Synthesis of new water soluble diorganotin(IV) complexes with hydrazones derived from Girard-T reagent as antibacterial and anticancer agents

Article abstract of DOI:10.1080/10426507.2016.1274751

Three new water-soluble organotin complexes R₂Sn(5-BrSalGT)Cl [R = Ph, Me] and Ph₂Sn(2-OHNaphGT)Cl have been synthesized by the reaction of R₂SnCl₂ (R = Ph or Me) with Schiff bases derived from condensation of G

Full text of DOI:10.1080/10426507.2016.1274751

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Water soluble tin(IV) complexes as antibacterial and anticancer agents
Synthesis of new water soluble diorganotin(IV) complexes with hydrazones derived from
Girard-T reagent as antibacterial and anticancer agents
Zeinab Ansari-Asl1,*, Tahereh Sedaghat1,*, Abbas Tarassoli1, Hossein Motamedi2, Elham
Hoveizi2
1Department of Chemistry, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz,
Iran
2Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
*Correspondence: z.ansari@scu.ac.ir
Abstract
Three new water soluble organotin complexes R2Sn(5-BrSalGT)Cl [R = Ph, Me] and Ph2Sn(2-
OHNaphGT)Cl have been synthesized by the reaction of R2SnCl2 (R = Ph or Me) with Schiff
bases derived from condensation of Girard-T reagent with 5-bromosalicylaldehyde and 2-
naphthaldehyde, (5-BrH2SalGT)Cl (1) and (2-OHH2NaphGT)Cl (2). The synthesized compounds
1
have been investigated by elemental analysis, conductometric measurements, IR, H NMR, and
119Sn NMR spectroscopy. These data show that the deporotonated ligand is coordinated to
Sn(IV) via ONO atoms and six-coordinate zwitterionic complexes are formed. The ligands and
their complexes were investigated for their in vitro toxicity against Gram-positive (Bacillus
subtilis and Staphylococcus aureus) and Gram-negative (Escherichia coli and Pseudomonas
aeruginosa) bacteria. The results show remarkable antibacterial activity against the studied
bacteria. All complexes exhibit more inhibitory effects than the parent ligand. The anticancer
activity of all compounds were also performed on HN5 cell line and (2-OHH2NaphGT)Cl with
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concentration of 1 mg mL1 was found to shows higher anticancer activity than other
compounds.
Keywords
Hydrazone, Organotin, Water solubility, Antibacterial activity, Anticancer activity
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1.
Introduction
During the past decades, the use of organotin compounds has increased dramatically, most likely
due to their diverse applications ranging from biological activity to catalysis for technical
processes, even though in recent years these have been circumscribed by environmental
considerations.1-3 One of the most interesting research areas in organotin compounds is the
investigation of their antitumor activities.4 Organotin complexes with a variety of ligands, such
as Schiff bases, have proven to be active against several tumor cell lines, but most of the
compounds reported to date are completely insoluble in water at physiological pH.5 Thus much
effort should be directed to overcome this obstacle. Solubility in water is an important issue,
dominating the in vivo testing of compounds with promising in vitro properties.6, 7 In addition,
organotins would be much more environmental friendly if their aqueous solubility could be
increased. Until now a few water soluble organotin compounds have been synthesized and tested
in vitro against some tumor cell lines. They have displayed significant activities, sometimes
much higher than that of cis-platin.8 During the last few years, condensation of Girard’s reagents
with ketones or aldehydes forms water-soluble ionic hydrazones represents an interesting
research subject and some transition metal complexes with these ligands have been reported.9-18
However, a survey of literature reveals that no attempt has been made to synthesize
organotin(IV) complexes of Girard reagent hydrazones. We have previously reported the first
organotin(IV) complexes with this type of ligands.19 In continuation of our studies, this paper
presents synthesis, characterization, anticancer activity, and antibacterial activity of three
organotin(IV) complexes with two Girard-T hydrazones, (5-BrH2SalGT)Cl (1) and (2-
OHH2NaphGT)Cl (2), derived from condensation of trimethylammoniumacetohydrazide
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chloride (Girard’s T reagent) with 5-bromosalicylaldehyde and 2-hydroxynaphthaldehyde,
respectively.
2.
Results and Discussion
2.1. Synthesis
The synthesis and crystal structure of (5-BrH2SalGT)Cl (1) have been reported earlier by
Revenko et. al.17 Herein we have prepared 1 and 2 according to a slightly modified procedure by
refluxing a solution of Girard’s T reagent and the corresponding aldehyde in 1:1 molar ratio in
methanol for 1 h (Figure 1). The organotin(IV) complexes, Ph2Sn(5-BrSalGT)Cl (3), Me2Sn(5-
BrSalGT)Cl (4) and Ph2Sn(2-OHNaphSalGT)Cl (5) were synthesized by refluxing a methanolic
solution of R2SnCl2 (R = Ph and Me) with the corresponding Schiff base in the presence of NEt3
as a base, in 1:1:2 molar ratio. As shown in Figure 1, the prepared ligands exist in two tautomeric
forms due to the ketoamide group in their structure. According to the literature,17 (5-
BrH2SalGT)Cl (1) in the solid state, is in the keto-amine form and the organic cation is
associated with chloride anion through hydrogen bond (Figure 1).
The Schiff bases and their complexes are well soluble in DMSO and DMF, less soluble in EtOH
and CHCl3 and insoluble in Et2O. The compounds 3 and 5 are relatively soluble and the others
are readily soluble in water and all of them are air-stable. The molar conductivity of Schiff bases
in DMF solutions refers to a 1:1 type electrolytes.20 The complexes have higher conductivity
than non-electrolytes. This can be due partly to solvation of the coordinated chloride.15 The new
compounds have been characterized by spectroscopic methods and our attempts for preparation
of crystals suitable for X-ray crystallography were unsuccessful.
2.2. Spectroscopic studies
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1
In the H NMR spectrum of 1 in DMSO, two groups of signals were observed that is related to
presence of two tautomeric forms in solution. A tautomeric form (I and II in Figure 1) ratio of
75:25 is obtained from the integrals of the signals. The 1H NMR spectrum of 2 is complex due to
presence of a mixture of tautomeric forms in solution and confident assignments are difficult.
1
However in the H NMR spectra of complexes, the absence of any signals at high frequency
assigned to acidic hydrogens suggests complete deprotonation of ligand and coordination of
phenolic and enolic oxygens to tin. Appearance of 117Sn satellites around the imine proton signal
3
in the spectra of 3, 4 and 5 with J(119Sn-H) coupling 34.0, 31.5 and 39.2 Hz, respectively,
indicates the involvment of imine nitrogen atom in the coordination with Sn(IV).
1
The H NMR spectrum of 4 shows a singlet at 1.33 ppm for SnMe2 protons accompanied by
2
satellites due to 119Sn-1H coupling. J(119Sn-1H) for this complex (89.6 Hz) is larger than
uncomplexed Me2SnCl2 (68.7 Hz) indicates the higher coordination number of tin. Substituation
of 2J(119Sn-1H) in the Lockhart-Manders equation,21 gives a value of 144.5° for Me-Sn-Me angle.
This value, in agreement with IR data, suggests a non-linear C-Sn-C moiety in the complexes.
The 119Sn{1H}NMR spectra of 3-5 show one sharp singlet at -456.3, -241.3 and -445.0 ppm.
These chemical shifts are at lower frequency than those of the original SnPh2Cl2 (-32 ppm) and
SnMe2Cl2 (+137 ppm) and indicate an increase in coordination number of tin. According to the
119Sn chemical shift ranges reported empirically,22-24 the Sn(IV) atom is six-coordinated in the all
synthesized complexes.
In the IR spectra of 1 and 2, a strong band which appeared at 1697 and 1704 cm1, respectively,
is assigned to ν(C = O) and indicates tautomeric form I for these compounds. The IR spectra of
complexes do not display this absorption band suggesting that the ligand coordinates with Sn(IV)
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in the enol form. The ν(O-H) and ν(N-H) are absent in the spectra of complexes due to
deprotonation of the Schiff base on coordination with tin(IV) atom. The new bands in the region
455-461 and 527-572 cm1 in the IR spectra of complexes are assigned to (Sn-N) and (Sn-O),
respectively.25-27 Presence of both sym(Sn-C) and asym(Sn-C) at 571 and 642 cm1, respectively,
in the IR spectrum of 4 is consistent with a nonlinear Me-Sn-Me configuration.28
Therefore, on the basis of our data and with considering the structure of transition metal
complexes with the similar ligands,9, 15, 17 the formally neutral structure shown in Figure 2 is
suggested for complexes.
[Insert Figure 2]
2.3. Antibacterial activity
The antibacterial activity of prepared compounds were assayed against four bacterium (Bacillus
sabtilis, Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa) under different
concentration with respect to Nalidixic acid, penicillin, Gentamycin, Streptomycin, and
Vancomycin as standard drugs. The results of the antibacterial activity, MIC, and MBC are
presented in Table S 1 and Table S 2 respectively. (Supplemental Materials)
The results showed that the all Schiff bases and their complexes have considerable activities
against both Gram-positive and Gram-negative bacteria species. In the most cases, organotin
complexes show more inhibitory effects than the parent ligands. It can be explained according to
Overton’s concept and Tweedy’s chelation theory.29, 30 On the basis of Overton’s concept, the
lipid membrane that surrounds the cell favors the passage of only the lipid-soluble materials
therefore lipo-solubility is an important factor, which controls the antimicrobial activity.
According to chelation theory the polarity of metal ions will be reduced due to the overlap of
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ligand orbitals and electron delocalization over the whole chelate ring enhances lipophilicity of
complexes. The inhibitory effects of complexes may be also related to the intrinsic biological
activity effects of organotin moiety. It is interesting that P. aeruginosa was remarkably inhibited
by all compounds, while many of the standard drugs are ineffective on this microorganism as
previously reported.31 The activity of 1 and its complexes may also be related to presence of
bromine in the structure. It agrees with previous reports that the compounds having halogens at
the aromatic ring showed a good inhibitory effect on bacterial growth.32, 33 In the case of
antibacterial activity studies it was found that synthesized Girard reagent-based Schiff bases and
their Sn(IV) complexes are more active than some non-zwitterionic Schiff bases such as N'-(5-
bromo-2-hydroxybenzylidene) isonicotinohydrazide, N'-((2-hydroxynaphthalen-1-yl)methylene)
isonicotinohydrazide,
(Furan-2-yl)(5-hydroxy-3-methyl-5-phenyl-4,5-dihydro-1H-pyrazol-1-
yl)methanone and their Sn(IV) complexes that previously reported by our research group.28, 34
This can be related to various factors such as higher conductivity, solubility in both water and
organic solvents, and dipole moment of prepared zwitterionic compounds.
2.4. Anticancer activity
Cell viability
The cytotoxicity assay (MTT assay) was carried out to evaluate the cell viability of cells in
culture. An augment in the % growth inhibition with increasing concentration of complexes on
HN5 cell line was determined. Cell viability is dependent on the interaction between the cells
and the medium culture. The results of MTT assay for 1-day cell cultures are shown in Figure S
1. These results showed that there is significantly higher viability in control samples than cells
exposure to the more complexes. (Data for control samples do not show separately in Figure S 1
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but it was used to calculate the cell’s viability values). It means that these complexes have
anticancer activity in tested concentrations. In the following days (Day 2 and Day 3) the viability
of treated cells decreased relative to cells cultured in the control samples. In this study the
synthesized compounds have been screened for their anticancer activity. The Me2Sn(5-
BrSalGT)Cl (indicated with number of 4 in Figure S 1) exhibited higher cytotoxic activity than
its corresponding ligand (indicated with number of 1 in Figure S 1). This may due to the
chelation process that increases the lipophilic character of complex and biological activity effects
of the organotin moiety.35, 36 According to our findings, diphenyltin(IV) complexes are less
effective for cytotoxic activity than their parent ligands. This is in disagreement with earlier
reports on the anticancer activity of similar complexes.37, 38 This observation can be related to
their moderate water solubility. The cell viability data of HN5 cells show that the 0.1 mg mL1,
and 1 mg mL1 doses of (2-OHH2NaphGT)Cl (more effective component indicated with number
of 2 in Figure S 1) resulted in significant reduction in cell viability of approximately 10.7% and
9% respectively as compared to control after 1 d. According to these data we can suggest these
complexes as effective components for cancer therapy in future.
Cell death
DAPI is a kind of specific dye for binding DNA. With the process of cell death, the ability of
permeability for dye is improved and the dead cells will produce high blue fluorescence. As
shown in Figure S 2, in the present investigation after 24 h exposure to the synthesized
compounds, the cells exhibited characteristic cell death features in a dose dependent manner such
as chromatin condensation and intensely fluorescent nuclear condensation as observed under a
fluorescence microscope using DAPI staining. Microscopic observation showed that the normal
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cells had normal forms with a round and uniformity nucleus while, dead cells had the round form
with chromatin condensation and fragmentation of the nucleus. The treated cells exhibited
fragmented and condensed nuclei’s showing cellular shrinkage which is a characteristic feature
of apoptosis.
3.
Conclusion
Three new zwitterionic organotin(IV) complexes, R2Sn(5-BrSalGT)Cl [R = Ph, Me] and
Ph2Sn(2-OHNaphGT)Cl were synthesized and characterized. On the basis of above disscussion,
it is suggested that the coordination number of Sn(IV) is six, involving one ONO tridentate schiff
base, two organic groups and one chloride. The Schiff base acts as a double-deprotonated ligand
coordinated through phenolic and enolic oxygens and imine nitrogen. The synthesized organotin
complexes show remarkable activity against both Gram-positive (B. subtilis and S. aureus) and
Gram-negative (E. coli and P. aeruginosa) bacterial species. Since most research studies on the
new anti-tumor drugs dealing with antibiotics affecting Gram-negative bacteria, it is possible that
these new synthesized organotin(IV) complexes have also anti-tumor effects. Although the
mechanism of biological action of organotin derivatives is still not clear, in designing new anti-
tumor tin compounds it is necessary to individuate a balance between solubility and lipophilicity
features in order to achieve ideal efficacy. Cell viability results proposed that treatment of ligand
and complexes significantly reduces the cell viability of cancer cell line in a dose dependent
manner and these compounds can enhance cytotoxic activities against tumor cell lines. Therefore
with due attention to water solubility of synthesized compounds they may be excellent
candidates to be used as drugs and have the potential to be a promising alternative to anticancer
agents.
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4.
Experimental
4.1. Materials and methods
All chemicals were obtained from Merck except diphenyltin dichloride and Girard-T reagent
which were respectively purchased from Alfa Aesar and Acros Company, and all were used as
received. All solvents were of reagent grade and used without further purification. Fourier
transform infrared spectra were recorded by a FT BOMEM MB102 spectrophotometer in the
1
400-4000 cm1 wavenumber range. The H and 119Sn{H} NMR spectra were obtained on a
Bruker 400 MHz Avance Ultrashield spectrometer using TMS and SnMe4, as references,
respectively. The molar conductivity of 1mM solutions of synthesized compounds in anhydrous
dimethylformamide were measured on a METROHM 644 conductometer. The Supplemental
Materials contians 1H and 119Sn NMR spectra of the ligands and complexes (Figures S 3 -- S 10)
4.2. Synthesis of ligands and theirs complexes
(5-BrH2SalGT)Cl (1)
(5-BrH2SalGT)Cl (1) was prepared according to a modified procedure described in the
literature:17 5-bromo-2-hydroxybenzaldehyde (1.005 g, 5 mmol) in methanol (5 mL) was
added to a stirring solution of Girard-T (0.838 g, 5 mmol) in methanol (7 mL). This
solution was refluxed for 60 min. A white precipitate was formed after slow evaporation
of solvent at room temperature. The resulting product was collected and washed with
ethanol.
(2-OHH2NaphGT)Cl (2)
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This compound was synthesized as described for (1) from 2-hydroxynaphthaldehyde (0.861 g, 5
mmol). Yield: 74%; m.p. 198 C; Anal. Calc. for C16H20N3O2Cl(%): C, 59.72; H, 6.22; N, 13.06.
Found: C, 60.02; H, 5.85; N, 12.76. ʌM (DMF): 101 S cm2 mol1. FT-IR (KBr, cm1): 3443-3438
br, (OH); 3020, 2949, (CH); 1704, ν(C = O); 1624, ν(C = N).
Ph2Sn(5-BrSalGT)Cl (3)
Triethylamine (0.28 mL, 2 mmol) was added to a stirring solution of (5-BrH2SalGT)Cl (0.351 g,
1 mmol) in absolute methanol (7 mL). This solution was stirred for 15 min. Then a solution of
Ph2SnCl2 (0.340 g, 1mmol) in methanol (3 mL) was added and the solution was refluxed for 120
min at 80 C. A yellow precipitate was formed after evaporation the solvent at room temperature.
This product was collected, washed with cool ethanol and dried in vacuum on CaCl2. Yield: 0.38
g (61%); m.p 298 C;Anal. Calc. for C24H25N3O2BrClSn (%): C, 46.38; H, 4.05; N, 6.76. Found:
C, 46.70; H, 4.03; N, 7.20. ʌM (DMF): 61 S cm2 mol1. FT-IR (KBr, cm1): 1617, ν(C = N); 545,
1
ν(Sn-O); 460, ν(Sn-N). H NMR (DMSO-d6): δ = 8.57 [s, 1H, H7, 3J(119Sn-1H) = 35.0 Hz], 7.63
(s, 1H, H6), 7.56 [d, 4H, Ho in SnPh2, 3JHH = 6.2, 3J(119Sn-1H) = 88.5 Hz], 7.40 (d, 1H, H4, 3JHH
=
3
8.9 Hz), 7.34-7.27 (m, 6H, Hm,p in SnPh2), 6.79 (d, 1H, H3, JHH = 8.9 Hz), 4.14 (s, 2H, CH2),
3.09 (s, 9H, N-CH3). 119Sn{1H}NMR (DMSO-d6): δ = - 456.3.
Me2Sn(5-BrSalGT)Cl (4)
This complex was synthesized as described for (3) from Me2SnCl2 (0.219 g, 1 mmol). Yield:
0.26 g (52%); m.p. 280 C; Anal. Calc. for C14H21N3O2BrClSn (%): C, 33.81; H, 4.25; N, 8.45.
Found: C, 34.01; H, 4.70; N, 8.83. ʌM (DMF): 79 S cm2 mol1. FT-IR (KBr, cm1): 1618, ν(C =
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1
N); 571, sym(Sn-C); 642,asym(Sn-C); 527, ν(Sn-O); 461, ν(Sn-N). H NMR (DMSO-d6): δ =
3
3
9.11 [s, 1H, H7, J(119Sn-1H) = 31.5 Hz], 8.06 (s, 1H, H6), 7.97 (d, 1H, H4, JHH = 9.0 Hz), 7.21
(d, 1H, H3, 3JHH = 8.9 Hz), 4.60 (s, 2H, CH2), 3.79 (s, 9H, N-CH3), 1.33 [s, 6H, Sn-CH3, 2J(119Sn-
1H) = 89.6 Hz]. 119Sn{1H}NMR (DMSO-d6): δ = - 214.3.
Ph2Sn(2-OHNaphGT)Cl (5)
This complex was synthesized as described for (3) from (2-OHNaphSalGT)Cl (0.322 g, 1
mmol). Yield: 0.38 g (64%); m.p. 270 C; Anal. Calc. for C28H28N3O2ClSn (%): C, 56.74; H,
4.76; N, 7.09. Found: C, 56.32; H, 4.60; N, 7.05. ʌM (DMF): 92 S cm2 mol1. FT-IR (KBr, cm1):
1603, ν(C = N); 572, ν(Sn-O); 455, ν(Sn- N). 1H NMR (DMSO-d6): δ = 9.40 [s, 1H, H7, 3J(119Sn-
1H) = 39.2 Hz], 8.13 (d, 1H, Hd, 3JHH = 8.6 Hz), 7.90 (d, 1H, H3, 3JHH = 9.0 Hz), 7.78 (d, 1H, Ha,
3
3
3JHH = 7.9 Hz), 7.62 [d, 4H, Ho in SnPh2, JHH = 7.0, J(119Sn-1H) = 88.6 Hz], 7.49 (t, 1H, Hc,
3JHH = 8.2 Hz), 7.33-7.25 (m, 6H, Hm,p in SnPh2 and Hb), 7.10 (d, 1H, H4, 3JHH = 9.0 Hz), 4.17 (s,
2H, CH2), 3.15 (s, 9H, N-CH3). 119Sn{1H}NMR (DMSO-d6): δ = - 445.0.
.3.4
Antibacterial tests
The antibacterial activity of synthesized compounds was investigated in vitro against two Gram-
positive (Bacillus subtilis ATCC 12711 and Staphylococcus aureus ATCC 6538) and two Gram-
negative (Escherichia coli ATCC 11303 and Pseudomonas aeruginosa ATCC 27853) bacteria
using the paper-disc diffusion method. The results were compared with standard antibacterial
drugs, Vancomycin (30 mg/disc), Nalidixic acid (30 mg/disc), Streptomycin (10 mg/disc),
penicillin (10 mg/disc), and Gentamicin (10 mg/disc). The solutions of 3 and 5 in DMSO and 1,
2, and 4 in H2O were prepared at 5, 10, 20 and 40 mg mL1 concentration. Basal media for the
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assay of the organisms was prepared by using Muller Hinton broth. Lawn culture of all strains
(0.5 MacFarland standard) were exposed to paper discs inoculated with 40 L of test compounds
or DMSO as a control. Finally, the plates were incubated at 37 C for 24 h where inhibition
zones diameters around each disc were measured in mm. The value of MIC and MBC for all
prepared compounds was also determined.
4.4. Anticancer tests
Cell line culture
HN5 cancer cell line was purchased from Iran Pasteur Institute, Tehran, Iran. Cell line were
cultured and maintained in DMEM medium supplemented with 10% FBS, 1%
penicillin/streptomycin at 37°C with 5% CO2. HN5 (3×106) cells were seeded in T-25 tissue
culture flask (Orange Scientific, USA) in 10 ml DMEM medium,10% FBS until confluent. When
90% confluence was obtained, the cells were passaged.
Cell viability analysis
MTT assay
The cell numbers of viable cells in the culture plates were quantitatively assessed with 3-(4,5-
dimethylthiazol-2-yl)-diphenyltetrazolium bromide (MTT, Sigma). The solutions of prepared
compounds were prepared at 0.1 and 1 mg mL1 concentration in water. After 1, 2 and 3 d of cell
culture with the prepared solutions, cells were washed with PBS and incubated with MTT (5 mg
mL1) containing serum free medium. After 3 h of incubation at 37 C in 5% CO2, The MTT
formazan were dissolved in DMSO (300 mL) and transferred to a 96-well plate. The absorbance
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of the content of each well was measured at 570 nm using a spectrophotometric plate reader
(Expert 96, Asys Hitch, Ec Austria).
Nuclear morphology assay:
DAPI staining was performed to determine cell death. Briefly the cells were seeded into
sterilized 24 well plate for 24 h and treated with the Schiff bases and their complexes for another
24 h. Untreated cells were used as controls. Treated cells and controls were rinsed with
phosphate buffered saline (PBS) fixed with paraformaldehyde 4% stained with 1μg mL1 4,6-
diamidino-2-phenylindose (DAPI) for 2 min to reduce the background, the stained cells were
washed with PBS and observed under a fluorescence microscope (Olympus, Japan).
Acknowledgments
Support of this work by Shahid Chamran University of Ahvaz, Ahvaz, Iran (Grant 1391) is
gratefully acknowledged.
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3
HO
2
H3C
H3C
HO
4
O
O
H3C
H3C
1
N
N
N
NH2
5
8
O
N
H
X
N
H
6
+
9
X
7
H3C
H3C
Cl
Y
H
Y
Cl
(I)
HO
(5-BrH2SalGT)Cl (1): X = Br, Y = H
H3C
OH
a
b
H3C
N
N
(2-OHH2NaphGT)Cl (2): X, Y =
c
N
X
d
H3C
Cl
Y
(II)
Figure 1 Synthetic pathway and tautomeric forms, keto-amine (I) and enol-imine (II), of Schiff
bases.
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Cl
R
R
O
Sn
H3C
O
(3) R = Ph, X = Br, Y = H
(4) R = Me, X = Br, Y = H
H3C
N
N
N
X
(5) R = Ph, X, Y =
H3C
Y
Figure 2 Suggested structure for organotin complexes.
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