md Yusof, Muhammad A.M. Latif, Mohamed I.M. Tahir, Jennette A.
Sakoff, Abhi Veerakumarasivam, Alister J. Page, Edward R.T. Tiekink, Thahira B.S.A.
Ravoof
PII:
S0022-2860(19)31744-2
DOI:
https://doi.org/10.1016/j.molstruc.2019.127635
MOLSTR 127635
Reference:
To appear in: Journal of Molecular Structure
Received Date: 27 September 2019
Revised Date: 19 December 2019
Accepted Date: 20 December 2019
Please cite this article as: E.N. Md Yusof, M.A.M. Latif, M.I.M. Tahir, J.A. Sakoff, A. Veerakumarasivam,
A.J. Page, E.R.T. Tiekink, T.B.S.A. Ravoof, Homoleptic tin(IV) compounds containing tridentate ONS
dithiocarbazate Schiff bases: Synthesis, X-ray crystallography, DFT and cytotoxicity studies, Journal of
Molecular Structure (2020), doi: https://doi.org/10.1016/j.molstruc.2019.127635.
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Abstract
Highlight
A series of octahedral homoleptic tin(IV) compounds were designed, synthesised and
evaluated for their in vitro cytotoxicity against ten cancer cells.

Homoleptic tin(IV) compounds containing tridentate ONS dithiocarbazate Schiff bases:
Synthesis, X-ray crystallography, DFT and cytotoxicity studies
Enis Nadia Md Yusofa,b, Muhammad A. M. Latifa, Mohamed I. M. Tahira, Jennette A.
Sakoffc, Abhi Veerakumarasivamd,e, Alister J. Pageb *, Edward R. T. Tiekinkf and Thahira B.
S. A. Ravoofa,g *
a Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, 43400 UPM
Serdang, Selangor Darul Ehsan, Malaysia.
b Discipline of Chemistry, School of Environmental and Life Sciences, University of
Newcastle, University Drive, Callaghan, NSW 2308, Australia.
c Experimental Therapeutics Group, Department of Medical Oncology, Calvary Mater
Newcastle Hospital, Edith Street, Waratah NSW 2298, Australia.
d Department of Biological Sciences, School of Science and Technology, Sunway University,
Bandar Sunway, 47500 Subang Jaya, Selangor Darul Ehsan, Malaysia.
e Medical Genetics Laboratory, Faculty of Medicine and Health Sciences, Universiti Putra
Malaysia, 43400 UPM Serdang, Selangor Darul Ehsan, Malaysia.
f Research Centre for Crystalline Materials, School of Science and Technology, Sunway
University, No. 5 Jalan Universiti, 47500 Bandar Sunway, Selangor Darul Ehsan, Malaysia.
g Foundry of Reticular Materials for Sustainability (FORMS), Materials Synthesis and
Characterization Laboratory, Institute of Advanced Technology, Universiti Putra Malaysia,
43400 Serdang, Selangor Darul Ehsan, Malaysia.
Abstract
Six new tin(IV) compounds derived from tridentate dinegatively charged ONS
dithiocarbazate Schiff bases derived from 2-hydroxy-3-methoxybenzaldehyde (H2L1, H2L2
and H2L3) and 2,3-dihydroxybenzaldehyde (H2L4, H2L5 and H2L6) (where H2Ln = di-acids
of Schiff base) are reported. The compounds were characterised by elemental analysis, FT-
IR and multinuclear NMR (1H, 13C and 119Sn) spectroscopy. The crystal structures of tin(IV)
[S-4-methybenzyl-β-N-(2-hydroxy-3-methoxybenzylmethylene)dithiocarbazate] (2) and
tin(IV) [S-benzyl-β-N-(2-hydroxy-3-methoxy benzylmethylene)dithiocarbazate] (3) were
determined by X-ray single crystal diffraction analysis. X-ray crystallography showed the
molecular geometries in homoleptic 2 and 3 to be quite similar in which the dinegative
tridentate ligand coordinated the tin atoms via thiolate-S, phenoxide-O and imine-N atoms.
The coordination geometries are based on an octahedron with like-atoms mutually trans. The
1

experimental findings were validated by density functional theory (DFT) calculations at the
B3LYP/LanL2DZ/6-311G(d,p) level of theory. All the tin(IV) compounds, except the
insoluble compound 2 were screened for their in vitro cytotoxicity against a panel ten of
cancer cell lines and one normal breast cell line (MCF-10A) by MTT assay. Interestingly, the
cytotoxicity of five tin(IV) compounds against HT29, MCF7 and MIA was higher than the
reference drug, cisplatin.
Keywords
tin complex; X-ray crystallography; cytotoxicity
1.
Introduction
Metal ions play an important role in biological systems and are involved in various
applications, such as cancer therapy and diagnosis of diseases [1]. Metal-based drugs
including compounds of mercury, copper, gold and arsenic have been used since ancient
Egyptian, Greek and Chinese societies to treat a broad spectrum of diseases including cancer
[2–4]. For example, mercury sulphide (cinnabar) was used in the treatment of ailments and
arsenic trioxide (ATO) for the treatment of rheumatoid diseases, syphilis and psoriasis. In the
18th century until early 20th century, ATO was among the first group of compounds used in
the treatment of leukemia, before it was replaced by radiation and chemotherapeutic agents
[4]. Targeting cancer with chemotherapy after the failure of other therapeutic treatments was
a valid option due to the effectiveness and action of the chemotherapeutic drugs throughout
the entire body [5]. In the 1960s, a platinum-based drug, cisplatin was discovered for cancer
treatments [6] and following its success, the development of platinum drugs flourished, with
some of them approved as chemotherapeutic drugs. However, platinum-based drugs suffer
from ineffectiveness in the treatment of platinum-resistant cancers and also have severe side
effects. Despite the wide use of platinum-based drugs, their biggest challenges - unclear
therapeutic mechanisms and high toxicity - remain. Hence, the development of improved
non-platinum-based anticancer drugs became one of the fundamental goals in medicinal
chemistry.
There are many possible advantages in using non-platinum-based compounds, such as: (i) a
variety of coordination sites, (ii) diversity of oxidation states and (iii) affinity and kinetics of
the bound organic ligands [7–9]. Keeping this in view, tin(IV) compounds have shown a wide
range of applications and were one of the most in-demand class of organometallic
2

compounds due to their biomedical effectiveness as antifouling, antimicrobial and antiviral
agents. Saxena and Huber (1989) reported that tin-based compounds were known to localise
in tumour tissues, hence explaining their effectiveness [10–12]. Since then, tin-based
compounds have been in the pipeline as potential chemotherapeutic drugs to modulate
toxicity effects. On top of reduced side effects, tin(IV) compounds exhibited no
gametogenesis, as cisplatin did, and had increased solubility in water. Tin(IV) compounds
also did not develop tumour drug resistance which was reported to be the major problem in
chemotherapy for cisplatin and its analogues towards certain cancer cells [13–15]. Further,
tin(IV) compounds had potential industrial applications, such as bactericides, fungicides and
pesticides [16–20].
Ligand selectivity can be introduced into a system in order to determine their effectiveness in
bioactivity, particularly in anticancer activity. Ligands not only modify the solubility in lipid
permeable membranes, but also play a role in transporting and addressing the compound to
their specific target site [21]. On this note, Schiff bases have long been studied as potential
target ligands to enhance the bioactivity of chemotherapeutic drugs. Schiff bases can
coordinate to the tin centre and form stable ligand-tin bonds. Therefore, any modification of
the structure could modulate the structural diversity and activity of the entire compound [22].
A number of reports [23–31] on the complexation of dithiocarbazate Schiff bases have
received much attention because of their special abilities, including (i) formation of an
interesting series of ligands where the properties can be greatly modified by introducing
different types of aldehyde or ketones and (ii) the interaction of donor atoms to the centre
metal ions creating different geometries and properties, as well as their potential biological
activities [32]. The number and diversity of applications of tin(IV) compounds, and the
synthesis and characterisation of tin(IV) compounds containing O-, N-, S- donor Schiff bases
have been a subject of interest for researchers in the inorganic field, where sulphur is of
paramount importance in the metal-ligand linkage. The well elucidated structures of the
Schiff base containing compounds showed interesting biological activities depending on their
substituents and geometries [33–35].
In view of all these findings and in continuation of our previously reported research work
[36] on the chemistry, therapeutic potential and structure-activity relationship of tin(IV)
compounds coordinated with two dithiocarbazate Schiff bases, we report here the synthesis of
six new octahedral tin(IV) compounds derived from 2-hydroxy-3-methoxybenzaldehyde and
3

2,3-dihydroxybenzaldehyde dithiocarbazate. The compounds were characterised by FT-IR,
multinuclear NMR (1H, 13C and 119Sn), mass spectroscopy, UV-vis and density functional
theory (DFT) calculations. The in vitro cytotoxicity studies were explored and the
compounds were found to have good activity against the tested cell lines.
2.
Experimental Section
2.1.
Materials and Instruments
All solvents and reagents were of analytical reagent grade and used without further
purification. Chemicals: hydrazine hydrate, 80% (Fluka), benzylchloride, ≥ 99% (Merck), 2-
methybenzyl chloride, 99% (ACROS), 4-methylbenzyl chloride (ACROS), potassium
hydroxide (HmbG), carbon disulphide (Merck), 2-hydroxy-3-methoxybenzaldehyde (Merck),
tin(II) dichloride, 97% (Merck), trimethylamine and > 99% (Sigma Aldrich). Solvents:
acetonitrile (Baker), absolute ethanol, 99.8% (Scharlau), ethanol, 95% (J. Kollin Chemical),
methanol (Fisher Scientific) and dimethylsulfoxide (Scharlau). Melting points were
determined using an Electrothermal digital melting point apparatus. C, H and N elemental
analyses were carried out using a LECO CHNS-932 instrument and Thermo Flash EA110
elemental analyser. FT-IR spectra were recorded using PerkinElmer Spectrum 100 with
Universal ATR Polarization in the range of 4000–280 cm-1 at room temperature. Molar
conductivities of 10−3 M solutions of the metal complexes in DMSO were measured at 27 °C
using a Jenway 4310 conductivity meter and a dip-type cell with a platinized electrode.
Electronic spectra were recorded on a Shimadzu UV-2501 PC recording spectrophotometer
(1000–200 nm). Multinuclear (1H and 13C) Nuclear Magnetic Resonance (NMR)
spectroscopic analyses were recorded using NMR JNM ECA400 spectrometer. 119Sn NMR
were measured using a Bruker BioSpin Avance III (600 MHz) spectrometer.
2.2.
Synthesis
2.2.1. Synthesis of Schiff bases
Schiff bases were synthesised following references [37,36]. Dithiocarbazate (S-2-
methylbenzyldithiocarbazate, S-4-methylbenzyldithiocarbazate or S-benzyldithiocarbazate)
(10 mmol) was dissolved in hot acetonitrile or ethanol (100 cm3) and added to an equimolar
4

amount of 2-hydroxy-3-methoxybenzaldehyde (1.52 g) or 2,3-dihydroxybenzaldehyde (1.38
g) in absolute ethanol (20 cm3). The mixture was heated (80 °C) with continuous stirring for
about 30 min and then allowed to stand overnight at room temperature. The resultant product
was recrystallised from CH3CN/EtOH (1:1) to give a light-yellow crystalline solid that was
filtered and washed with cold absolute ethanol.
2.2.2. Synthesis of tin(IV) compounds (1-3)
The Schiff base (0.35 g (H2L1, H2L2); 0.33 g (H2L3, H2L4, H2L5); 0.32g (H2L6), 1
mmol) was dissolved in absolute ethanol (50 cm3) and dichloromethane (20 cm3) and was
mixed with an ethanolic solution (2 mmol) of triethylamine. With continuous stirring, an
ethanolic solution of SnCl2 (0.20 g, 1 mmol) was added to the mixture. A cloudy solution
formed which was filtered. The yellow filtrate was then heated under reflux for ca 6 h. The
mixture was left overnight and the reduction of the volume of the reaction mixture resulted in
an orange precipitate, which was filtered off. The precipitate was recrystallised in dry ether to
remove the remaining triethylamine hydrochloride salt from the mixture.
2.2.2.1.
Tin(IV)
[S-2-methylbenzyl-β-N-(2-hydroxy-3-methoxybenzylmethylene)
dithiocarbazate] (1)
Orange solid. Yield: 82%. Melting point: >300°C. Analysis calculated for
C34H32N4O4S4Sn: C, 50.56; H, 3.99; N, 6.94%. Found: C, 50.87; H, 3.58; N, 5.27%. FT-IR
1
(ATR, cm-1): 1587, v(C=N); 1088, v(N-N); 955, v(C-S). H NMR (CDCl3) δ (ppm.): 8.81,
8.45 (s, 2H, CH), 6.77-7.32 (multiplet, 14H, Ar-H), 4.35, 4.47 (s, 4H, CH2), 3.57, 3.85 (s, 6H,
O-CH3), 2.40, 2.36 (s, 6H, CH3); 13C NMR (CDCl3) δ (ppm.): 177.2, 171.0 (C-S), 165.4,
161.7 (C=N); 115.2, 117.2, 118.4, 119.0, 120.2, 121.9, 126.1, 126.2, 126.4, 126.7, 127.6,
128.0, 130.4, 130.4, 130.5, 130.6, 133.5, 134.5, 137.2, 137.3, 147.6, 150.4, 152.0, 156.7
(aromatic-C), 55.3, 56.9 (O-CH3), 36.2, 34.0 (CH2), 19.4 (CH3),.119Sn NMR (CDCl3) δ
(ppm.): -446.
2.2.2.2.
Tin(IV)
[S-4-methybenzyl-β-N-(2-hydroxy-3-methoxybenzylmethylene)
dithiocarbazate] (2)
Orange crystals. Yield: 87%. Melting point: 211-214°C. Analysis calculated for
C34H32N4O4S4Sn: C, 51.56; H, 3.99; N, 6.94%. Found: C, 51.89; H, 4.22; N, 6.53%. FT-IR
5

(ATR, cm-1): 1593, v(C=N); 1083, v(N-N); 958, v(C=S). 1H NMR (CDCl3) δ (ppm.): 8.77, (s,
2H, CH), 6.76-7.24 (multiplet, 14H, Ar-H), 4.36 (s, 4H, CH2), 3.56 (s, 6H, O-CH3), 2.33 (s,
6H, CH3); 13C NMR (CDCl3) δ (ppm.): 170.8 (C-S), 165.4 (C=N); 117.2, 118.4, 119.0, 126.7,
129.2, 129.4, 133.1, 137.3, 152.0, 156.7 (aromatic-C), 56.9 (O-CH3), 35.5 (CH2), 21.2 (CH3).
119Sn NMR (CDCl3) δ (ppm.): -446.
2.2.2.3. Tin(IV) [S-benzyl-β-N-(2-hydroxy-3-methoxybenzylmethylene)dithiocarbazate] (3)
Orange crystals. Yield: 53%. Melting point: >300°C. Analysis calculated for
C32H28N4O4S4Sn: C, 49.30; H, 3.62; N, 7.19%. Found: C, 49.26; H, 3.26; N, 6.02 %. FT-IR
(ATR, cm-1): 1582, v(C=N); 1031, v(N-N); 958, v(C-S). 1H NMR (CDCl3) δ (ppm.): 8.78 (s,
2H, CH), 6.76-7.36 (multiplet, 16H, Ar-H), 4.44 (s, 4H, CH2), 3.55 (s, 6H, O-CH3); 13C NMR
(CDCl3) δ (ppm.): 170.7 (C-S), 165.5 (C=N); 117.2, 118.4, 119.0, 126.7, 127.6, 128.7, 129.3,
136.3, 152.0, 156.9 (aromatic-C), 56.9 (CH3), 35.7 (CH2).119Sn NMR (CDCl3) δ (ppm.): -
447.
2.2.2.4.
Tin(IV)[S-2-methylbenzyl-β-N-(2,3-dihydroxybenzylmethylene)
dithiocarbazate] (4)
Orange powder. Yield: 40%. Melting point: 188-192 °C. Analysis calculated for
C32H28N4O4S4Sn: C, 49.30; H, 3.62; N, 7.19%. Found: C, 49.14; H, 3.43; N, 7.50%. FT-IR
(ATR, cm-1): 1610, v(C=N); 1035, v(N-N); 964, v(C-S). 1H NMR (CDCl3) δ (ppm.) : 8.90 (s,
13
2H, CH), 6.02-7.34 (multiplet, 14H, Ar-H), 4.48 (s, 4H, CH2), 2.42 (s, 6H, CH3); C NMR
(CDCl3) δ (ppm.): 171.3 (C-S), 165.6 (C=N), 115.1, 119.0, 119.6, 125.4, 126.5, 128.3, 130.5,
130.8, 133.2, 137.4, 148.2, 152.1 (aromatic-C), 34.3 (CH2), 19.5 (CH3).119Sn NMR (DMSO-
d6) δ (ppm.): -441.
2.2.2.5.
Tin(IV) [S-4-methybenzyl-β-N-(2,3-dihydroxybenzylmethylene)
dithiocarbazate] (5)
Orange powder. Yield: 83%. Melting point: 206-209 °C. Analysis calculated for
C32H28N4O4S4Sn: C, 49.30; H, 3.62; N, 7.19%. Found: C, 49.02; H, 3.16; N, 7.85%. FT-IR
(ATR, cm-1): 1620, v(C=N); 1006, v(N-N); 965, v(C-S). 1H NMR (DMSO-d6) δ (ppm.): 8.65,
(s, 2H, CH), 6.50-7.35 (multiplet, 14H, Ar-H), 4.41 (s, 4H, CH2), 2.29 (s, 6H, CH3); 13C
NMR (DMSO-d6) δ (ppm.): 150.8 (C-S), 145.2 (C=N); 118.4, 129.5, 129.6, 134.2, 136.8
(aromatic-C), 21.2 (CH3), 37.8 (CH2).119Sn NMR (DMSO-d6) δ (ppm.): -443.
6

2.2.2.6.
Tin(IV) [S-benzyl-β-N-(2,3-dihydroxy-benzylmethylene)dithiocarbazate] (6)
Orange powder. Yield: 67%. Melting point: 206-208 °C. Analysis calculated for
C30H24N4O4S4Sn: C, 47.95; H, 3.22; N, 6.46%. Found: C, 47.72; H, 2.93; N, 6.25%. FT-IR
(ATR, cm-1): 1612, v(C=N); 1016, v(N-N); 960, v(C-S). 1H NMR (DMSO-d6) δ (ppm.): 8.60,
13
(s, 2H, CH), 6.27-7.41 (multiplet, 16H, Ar-H), 4.44 (s, 4H, CH2); C NMR (DMSO-d6) δ
(ppm.): 155.9 (C-S), 153.4 (C=N); 111.6, 114.3, 115.9, 116.9, 127.5, 128.9, 129.7, 137.6,
146.9 (aromatic-C), 38.1 (CH2).119Sn NMR (DMSO-d6) δ (ppm.): -462.
2.3
Single crystal X-ray structure determination
An Oxford Diffraction Gemini Eos CCD diffractometer fitted with Mo Kα radiation ( =
0.71073 Å) was employed to measure intensity data for the orange crystals of 2 and 3 at T =
150 K. The data reduction and analytical absorption corrections were accomplished with
CrysAlisPro [38]. The structures were solved by direct-methods [39] and refined (anisotropic
displacement parameters, C-bound H atoms in the riding model approximation) on F2 [40].
2
2
A weighting scheme w = 1/[σ 2(Fo ) + (aP)2 + bP] where P = (Fo + 2Fc2)/3) was introduced
in each case. In the final cycles of the refinement of 2, a reflection, i.e. (-6 -4 8), was omitted
owing to poor agreement. The molecular structure diagrams was generated with ORTEP for
Windows [41] with 50% displacement ellipsoids and the packing diagrams were drawn with
DIAMOND [42]. Additional data analysis was made with PLATON [43]. Crystal data and
refinement details are given in Table 1.
2.4
Computational calculations
DFT calculations were performed as reported previously from our group [36].
2.5
In vitro cytotoxic activity
The cytotoxicity of tin(IV) compounds against HT29 (colon), U87 and SJ-G2 (glioblastoma),
MCF-7 (breast), A2780 (ovarian), H460 (lung), A431 (skin), Du145 (prostate), BE2-C
(neuroblastoma), MIA (pancreas) cell lines and one normal breast cell line, MCF-10A
7

(normal breast) were performed by MTT assay using the same method reported by Yusof et
al [36].
Table 1
Crystal data and refinement details for complexes 2 and 3.
Complex
2
3
Formula
C34H32N4O4S4Sn
807.56
C32H28N4O4S4Sn
779.51
Formula weight
Crystal system
Space group
a/Å
Monoclinic
P21/n
Monoclinic
P21/c
12.8540(2)
19.4686(5)
27.2466(6)
101.109(2)
6690.7(3)
8
12.8656(3)
8.4693(2)
29.8639(7)
96.634(2)
3232.26(13)
4
b/Å
c/Å
/°
V/Å3
Z
Dc/g cm-3
1.603
1.602
F(000)
3280
1576
(MoK)/mm-1
Measured data
 range/°
1.059
1.093
44247
36728
3.3 – 25.2
15972
3.4 – 25.2
7934
Unique data
Observed data (I  2.0(I))
No. parameters
R, obs. data; all data
a; b in weighting scheme
Rw, obs. data; all data
GoF
10737
6324
855
408
0.041; 0.079
0.036; 1.389
0.076; 0.093
1.05
0.035; 0.072
0.032; 2.061
0.052; 0.080
1.02
Range of residual electron
density peaks/eÅ-3
-0.75 – 0.91
-0.57 – 0.50
8

3.
Results and discussion
3.1
Synthesis
Six new homoleptic tin(IV) compounds were synthesised by the condensation reaction of S-
substituted dithiocarbazate Schiff bases of 2-hydroxy-3-methoxybenzaldehyde or 2,3-
dihydroxybenzaldehyde with tin(II) chloride (Scheme 1), whereby the tin(II) precursor
underwent oxidation to tin(IV) after reflux for 6 hours [44]. The tin(IV) compounds were
stable at room temperature and soluble in most organic solvents, especially dimethylsulfoxide
(DMSO) and dimethylformamide (DMF), except 2 which was not soluble in DMSO. Due to
the insolubility of 2, cytotoxic activity was not determined. The molar conductance of 10-3 M
solutions of synthesised compounds in DMSO were in the range 1.12-6.07 Ω-1 cm2 mol-1,
indicating their non-electrolytic nature [45].
R
N
S
N
R'
SnCl2
S
HO
O
Et3N, EtOH
S
R'
Sn
N
R'
S
N
reflux (6 hours)
O
R
H
S
N
S
N
R
Where: R = o-CH3, R' = O-CH3 (1)
R = p-CH3, R' = O-CH3 (2)
R = H, R' = O-CH3
R = o-CH3, R' = OH
R = p-CH3, R' = OH
R = H, R' = O-H
(3)
(4)
(5)
(6)
Scheme 1: Synthetic pathway for the synthesis of 1-6.
9

3.2
Infrared spectra analysis
The infrared spectra of 1-6 were measured in the range of 4000 to 280 cm−1 and verified
using frequencies predicted using DFT. Complete experimental and calculated IR data are
provided in Supplementary Information, Table S1. In the experimental IR spectra of Schiff
bases (H2L1-6), the vibration bands of v(o-O-H), v(NH), v(C=N), v(N-N) and v(C-S) were
observed in the range of 3488-3501, 3084-3106, 1598-1608, 1114-1125 and 1012-1030 cm-1,
respectively. However, the v(O-H) of H2L1, H2L2 and H2L3 were not observed in the IR
spectra due to the intra- and inter-molecular interactions between the molecules, which was
similar to that reported in our previous work [36]. The disappearance of the v(N-H) band for
all Schiff bases and the v(O-H) band for H2L4, H2L5 and H2L6 indicate the deprotonation of
N-H and O-H groups and its subsequent coordination to the central tin atom. The shifting of
v(C=N) band observed in the spectra of tin(IV) compounds proves that the complexation
occurred through the azomethine nitrogen. The IR group assignments for the experimental
and theoretical calculation in gas phase appeared in good agreement with experimental data,
shown in Fig. S1.
3.3
Multinuclear (1H, 13C and 119Sn) NMR spectral analysis
The important signals observed in the range of 9.51-9.61 ppm and 13.32-13.41 ppm were
assigned to the proton of -OH and -NH in the Schiff base, respectively, which were reported
1
in our previous publications [36]. Both of the signals disappeared in the H NMR of the
tin(IV) compounds indicating the deprotonation of the -OH and -NH groups upon
complexation. This confirmed the coordination of the oxygen and nitrogen donor atom of
Schiff bases to the tin ion. Moreover, the signal of the HC=N proton in the spectra of tin(IV)
compounds shifted to the downfield region due to the coordination of –NH to tin atom, which
was a result of the formation of the C=N-N=C conjugated systems [46]. The downfield shift
13
of the HC=N signal in the C NMR spectra, due to electron density transfer from the Schiff
bases to the acceptor (Sn atom), was consistent with that observed in earlier reports [47,48].
Furthermore, the signal attributable to the C–S moiety in the 13C NMR spectra of the tin(IV)
compounds was shifted upfield compared to their Schiff bases, suggesting coordination of the
sulphur atom to the tin centre. These observations supported the FTIR analysis noted above.
10

1
13
All the data obtained in the H NMR and C NMR spectra are listed in Tables S2 and S3,
respectively.
The geometry of compounds 1-6 was verified further via 119Sn NMR spectroscopy. A sharp
signal was observed in the range δ -441 to -462 in the 119Sn NMR spectra of compounds 1-6,
which strongly supported a six-coordinated, distorted octahedral geometry around tin,
comparable to reported literature [49].
3.4
UV-vis absorption spectral analysis
The experimental UV-vis spectra of tin(IV) compounds in DMSO showed a prominent
absorption peak in the range of 343-355 nm, which is attributed to the n→π* and π→π*
transitions, and showed excellent correlation with the TD-DFT electronic excitations between
348-353 nm (gas phase). The other experimental absorption peak to take into account ranged
from 415-427 nm, which indicated the presence of the S→SnIV LMCT band; TD-DFT
predicted equivalent transitions between 428-438 nm. The HOMO in 1-6 was primarily
located on the dithiocarbazate backbone, the phenyl ring of the aldehyde moiety, and the
oxygen atom coordinated to central tin. The LUMO centred on the dithiocarbazate backbone
and phenyl ring of aldehyde. Analysis of these frontier MO’s (Fig. 1) supported the
hypothesis that the n→π* transition occurred due to the presence of the electron lone-pairs in
the azomethine nitrogen, thiolate sulphur and phenoxide oxygen atoms. The π→π* transition
observed in all tin(IV) compounds corresponded to the electron delocalisation around the
aromatic rings. Complete transitions are tabulated in Table S4.
11

Fig. 1. Frontier MOs of (a) 1, (b) 2, (c) 3, (d) 4, (e) 5 and (f) 6.
3.5
X-ray crystallography
Crystal structure determinations were achieved for each of the homoleptic compounds 2 and
3; selected geometric parameters are collected in Table S5. The crystallographic asymmetric
unit of 2 comprises two independent molecules with the first shown in Fig. 2(a) and the
second molecule shown in Fig. S2. For 3, one molecule comprises the asymmetric unit, Fig.
2(b). For the first independent molecule of 2, the dinegative tridentate ligand coordinates the
tin atom via thiolate-S, phenoxide-O and imine-N atoms to establish five-membered
Sn,S,C,N2 and six-membered Sn,O,C3,N rings. Evidence for the presence of thiolate-sulphur
12

atoms is found in the elongation of the C1−S1 and C18−S3 bond lengths (Table S5) from
1.670(2) Å, which is found in the most closely related acid molecule for which a
crystallographic analysis has been reported, i.e. the benzyl ester rather than the 4-tolylCH2
ester [37]. Concomitantly, the C1−N1 and C18−N3 bond lengths (Table S5) have decreased
considerably from 1.338(2) Å in the acid [37]. The conformation of the two tridentate ligands
is such that all like atoms are mutually trans in a distorted octahedral environment. The
major distortions from the ideal octahedral geometries are due to the acute chelate angles in
the five-membered rings, i.e. 78.88(7)° for S1−Sn−N2 and 78.94(7)° for the S3−Sn−N4
angle.
The S1-five-membered chelate ring formed by the tridentate ligand is strictly planar with the
RMSD of the fitted atoms being 0.0036 Å. However, the S3-ring is less planar with the
RMSD being 0.0629 Å. A better description for the latter is an envelope in which the tin
atom lies 0.308(4) Å out of the least-squares plane defined by the remaining four atoms
(RMSD = 0.0060 Å). Envelope conformations also apply for the six-membered chelate
rings. For the O1-ring, the tin atom lies 0.579(4) Å out the plane through the five remaining
atoms. For the O3-ring the envelope is somewhat flattened with the tin atom 0.135(4) Å out
of the plane (RMSD = 0.0234 Å), see Table S6. The dihedral angle between the five-
membered chelate rings is 81.56(8)°.
As seen from the overlay diagram in Fig. 2(c), there are conformational differences between
the independent molecules of 2, at least with respect to the terminal thioester residues. The
data in Table S5 and Table S6 confirm the close similarity between the independent
molecules in terms of the tin-atom geometries.
The trends in the structure of 3 follow those established for 2, with the most obvious
difference relating to the coordination of the imine-N2 and N4 atoms. The angle they
subtend at the tin atom is wider by ca 6-7°, and there is evidence to suggest the Sn–N2, N4
bond lengths are marginally shorter than the equivalent bonds in the molecules of 2. Each of
the chelate rings adopts an envelope conformation with data presented in Table S6. The
dihedral angle between the five-membered chelate rings in 3 is 81.77(5)°, i.e. within
experimental error of the value computed for 2.
13

Fig. 2. Molecular structures of the molecules in (a) 2 (first independent molecule; the
structure for the second independent molecule is shown in Fig. S2) and (b) 3, showing atom
labelling schemes and 50% displacement ellipsoids. (c) Overlay diagram of the molecules in
14

2 (red image for the first independent molecule), 2a (green, inverted second molecule) and 3
(blue). Molecules have been overlapped so the Sn,S1,N2 chelate rings are coincident.
There are three related homoleptic tin(IV) compounds that have been structurally
characterised in the literature, namely the ethyl thioester and unsubstituted phenoxide residue
[50], benzyl thioester, unsubstituted phenoxide residue and methyl bound to the imine-carbon
[51] and benzyl thioester with a ferrocenyl substituent adjacent to the alkoxide-oxygen atom
[44]. The contrasting and curious feature of the literature structures is that the thiolate-
sulphur atoms are mutually cis, as are the alkoxide-oxygen atoms. The reasons for the
different conformations observed in 2 and 3, and those in the literature remain unclear.
In the absence of conventional hydrogen bonding, the crystals of 2 and 3 are sustained by a
variety of other non-covalent interactions; the geometric parameters characterising these are
included in the captions to the respective figures in the Tables 2 and 3. In the molecular
packing of 2, each of the independent molecules form equivalent intermolecular contacts with
the other independent molecule to sustain a supramolecular layer in the ab-plane. These are
imine-C2-H…S3(thiolate), imine-C19-H…S1(thiolate), methoxybenzene-C7-H…O2(methoxy),
methoxybenzene-C24-H…O4(methoxy) and π(C3-C8)…π(C20-C25). The connections
between layers along the c-axis direction are of the type methyl-C16a-H…O2a, methyl-C16-
H…π(C10-C15) and methoxy-C34-H…π(C10-C15). These occur between like-molecules and
hence, differentiate the independent molecules comprising the asymmetric unit in terms of
their supramolecular association. Images of the supramolecular association operating in the
crystal of 2 are shown in Fig. S3.
As seen in Fig. S4, supramolecular layers in the ab-plane are also formed in the crystal of 3
via a combination of methoxybenzene-C7–H…O4(methoxy), methoxybenzene-C23–
H…O2(methoxy), methylene-C25–H…S1(thiolate), methoxy-C16–H…π(C10-C15) and π(C3-
C8)…π(C3…C8) interactions. Layers inter-digitate along the c-axis direction but, without
directional interactions between them. Geometric parameters characterising intermolecular
interactions in the crystal of 3 are given in Table 3.
15

Table 2
Geometric parameters (Å, °) characterising intermolecular interactions in the crystal of 2.
A
H
B
H…B A…B
A–H…B Symmetry operation
C2
H2
H2a
H7
H7a
S3a
S3
2.81
2.81
2.49
2.49
2.56
2.72
2.77
2.45
2.53
2.85
2.84
3.721(3) 162
3.628(3) 145
-1+x, y, z
C2A
C7
1+x, y, z
O2a
O2
3.421(4) 166
3.267(4) 139
3.425(4) 147
3.564(3) 148
3.699(3) 166
3.267(4) 144
3.464(3) 169
3.533(4) 127
3.609(4) 136
3.4564(19)
½-x, -½+y, ½-z
1½-x, ½+y, ½-z
-1+x, y, z
C7a
C16a H16f O2a
C19 H19 S1a
C19a H19a S1
C24 H24 O4a
C24a H24a O4
x, y, z
x, y, z
1½-x, -½+y, ½-z
½-x, ½+y, ½-z
-x, -y, -z
C16
C34
H16b Cg(C10-C15)
H34b Cg(C10-C15)
-x, -y, -z
Cg(C3-C8)
Cg(C20a-C25a)
Cg(C3a-C8a)
½-x, -½+y, ½-z
1½-x, -½+y, ½-z
Cg(C20-C25)
3.5716(19)
Table 3
Geometric parameters (Å, °) characterising intermolecular interactions in the crystal of 3.
A
H
B
H…B A…B
A–H…B Symmetry operation
C7
H7
H23
O4
O2
2.60
2.37
2.79
2.95
3.487(3) 156
3.140(3) 138
1-x, -y, 2-z
C23
C25
C16
2-x, -y, 2-z
2-x, 1-y, 2-z
1-x, -y, 2-z
1-x, -y, 2-z
H25b S1
3.645(3) 145
3.354(4) 106
3.5623(15)
H16a Cg(C10-C15)
Cg(C3-C8)
Cg(C3-C8)
16

3.6
In vitro cytotoxic activity
The cytotoxic assay of 1, 3, 4, 5 and 6 were carried out against a panel ten of cancer cell lines
and one normal cancer cell line. All the compounds, except compound 2 used in this work
were insoluble in water. However, they were very soluble in DMSO, and the presence of 1%
DMSO proved sufficient for their dissolution in aqueous media for cytotoxicity test. The
stability of the compounds was analysed by monitoring the electronic spectra of the
compounds in DMSO as well as DMSO-H2O (1:99) over 72 h at room temperature, and an
unchanged pattern in the spectra was indicative that the compounds were stable in both the
solvent systems tested. We were unable to determine the cytotoxicity of 2 due to its
insolubility in 100% DMSO at 1 mM. Cisplatin (standard drug) was used as a positive control
and DMSO was used as the negative control. Table 4 shows that the cytotoxicity of the
tin(IV) compounds and their respective Schiff bases. 1, 3, 4, 5 and 6 exhibited moderate
activity against all the tested cancer cell lines. The cytotoxicities of these compounds against
HT29, MCF7 and MIA were higher than cisplatin. With respect to the cytotoxicity of the
precursor Schiff bases, 1, 2, 5 and 6 were equipotent to their corresponding Schiff bases, with
the exception of 4. Compound 4 demonstrated higher potency than their corresponding Schiff
bases against HT29, U87, MCF-7, A431 and Du145 cells. The mechanism of action of 4 is
worthy of further in-depth investigation. In general, for compounds 1, 2, 5 and 6, it can be
inferred that the presence of tin does not influence cytotoxicity. This is possibly due to the
bulkiness of the compound and only the coordinated Schiff bases playing a role in binding to
macromolecules [52].
17

Table 4
Summary of the in vitro cytotoxicity of tin(IV) compounds in several cell lines, determined by the MTT assay and expressed as a GI50 value with
standard error. GI50 is the concentration of tin(IV) compounds at which cell growth is inhibited at 50% over 72 hours.
Growth inhibition concentration, GI50 (µM)
Compounds
HT29
U87
MCF-7
A2780
H460
A431
Du145
BE2-C
SJ-G2
MIA
MCF10A
H2L1
1
H2L2
2
3.9 ± 0.71
3.9 ± 0.53
8.0 ± 3.5
nd
4.3 ± 0.30
4.2 ± 0.03
3.9 ± 0.00
nd
2.7 ± 0.21
2.9 ± 0.07
3.5 ± 0.00
nd
3.2 ± 0.15
3.3 ± 0.10
3.1 ± 0.40
nd
4.3 ± 0.12
4.0 ± 0.09
5.5 ± 0.73
nd
3.8 ± 0.033
3.8 ± 0.15
4.2 ± 0.74
nd
4.1 ± 0.09
4.6 ± 0.17
5.4 ± 0.23
nd
3.1 ± 0.00
3.0 ± 0.13
3.6 ± 0.27
nd
3.0 ± 0.09
2.9 ± 0.12
3.3 ± 0.87
nd
4.9 ± 0.37
4.2 ± 0.27
11 ± 2.3
nd
3.1 ± 0.07
3.2 ± 0.21
3.5 ± 0.23
nd
H2L3
3
2.2 ± 0.033
2.5 ± 0.30
3.1 ± 0.26
3.1 ± 0.13
2.5 ± 0.12
2.5 ± 0.23
3.0 ± 0.06
2.6 ± 0.12
3.3 ± 0.21
3.0 ± 0.12
3.0 ± 0.15
2.5 ± 0.32
3.4 ± 0.30
3.5 ± 0.26
2.8 ± 0.20
2.1 ± 0.00
2.4 ± 0.26
1.4 ± 0.36
4.5 ± 0.25
2.7 ± 0.21
3.0 ± 0.067
2.8 ± 0.19
H2L4
4
H2L5
5
H2L6
6
SnCl2
Cisplatin
10 ± 3.5
4.4 ± 0.83
2.8 ± 0.033
3.3 ± 0.26
2.1 ± 0.35
2.1 ± 0.44
> 25
20 ± 5.2
9.3 ± 1.8
4.0 ± 0.43
4.8 ± 0.52
2.7 ± 0.47
3.3 ± 0.23
> 25
10 ± 3.1
4.4 ± 1.9
2.8 ± 0.067
3.0 ± 0.15
2.3 ± 0.32
2.2 ± 0.20
> 25
1.8 ± 1.2
2.7 ± 0.20
2.8 ± 0.20
3.3 ± 0.26
2.2 ± 0.25
2.4 ± 0.38
> 25
8.7 ± 1.9
4.7 ± 0.23
3.7 ± 0.10
4.2 ± 0.12
2.6 ± 0.27
2.1 ± 0.28
> 25
14 ± 1.5
3.7 ± 0.25
3.7 ± 0.20
3.7 ± 0.32
2.4 ± 0.26
2.8 ± 0.23
> 25
23 ± 3.6
6.4 ± 1.4
4.2 ± 0.59
6.0 ± 0.58
2.8 ± 0.15
3.8 ± 0.52
> 25
0.38 ± 0.07
1.7 ± 0.33
3.2 ± 0.30
2.7 ± 0.43
2.0 ± 0.23
2.1 ± 0.17
> 25
6.4 ± 2.2
1.9 ± 0.36
3.3 ± 0.30
3.0 ± 0.27
2.2 ± 0.47
1.4 ± 0.23
> 25
5.5 ± 1.1
4.6 ± 0.97
6.6 ± 1.7
11 ± 0.88
2.2 ± 0.64
2.5 ± 0.64
> 25
3.7 ± 0.50
3.3 ± 0.19
2.9 ± 0.033
2.8 ± 0.33
2.9 ± 0.21
2.8 ± 0.088
> 25
11.0 ± 2.0
4.0 ± 1.0
6.5 ± 0.8
1.0 ± 0.1
0.9 ± 0.2
2.4 ± 0.3
1.2 ± 0.1
1.9 ± 0.2
0.4 ± 0.1
8.0 ± 1.0
nd
GI50 (μM): (the colors indicate) = 0.1 – 0.99; = 1.0 – 9.9; = 10 - 100; = nd (not determined)
(The compounds H2L1, H2L2 and H2L3 published as S2MoVaH, S4MoVaH, SBoVaH, respectively in ref [36])
18

4.
Conclusions
Six octahedral tin(IV) compounds were synthesised by the condensation reaction of tin(II)
chloride with dithiocarbazate Schiff bases. The oxidation of tin(II) to tin(IV) occurred in this
work as two binegatively charged Schiff bases ONS-bonded to the tin centre with general
formulae [Sn(Ln)2]. X-ray crystallography indicated that the dinegative tridentate ligands of 2
and 3 coordinated to the tin atoms via thiolate-S, phenoxide-O and imine-N atoms, leading to
octahedral geometries in which the like-atoms were mutually trans. The in vitro cytotoxicity
against a panel of cancer cell lines viz., HT29, U87, SJ-G2, MCF-7, A2780, H460, A431,
Du145, BE2-C and MIA cancer cell lines revealed that compounds 1, 3, 5 and 6 showed
moderate cytotoxicity; similar to that of their respective Schiff bases. However, compound 4
exhibited a higher potency against HT29, U87, MCF-7, A431 and Du145 cells as compared
to the precursor Schiff base.
Acknowledgements
We thank the Department of Chemistry, the Discipline of Chemistry, University of Newcastle
and the Calvary Mater Hospital, Newcastle, Australia for their facilities. This research was
funded by Universiti Putra Malaysia under the Putra Group Initiative (IPB No. 9581001) and
the Malaysian Fundamental Research Grant Scheme (FRGS No. 01-01-16-1833FR).
Crystallographic research at Sunway University is supported by Sunway University Sdn Bhd
(Grant. no. STR-RCTR-RCCM-001-2019). E.N.M.Y wishes to thank Ministry of Higher
Education Malaysia for the award of MyPhD, MyBrain15 and University of Newcastle for
the award of University of Newcastle International Postgraduate Research Scholarship,
University of Newcastle Research Scholarship Central. We thank Michela Simone, Robert
Burns, Karen A. Crouse and Adam McCluskey for helpful discussions.
Supplementary data
Crystallographic data for 2 and 3 reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre (CCDC) as supplementary publication nos 1916354
(2) and 1916354 (3).
These data can be obtained free of charge via
19

www.ccdc.cam.ac.uk/getstructures. Crystallographic diagrams and details of intermolecular
interactions are given in Figures S2-S4, Tables S5-S6.
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23

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Manuscript title: Homoleptic tin(IV) compounds containing tridentate ONS
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