Triphenylstannyl((arylimino)methyl)benzoates with selective potency that induce G1 and G2/M cell cycle arrest and trigger apoptosis: Via ROS in human cervical cancer cells

Article abstract of DOI:10.1039/c7dt04037g

Metal complexes with organelle specificity and potent but selective cytotoxicity are highly desirable. A novel series of triphenylstannyl 4-((arylimino)methyl)benzoates (2-8) were obtained by the reactions of triphenylstannyl 4-formylbenzoate [Ph₃Sn(L¹)] 1 with primary aromatic amines. Two representative compounds (10, 11) were also synthesized by reacting aqua-triphenylstannyl 2-formylbenzoate [Ph₃Sn(L⁹)(H₂O)] (9) with aniline and p-fluoroaniline, respectively. These compounds were characterized by elemental analysis, IR and ¹H, ¹³C and ¹¹⁹Sn NMR spectroscopy, as well as single-crystal X-ray diffraction for compounds 5, 7-11 and three pro-ligands. The in vitro cytotoxic activities of 1-11 were assessed using the MTT tetrazolium dye assay against HeLa (human cervical) and MDA-MB-231 (breast) cancer cells, with IC₅₀ values revealing high activity. Compared to cisplatin, compounds 1-11 exhibited enhanced cytotoxic efficacy, indicating their potential as potent anticancer agents. Among these, 1 and 5 demonstrated maximum inhibition in HeLa cells, with negligible effect on normal human embryonic kidney (HEK) cells. The combined results of the DCFH-DA dye and Hoechst 33342/PI nuclear staining assays, along with flow cytometry analysis, show that they possess a dual mode of action: They induced apoptotic cell death, attributable to the tin-assisted generation of reactive oxygen species. Cell cycle analyses indicated that compounds 1 and 5 exhibit cell growth inhibition and may cause turbulences in the G1 and G2/M phases.

Full text of DOI:10.1039/c7dt04037g

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Triphenylstannyl((arylimino)methyl)benzoates with selective potency that
induce G1 and G2/M cell cycle arrest and trigger apoptosis via ROS in human
cervical cancer cells
Tushar S. Basu Baul,*a Imliwati Longkumer, Andrew Duthie,b Priya Singh,c Biplob Koch,*c
M. Fátima C. Guedes da Silva,*d
Abstract
Metal complexes with organelle specificity and potent but selective cytotoxicity are highly desirable. A
novel series of triphenylstannyl 4ꢀ((arylimino)methyl)benzoates (2ꢀ8) were obtained by reactions of
triphenylstannyl 4ꢀformylbenzoate [Ph3Sn(L1)] 1 with primary aromatic amines. Two representative
compounds (10, 11) were also synthesized by reacting aquaꢀtriphenylstannyl 2ꢀformylbenzoate
[Ph3Sn(L9)(H2O)] (9) with aniline and pꢀfluoroaniline, respectively. These compounds were characterized
1
by elemental analysis, IR and H, 13C and 119Sn NMR spectroscopies, as well as singleꢀcrystal Xꢀray
diffraction for compounds 5, 7ꢀ11 and three proꢀligands. In vitro cytotoxic activities of 1ꢀ11 were
assessed by MMT tetrazolium dye assay against HeLa (human cervical) and MDAꢀMBꢀ231 (breast)
cancer cells; with IC50 values revealing high activity. Compared to cisplatin, compounds 1ꢀ11 exhibited
enhanced cytotoxic efficacy, indicating their potential as potent anticancer agents. Among these, 1 and 5
demonstrated maximum inhibition in HeLa cells, with negligible effect on normal human embryonic
kidney (HEK) cells. Combined results of DCFHꢀDA dye and Hoechst 33342/PI nuclear staining assays,
along with flow cytometry analysis, show they possess a dual mode of action; induced apoptotic cell
death, attributable to tinꢀassisted generation of reactive oxygen species. Cell cycle analyses indicated that
compounds 1 and 5 exhibit cell growth inhibition and may cause turbulences in G1 and G2/M phases.
_______________________________________________
1

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DOI: 10.1039/C7DT04037G
aCentre for Advanced Studies in Chemistry, NorthꢀEastern Hill University, NEHU Permanent Campus,
Umshing, Shillong 793 022, India; Eꢀmail: basubaul@nehu.ac.in, basubaulchem@gmail.com; Fax: +91ꢀ
3642721000; Tel: +91ꢀ3642722626
bSchool of Life & Environmental Science, Deakin University, Geelong, Victoria 3217, Australia
cGenotoxicology and Cancer Biology Lab, Department of Zoology, Banaras Hindu University, Varanasi,
India
dCentro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1,
1049ꢀ001 Lisboa, Portugal
†Electronic supplementary information (ESI) available: CCDC reference numbers 1533444ꢀ1533452. For
ESI and crystallographic data in CIF format see DOI: XXXXX
2

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Introduction
The extensive usage of cisplatin, cisꢀdiamminedichloroplatinum(II) (CDDP) and analogous drugs is limited
by drug resistance and severe side effects including neurotoxicity, gastrointestinal toxicity, and
nepthrotoxicity.1ꢀ3 The first two are the major driving force behind current investigations and it is therefore
of great significance to develop other metal based cancer chemotherapies. The substantial current
investigation of other metal complexes (of Ru, Cu, Au, Pd, Fe, Co, Ti, Ga, Ni, Rh, Ir, Sn, Os, Zn, V, Ag,
Re, Mo and lanthanide) is underway that may help to avoid or improve the problems associated with the
use of platinum compounds.4,5 The chemistry of organotin(IV) compounds is one of the wellꢀstudied areas
in organometallic chemistry and have shown acceptable in vitro cytoxicity and antiproliferative in vivo
activity as new chemotherapy agents besides diverse medicinal applications such as antiꢀviral, antiꢀ
microbial, antiꢀparasitic, antiꢀhypertensive, antiꢀhyperbilirubinemia activities.6ꢀ11 Other sustainable
chemistry applications include wood preservation to organic syntheses,12 carbon dioxide capture,13
homogenous catalysts in PVC stabilisation, polyurethane formation and trans esterification.14 In the cancer
chemotherapy arena, organotin(IV) compounds offer attractive properties such as not developing tumor
drug tolerance, lower general toxicity than platinum drugs, fewer side effects, and no emetogenesis, better
body clearance and increased water solubility.15 The current scenario in organotin chemistry is to attain an
ideal point between the activity and toxicity of the compounds for their novel uses as antitumor agents. For
this purpose, several triphenyltin(IV) carboxylates were investigated because the carboxylate group in the
molecule is vital for aqueous solubility, which results in increased cellular accumulation,16,17 while the
incorporation of the triphenyltin(IV) moiety in the molecule offers much higher activities when compared
with titanocene derivatives and cisplatin.18ꢀ20 In this pursuit, a biocompatible strategy of drug delivery
employing nanostructured silicaꢀbased material loaded with a triphenyltin(IV) compound has been used,
resulting in an increase in efficacy of the drug.21 However, the design of organotinꢀbased compounds with
good therapeutic index is still rather empirical. Details of specific or selective bonding of organotin(IV)
moiety to donor sites in biological structures is very limited and consequently reliable mechanisms of
biological activity and valid structureꢀactivity relationships are also limited. In previous studies, we have
3

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shown how triphenyltin(IV) carboxylates of the appropriate diazoꢀ and its isoelectronic iminoꢀ scaffolds
were endowed with anticancer properties when the carboxylate functionality was varied between orthoꢀ,
metaꢀ and paraꢀpositions.22
On the other hand, Schiff bases are versatile ligands that have been utilized in modern
organometallic and bioorganometallic chemistry.23ꢀ25 Schiff bases exhibit πꢀacceptor properties owing to
the basic nature of the imine nitrogen atom and the presence of proximate donor groups influences the
chelating ability, with the metal complexes used as catalysts in various reactions.26ꢀ28 The reversible nature
of imine bonds provides access to dynamic covalent chemistry, which is employed for the creation of
metalꢀorganic materials, covalent organic frameworks, and selfꢀassembled architectures that are promising
for sustainable energy, environmental, and biological applications.29ꢀ39
At this juncture, it was thought worthwhile to combine the anticancer properties exhibited by the
organotin(IV) compounds with the established biological effects of Schiff bases. The primary objective of
this work was the synthesis and characterization of a large group of new organotin(IV) Schiff base
derivatives where triphenyltin(IV) compounds are the focus of cytotoxicity studies. The choice of the
triphenyltin(IV) derivatives was based upon previously established optimal balance between the
cytotoxicity, solubility, and lypophilicity.22 With this precedent, in the current work the carboxylated Schiff
base ligands were combined with the biologically and pharmacologically active triphenyltin moiety in a
single chemical entity. It is believed that phenyltin(IV) derivatives may demonstrate efficacy with less
toxicity than other organotin(IV) derivatives due to their interaction with the cell membrane.40 Thus, it may
be anticipated that combined effects of the resulting coordination compounds may improve the activity and
this strategy perhaps could produce enhanced efficacy and reduced toxic effects.41 In an effort to improve
the cytotoxic potential of the compounds, we investigated triphenylstannyl 4ꢀformylbenzoate [Ph3Sn(L1)]
(1) and its reaction products with primary aromatic amine condensates i.e. triphenylstannyl 4ꢀ
((arylimino)methyl)benzoates (2ꢀ8), where the aniline Rꢀgroup moiety was varied and the benzoic acid part
of the molecule held constant. Additionally, two orthoꢀanalogues i.e. triphenylstannyl 2ꢀ
((arylimino)methyl)benzoates (10ꢀ11) were also isolated from the reactions of aquaꢀtriphenylstannyl 2ꢀ
4

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formylbenzoate [Ph3Sn(L9)(H2O)] (9) with aniline and pꢀfluoroaniline, respectively (Scheme 1). These two
derivatives are also reported here because modification of the carboxylate ligands can optimize
cytotoxicity22 while varying the location of the triphenyltin ester can modulate the activity at a specific
target. The proꢀligands HLn (n = 2ꢀ8) and the triphenyltin complexed Schiff bases (2ꢀ8, 10 and 11) were
spectroscopically characterized and the crystal structures of representative compounds 5, 7ꢀ11, along with
three proꢀligands HL3, HL5 and HL6, were determined by singleꢀcrystal Xꢀray diffraction.
In preceding studies, we have shown how [Ph3Sn(Ln)] compounds (Ln is isomeric 2/3/4ꢀ{(E)ꢀ2ꢀ[4ꢀ
(dimethylamino)phenyl]diazenyl}benzoates and their corresponding isoelectronic imino analogues 2/3/4ꢀ
[(E)ꢀ{[4ꢀ(dimethylamino)phenyl]methylidene}amino]benzoates) were endowed with anticancer properties. 22
Among these, triphenyltin(IV)ꢀ2ꢀ{(E)ꢀ2ꢀ[4ꢀ(dimethylamino)phenyl]diazenyl}benzoate and triphenyltin(IV)ꢀ
4ꢀ{(E)ꢀ2ꢀ[4ꢀ(dimethylamino)phenyl]diazenyl}benzoate, both functionalized with a diazo group, displayed
comparable activity towards MDAꢀMBꢀ231 (human breast cancer) cells. On the other hand, triphenyltin(IV)ꢀ
3ꢀ[(E)ꢀ{[4ꢀ(dimethylamino)phenyl]methylidene}amino]benzoate containing an imino framework
demonstrated superior activity (31ꢀfolds compared to CDDP) towards HeLa (human cervical cancer) cells,
importantly without affecting normal cells. The underlying investigation suggested that the compounds exert
potent antitumor effect by elevating intracellular ROS (reactive oxygen species) generation and induce delay
in cell cycle by inhibiting cells at G2/M phase. In accordance with this and with the intention of selecting the
best performing compounds for subsequent studies from a larger pool, the cytotoxic potential of the proꢀ
ligands
HLn,
3ꢀ(phenylamino)isobenzofuranꢀ1(3H)ꢀone
(PhthalideꢀH),
3ꢀ((4ꢀ
fluorophenyl)amino)isobenzofuranꢀ1(3H)ꢀone (PhthalideꢀF), triphenyltin(IV) compounds 2ꢀ8, 10 and 11, as
well as the two triphenyltin(IV) precursors 1 and 9, were probed on the HeLa and MDAꢀMBꢀ231 cells and
to find a link between the structural modifications and the cytotoxic performances. In this work, we aimed to
investigate whether triphenyltin compounds can induce intracellular oxidative stress and play a role in
delaying cell cycle. This was probed using MTT (3ꢀ(4,5ꢀdimethylthiazolꢀ2ꢀyl)ꢀ2,5ꢀdiphenyltetrazolium
bromide) assay, DCFHꢀDA (dichlorodihydroꢀfluorescein diacetate) dye, Hoechst 33342/PI (propidium
iodide), and PI staining studies.
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Experimental
Materials and physical measurements.
Aniline (Sd Fine) was freshly distilled prior to use, while all other chemicals were used as purchased
without purification: 4ꢀformylbenzoicacid (HL1), 2ꢀformylbenzoic acid (HL9), triphenyltin hydroxide
(Sigma Aldrich), pꢀtoludine (Merck), pꢀethylaniline (Sd Fine), pꢀanisidine (Sisco), pꢀethoxyaniline, pꢀ
fluoroaniline (Spectrochem) and N,Nꢀdimethylꢀ4ꢀphenylenediamine (Alfa Aesar). Solvents were purified
by standard procedures and were freshly distilled prior to use. Dulbecco’s modified eagle medium
(DMEM), fetal bovine serum (FBS) (Gibco, Life technologies), penicillin 1000 IU, streptomycin 10
mg/mL, Lꢀglutamine, trypsin, EDTA (Genetix Biotech Asia) 3ꢀ(4,5ꢀdimethylthiazolꢀ2ꢀyl)ꢀ2,5ꢀ
diphenyltetrazoliumbromide dye (MTT) (Himedia), dimethyl sulphoxide (DMSO), RNAse (GeNie,
Merck), 2',7'ꢀdichlorodihydrofluorescein diacetate (DCFHꢀDA), Hoechst 33342 (Sigma), propidium iodide
(PI) (EMD MilliporeꢀCalbiochem), cytoplatin (Cipla; generic nameꢀ cisplatin), Triton Xꢀ100 and other
analytical grade chemicals (Lobachemie) were used. Melting points were measured using a Büchi melting
point apparatus Mꢀ560 and are uncorrected. Elemental analyses were performed using a Perkin Elmer 2400
series II instrument. IR spectra in the range 4000ꢀ400 cm–1 were obtained on a Perkin Elmer Spectrum BX
1
13
series FTꢀIR spectrophotometer with samples investigated as KBr discs. H and C NMR spectra of proꢀ
ligands and triphenyltin(IV) compounds (1-11) were recorded on a Bruker AMX 400 spectrometer and
measured at 400.13 and 100.62 MHz, respectively. 119Sn NMR spectra were measured on a Jeol GX 270
spectrometer at 100.75 MHz. The 1H, 13C and 119Sn chemical shifts were referenced to Me4Si (δ 0.00 ppm),
CDCl3 (δ 77.00 ppm), and Me4Sn (δ 0.00 ppm), respectively. Equipment such as ELISA plate reader
microscan (ECIL, Hyderabad, MS 5608A), inverted fluorescence microscopy (Nikkon E800) and inverted
fluorescent microscope (Evos FL, Life technologies, AMF4300) were used for biological work.
Synthesis of pro-ligands
Synthesis of (E)-4-((phenylimino)methyl)benzoic acid (HL2). A toluene solution (2 mL) of aniline (0.15
g, 1.611 mmol) was added to a hot toluene solution (50 mL) containing 4ꢀformylbenzoic acid (0.25 g,
6

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1.665 mmol). The reaction mixture was heated to reflux for 4 h using a DeanꢀStark apparatus, whereupon
the solution turned yellow. It was was filtered while hot and the filtrate concentrated to one third of its
initial solvent volume, which upon standing at room temperature deposited a yellow microcrystalline
product. The residue was boiled with hexane (3 x 5 mL), filtered and dried in vacuo. The crude product was
then recrystallized from acetonitrile to give a yellow crystalline material in 51 % (0.21 g) yield. M.p.: 228ꢀ
230 °C. Anal. Found. C, 74.50; H, 5.10; N, 6.28. Calc. for C14H11NO2: C, 74.65; H, 4.92; N, 6.22 %. IR
1
(cmꢀ1): 1679 ν(OCO)asym, 1621 ν(C(H)=N), 1424, 1318, 1287, 1193, 775, 763, 699. H NMR (DMSOꢀd6):
δH; 8.70 [s, 1H, Hꢀ6], 7.57ꢀ8.15 [m, 4H, Hꢀ3 and Hꢀ4], 7.35ꢀ7.5 [m, 2H, Hꢀ8], 7.20ꢀ7.35 [m, 3H, Hꢀ9 and
13
Hꢀ10] ppm. C NMR (DMSOꢀd6): δC; 166.9 [Cꢀ1], 159.8 [Cꢀ6], 150.9, 139.5, 132.9, 129.7, 129.2, 128.7,
126.4, 121.1, 115.6, 113.8 [ArꢀC] ppm.
Synthesis of (E)-4-((p-tolylimino)methyl)benzoic acid (HL3). An analogous method to that used for the
preparation of HL2 was followed except that aniline was replaced by pꢀtoluidine (0.18 g, 1.682 mmol). The
product was crystallized from acetonitrileꢀDMF (10:1 v/v) mixture, giving yellow crystals of HL3 in 63%
yield. M.p.: 260ꢀ262 °C. Anal. Found. C, 74.90; H, 5.10; N, 6.28. Calc. for C15H13NO2: C, 75.30; H, 5.48;
1
N, 5.85 %. IR (cmꢀ1): 1685 ν(OCO)asym, 1624 ν(C(H)=N), 1501, 1423, 1309, 1288, 1125, 858, 539. H
NMR (DMSOꢀd6): δH; 8.48 [s, 1H, Hꢀ6], 7.75ꢀ7.90 [m, 4H, Hꢀ3 and Hꢀ4], 6.95ꢀ7.08 [m, 4H, Hꢀ8 and Hꢀ9],
2.09 [s, 3H, Hꢀ11] ppm. 13C NMR (DMSOꢀd6): δC; 166.9 [Cꢀ1], 158.7 [Cꢀ6], 148.3, 139.7, 135.9, 132.9,
129.7, 129.6, 128.5, 121.1 [ArꢀC], 20.6 [Cꢀ11] ppm.
Synthesis of (E)-4-(((p-ethylphenyl)imino)methyl)benzoic acid (HL4). An analogous method to that used
for the preparation of HL2 was followed except that aniline was replaced by pꢀethylaniline (0.17 g, 1.665
mmol). The product was crystallized from acetonitrile, giving yellow crystals of HL4 in 82% yield. M.p.:
240ꢀ242 °C. Anal. Found. C, 76.10; H, 5.90; N, 5.29. Calc. for C16H15NO2: C, 75.87; H, 5.97; N, 5.53 %.
IR (cmꢀ1): 1683 ν(OCO)asym, 1625ν(C(H)=N), 1610, 1499, 1426, 1319, 1291, 944, 553. 1H NMR (DMSOꢀ
d6): δH; 8.49 [s, 1H, Hꢀ6], 7.75ꢀ7.90 [m, 4H, Hꢀ3 and Hꢀ4], 6.95ꢀ7.10 [m, 4H, Hꢀ8 and Hꢀ9], 2.39 and 0.96
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[q, 7Hz, 2H and t, 6 Hz, 3H, Hꢀ11] ppm. 13C NMR (DMSOꢀd6): δC; 166.9 [Cꢀ1], 158.8 [Cꢀ6], 148.5, 142.3,
139.7, 132.8, 129.6, 128.5, 121.1, 113.9 [ArꢀC], 27.7 and 15.6 [Cꢀ11] ppm.
Synthesis of (E)-4-(((p-methoxyphenyl)imino)methyl)benzoic acid (HL5). An analogous method to that
used for the preparation of HL2 was followed except that aniline was replaced by pꢀanisidine (0.21 g, 1.705
mmol). The product was crystallized from methanol, giving yellow crystals of HL5 in 68% yield. M.p.:
224ꢀ226 °C. Anal. Found. C, 70.44; H, 5.20; N, 5.22. Calc. for C15H13NO3: C, 70.58; H, 5.13; N, 5.49 %.
IR (cmꢀ1): 1686 ν(OCO)asym, 1621 ν(C(H)=N), 1501, 1429, 1364, 1310, 1287, 1247, 1030, 835, 791, 549.
1H NMR (DMSOꢀd6): δH; 8.78 [s, 1H, Hꢀ6], 8.00ꢀ8.20 [m, 4H, Hꢀ3 and Hꢀ4], 7.41 [d, 8 Hz, 2H, Hꢀ8], 7.05
[d, 8 Hz, 2H, Hꢀ9], 3.84 [s, 3H, Hꢀ11] ppm. 13C NMR (DMSOꢀd6): δC; 166.9 [Cꢀ1], 158.3 [Cꢀ6], 157.2,
143.5, 139.9, 132.5, 129.6, 128.3, 122.6, 114.4 [ArꢀC], 55.2 [Cꢀ11] ppm.
Synthesis of (E)-4-(((p-ethoxyphenyl)imino)methyl)benzoic acid (HL6). An analogous method to that
used for the preparation of HL2 was followed except that aniline was replaced by pꢀethoxyaniline (0.23 g,
1.677 mmol). The product was crystallized from acetonitrileꢀDMF (10:1 v/v) mixture, giving yellow
crystals of HL6 in 80% yield. M.p.: 237ꢀ239 °C. Anal. Found. C, 70.94; H, 5.28; N, 5.22. Calc. for
C16H15NO3: C, 71.36; H, 5.61; N, 5.20 %. IR (cmꢀ1): 1678 ν(OCO)asym, 1625 ν(C(H)=N), 1591, 1503, 1424,
1
1288, 1245, 1116, 1046, 797, 541. H NMR (DMSOꢀd6): δH; 8.71 [s, 1H, Hꢀ6], 7.90ꢀ8.10 [m, 4H, Hꢀ3 and
Hꢀ4], 7.32 [d, 8 Hz, 2H, Hꢀ8], 6.96 [d, 8 Hz, 2H, Hꢀ9], 4.02 and 1.31 [q, 7Hz, 2H and t, 6Hz, 3H, Hꢀ11]
ppm. 13C NMR (DMSOꢀd6): δC; 166.9 [Cꢀ1], 157.6, 157.1 [Cꢀ6], 143.4, 139.9, 132.5, 129.6, 128.3, 122.6,
114.8 [ArꢀC], 63.2 and 14.6 [Cꢀ11] ppm.
Synthesis of (E)-4-(((p-fluorophenyl)imino)methyl)benzoic acid (HL7). An analogous method to that
used for the preparation of HL2 was followed except that aniline was replaced by pꢀfluoroaniline (0.18 g,
1.665 mmol). The product was crystallized from ethanol, giving yellow crystals of HL7 in 59% yield. M.p.:
232ꢀ234 °C. Anal. Found. C, 69.40; H, 4.28; N, 6.12. Calc. for C14H10FNO3: C, 69.13; H, 4.14; N, 5.76 %.
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IR (cmꢀ1): 1680 ν(OCO)asym, 1622 ν(C(H)=N), 1568, 1500, 1424, 1369, 1289, 1218, 1189, 1126, 860, 836,
801, 774, 538. 1H NMR (DMSOꢀd6): δH; 8.78 [s, 1H, Hꢀ6], 8.0ꢀ8.20 [m, 4H, Hꢀ3 and Hꢀ4], 7.40 [m, 2H, Hꢀ
13
8], 7.25ꢀ7.50 [m, 2H, Hꢀ9] ppm. C NMR (DMSOꢀd6): δC; 166.8 [Cꢀ1], 162.0, 159.8 [Cꢀ6], 159.6, 147.2,
139.5, 132.9, 129.7, 128.6, 123.0 and 122.9, 116.0 and 115.8 [ArꢀC] ppm.
Synthesis of (E)-4-(((p-(dimethylamino)phenyl)imino)methyl)benzoic acid (HL8). An analogous
method to that used for the preparation of HL2 was followed except that aniline was replaced by N,Nꢀ
dimethylꢀpꢀphenylenediamine (0.20 g, 1.644 mmol). The product was crystallized from acetonitrile, giving
dark yellow crystals of HL8 in 67% yield. M.p.: 265ꢀ267 °C (dec.). Anal. Found. C, 71.40; H, 6.28; N,
10.42. Calc. for C16H16N2O2: C, 71.62; H, 6.01; N, 10.44 %. IR (cmꢀ1): 1683 ν(OCO)asym, 1621 ν(C(H)=N),
1
1586, 1514, 1420, 1358, 1282, 1123, 944, 820, 603. H NMR (DMSOꢀd6): δH; 8.64 [s, 1H, Hꢀ6], 7.85ꢀ8.00
13
[m, 4H, Hꢀ3 and Hꢀ4], 7.25 [d, 8 Hz, 2H, Hꢀ8], 6.68 [d, 8 Hz, 2H, Hꢀ9], 2.86 [s, 3H, Hꢀ11] ppm. C NMR
(DMSOꢀd6): δC; 167.0 [Cꢀ1], 153.6 [Cꢀ6], 149.7, 140.4, 139.0, 131.9, 129.6, 127.9, 122.7, 112.4 [ArꢀC],
40.1 [Cꢀ11] ppm.
Note:
Synthesis
of
(E)ꢀ2ꢀ((phenylimino)methyl)benzoic
acid
and
(E)ꢀ2ꢀ(((4ꢀ
fluorophenyl)imino)methyl)benzoic acid could not be accomplished since equimolar reactions of aniline
and pꢀfluoroaniline with 2ꢀformylbenzoic acid in refluxing toluene proceeded via cyclization to give 3ꢀ
(phenylamino)isobenzofuranꢀ1(3H)ꢀone (PhthalideꢀH) and 3ꢀ((4ꢀfluorophenyl)amino)isobenzofuranꢀ
1(3H)ꢀone (PhthalideꢀF), respectively. PhthalideꢀH was isolated as colorless crystals from acetonitrile in
77% yield, M.p.: 182ꢀ183 °C (180ꢀ181°C when crystallized from aqueous acetone,42 179ꢀ180°C when
crystallized from dimethylformamide.43). IR (cmꢀ1): 1740 ν(OCO) lactonic moiety, 1606, 1529, 1500, 1358,
1305, 1262, 1208, 1099, 1080, 871, 744, 693, 503. Formation of the products was also confirmed from the
1H NMR and single crystal Xꢀray diffraction.43 PhthalideꢀF was isolated as colorless crystals from
acetonitrile in 75% yield, M.p.: 189ꢀ191 °C. IR (cmꢀ1): 1736 ν(OCO) lactonic moiety, 1611, 1528, 1511,
1
1308, 1230, 1159, 1093, 870, 824, 787, 747, 512. H NMR (DMSOꢀd6): δH; 7.80ꢀ7.92 [m, 2H, ArH], 7.65ꢀ
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7.75 [m, 2H, ArH], 7.0ꢀ7.18 [m, 3H, ArH], 6.85ꢀ7.0 [m, 2H, ArH] ppm. C NMR (DMSOꢀd6): δC; 168.8,
157.5, 155.1, 145.4, 141.2, 133.8, 130.1, 127.5, 124.5, 123.7, 115.3, 115.1, 88.2 [ArꢀC] ppm.
Synthesis of triphenyltin(IV) compounds 1-11
The triphenyltin(IV) compounds reported here are numbered as 1ꢀ11 (see Scheme 1) for convenience of
discussion. Details of the procedures have been outlined below.
Synthesis of [Ph3Sn(L1)] (1). Ph3SnOH (0.2 g, 0.545 mmol) in toluene (20 mL) was added to a hot toluene
solution (20 mL) containing 4ꢀformylbenzoic acid (0.08 g, 0.533 mmol). The reaction mixture was heated
to reflux for 4 h using a DeanꢀStark apparatus and waterꢀcooled condenser, then filtered while hot and the
filtrate evaporated to dryness. The dry residue was washed with hexane (3 × 5 mL) and dried in vacuo. The
residue was dissolved in the minimum amount of anhydrous benzene and filtered to remove any suspended
particles. The filtrate was concentrated to approximately oneꢀfourth of its initial solvent volume, cooled to
room temperature, precipitated with hexane, filtered and the residue was dried in vacuo. The dried powder
was recrystallized from benzene, which afforded white crystalline material of 1. Yield: 40 %. M.p.: 155ꢀ
157 °C. Anal. Found. C, 62.40; H, 4.28. Calc. for C26H20O3Sn: C, 62.56; H, 4.04 %. IR (cmꢀ1): 1661
1
ν(OCO)asym, 1572, 1429, 1330, 1317, 1213, 1128, 816, 765, 732, 696, 584. H NMR (CDCl3): δH; 10.1 [s,
1H, Hꢀ6], 8.28 [d, 8 Hz, 2H, Hꢀ4], 7.91 [d, 8 Hz, 2H, Hꢀ3], 7.75ꢀ7.84 [m, 6H, Hꢀ2* (SnꢀPh)], 7.40ꢀ7.51 [m,
13
9H, Hꢀ3* and H4* (SnꢀPh)] ppm. C NMR (CDCl3): δC; 191.9 [Cꢀ6], 171.5 [Cꢀ1], 138.9 [Cꢀ5], 136.0 [Cꢀ
2], 131.2 [Cꢀ3], 129.5 [Cꢀ4]; SnꢀPh: 137.9 [1J(13Cꢀ119Sn) = 643 Hz, Cꢀ1*], 137.0 [2J(13Cꢀ119Sn) = 48 Hz, Cꢀ
2*], 130.4 [4J(13Cꢀ119Sn) = 13 Hz, Cꢀ4*], 129.1 [3J(13Cꢀ119Sn) = 62 Hz, Cꢀ3*] ppm. 119Sn NMR (CDCl3);
δSn: ‒ 99.8 ppm. (Note: 1*, 2*, 3* and 4* refer to ipsoꢀ, orthoꢀ, metaꢀ and paraꢀ carbon and proton numbers
of SnꢀPh moiety used for the assignment of NMR signals and applies to all triphenyltin(IV) compounds).
Synthesis of [Ph3Sn(L2)] (2). A toluene solution (2 mL) of aniline (0.046 g, 0.490 mmol) was added to a
hot clear toluene solution (40 mL) containing 1 (0.25 g, 0.500 mmol) and then heated to reflux for 4 h
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using a DeanꢀStark apparatus, whereupon the solution turned pale yellow. The reaction mixture was
filtered while hot and the filtrate concentrated to dryness, affording a viscous mass that was stored in vacuo
overnight. The solid material was dissolved by boiling in benzene and filtered to remove any suspended
particles. The filtrate was concentrated to oneꢀfourth of its initial volume and precipitated with hexane,
affording the crude product. Several crystallizations using benzene/hexane mixture afforded a pale yellow
crystalline material in 57 % (0.17 g) yield. M.p.: 158ꢀ160 °C. Anal. Found. C, 67.10; H, 4.60; N, 2.28.
Calc. for C32H25NO2Sn: C, 66.93; H, 4.39; N, 2.44 %. IR (cmꢀ1): 1635 ν(OCO)asym, 1619 ν(C(H)= N), 1481,
1
1338, 1127, 730, 695. H NMR (CDCl3): δH; 8.70 [s, 1H, Hꢀ6], 8.16 [d, 8.0 Hz, 2H, Hꢀ3], 7.86 [d, 2H, Hꢀ
4], 7.70ꢀ7.80 [m, 6H, Hꢀ2* (SnꢀPh)], 7.25ꢀ7.50 [m, 11H, Hꢀ3*, Hꢀ4* and Hꢀ8], 7.10ꢀ7.25 [m, 3H, Hꢀ9 and
Hꢀ10] ppm. 13C NMR (CDCl3): δC; 172.1 [Cꢀ1], 159.4 [Cꢀ6], 151.6, 138.1, 133.0, 131.2, 131.0, 129.2,
128.5, 126.4 [ArꢀC], SnꢀPh: 139.7 [1J(13Cꢀ119Sn) = 640 Hz, Cꢀ1*],137.0 [2J(13Cꢀ119Sn) = 48 Hz, Cꢀ2*],
130.3 [4J(13Cꢀ119Sn) = 13 Hz, Cꢀ4*],129.0 [3J(13Cꢀ119Sn) = 62 Hz, Cꢀ3*] ppm. 119Sn NMR (CDCl3); δSn: ‒
104.9 ppm.
Synthesis of [Ph3Sn(L3)] (3). An analogous method to that used for the preparation of 2 was followed
using 1 and pꢀtoluidine (0.05 g, 0.478 mmol). The product was crystallized from nꢀheptane, giving yellow
crystals of compound 3 in 40% yield. M.p.: 150ꢀ152 °C. M.p.: 150ꢀ152 °C. Anal. Found. C, 67.60; H, 4.80;
N, 2.08. Calc. for C33H27NO2Sn: C, 67.37; H, 4.63; N, 2.38 %. IR (cmꢀ1): 1625 ν(OCO)asym + ν(C(H)=N),
1
1539, 1430, 1341, 1128, 814, 731, 697. H NMR (CDCl3): δH; 8.40 [s, 1H, Hꢀ6], 8.11 [d, 8 Hz, 2H, Hꢀ3],
7.84 [d, 8 Hz, 2H, Hꢀ4], 7.65ꢀ7.75 [ m, 6H, Hꢀ2* (SnꢀPh)], 7.25ꢀ7.45 [m, 9H, Hꢀ3* and Hꢀ4*], 7.0ꢀ7.15 [m,
13
4H, Hꢀ8 and Hꢀ9], 2.72 [s, 3H, Hꢀ11] ppm. C NMR (CDCl3): δC; 172.2 [Cꢀ1], 158.5 [Cꢀ6], 149.0, 138.2,
136.4, 132.8, 131.0, 129.9, 128.4, 120.9 [ArꢀC], 21.1 [Cꢀ11], SnꢀPh: 139.9 [1J(13Cꢀ119Sn) = 645 Hz, Cꢀ1*],
137.0 [2J(13Cꢀ119Sn) = 48 Hz, Cꢀ2*], 130.3 [4J(13Cꢀ119Sn) = 13 Hz, Cꢀ4*], 129.0 [3J(13Cꢀ119Sn) = 62 Hz, Cꢀ
3*] ppm. 119Sn NMR (CDCl3); δSn: ‒ 105.2 ppm.
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Synthesis of [Ph3Sn(L4)] (4). An analogous method to that used for the preparation of 2 was followed
using pꢀethylaniline (0.06 g, 0.495 mmol). The product was crystallized from benzene/hexane (3:1 v/v)
mixture, giving bright yellow crystals of compound 4 in 41% yield. M.p.: 120ꢀ122 °C. Anal. Found. C,
67.98; H, 4.95; N, 2.11. Calc. for C34H29NO2Sn: C, 67.80; H, 4.85; N, 2.33 %. IR (cmꢀ1): 1624 ν(OCO)asym
+ ν(C(H)=N), 1345, 1128, 1077, 777, 729, 697. 1H NMR (CDCl3): δH; 8.44 [s, 1H, Hꢀ6], 8.15 [d, 8 Hz, 2H,
Hꢀ3], 7.87 [d, 8 Hz, 2H, Hꢀ4], 7.70ꢀ7.80 [m, 6H, Hꢀ2* (SnꢀPh)], 7.35ꢀ7.50 [m, 9H, Hꢀ3* and Hꢀ4* (Snꢀ
Ph)], 7.05ꢀ7.20 [m, 4H, Hꢀ8 and Hꢀ9], 2.60 and 1.18 [q, 7 Hz, 2H and t, 6 Hz, 3H, Hꢀ11] ppm. 13C NMR
(CDCl3): δC; 172.8 [Cꢀ1], 158.5 [Cꢀ6], 149.1, 142.8, 138.1, 131.2, 131.0, 129.3, 128.7, 128.4, 121.0 [ArꢀC],
28.5 and 15.7 [Cꢀ11], SnꢀPh: 140.0 [1J(13Cꢀ119Sn) = 640 Hz, Cꢀ1*], 136.9 [2J(13Cꢀ119Sn) = 48 Hz, Cꢀ2*],
130.3 [4J(13Cꢀ119Sn) = 13 Hz, Cꢀ4*], 129.0 [3J(13Cꢀ119Sn) = 62 Hz, Cꢀ3*] ppm. 119Sn NMR (CDCl3); δSn: ‒
105.3 ppm.
Synthesis of [Ph3Sn(L5)] (5). An analogous method to that used for the preparation of 2 was followed
using pꢀanisidine (0.07 g, 0.557 mmol). The product was crystallized from acetonitrile, giving yellow
crystals of compound 5 in 56% yield. M.p.: 160ꢀ162 °C. Anal. Found. C, 67.08; H, 4.85; N, 2.05. Calc. for
C33H27NO3Sn: C, 66.59; H, 4.50; N, 2.32 %. IR (cmꢀ1): 1629 ν(OCO)asym + ν(C(H)=N, 1501, 1430, 1340,
1250, 1128, 1035, 829, 736, 697. 1H NMR (CDCl3): δH; 8.43 [s, 1H, CH=N], 8.13 [d, 8 Hz, 2H, Hꢀ3], 7.84
[d, 8 Hz, 2H, Hꢀ4], 7.70ꢀ7.80 [m, 6H, Hꢀ2* (SnꢀPh)], 7.35ꢀ7.50 [m, 9H, Hꢀ3* and Hꢀ4* (SnꢀPh)], 7.18 [d, 8
13
Hz, 2H, Hꢀ8], 6.85 [d, 8 Hz, 2H, Hꢀ9], 3.75 [s, 3H, Hꢀ11] ppm. C NMR (CDCl3): δC; 172.3 [Cꢀ1], 158.7,
157.1 [Cꢀ6], 144.4, 138.2, 132.6, 131.0, 128.3, 122.4, 114.4 [ArꢀC], 55.5 [Cꢀ11]; SnꢀPh: 140.1 [1J(13Cꢀ
119Sn) = 640 Hz, Cꢀ1*], 137.0 [2J(13Cꢀ119Sn) = 48 Hz, Cꢀ2*], 130.3 [4J(13Cꢀ119Sn) = 13 Hz, Cꢀ4*], 129.0
[3J(13Cꢀ119Sn) = 62 Hz, Cꢀ3*] ppm. 119Sn NMR (CDCl3); δSn: ‒ 105.6 ppm.
Synthesis of [Ph3Sn(L6)]·C6H6 (6). An analogous method to that used for the preparation of 2 was
followed using pꢀethoxyaniline (0.08 g, 0.572 mmol). The product was crystallized from methanol/benzene
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(3:1 v/v) mixture, giving bright yellow crystals of compound 6 in 66% yield. M.p.: 136ꢀ138 °C. Anal.
Found. C, 68.50; H, 4.75; N, 2.45. Calc. for C40H35NO3Sn: C, 68.97; H, 5.07; N, 2.01 %. IR (cmꢀ1): 1628
1
ν(OCO)asym, 1590 ν(C(H)=N), 1503, 1430, 1338, 1285, 1251, 1126, 827, 731, 698. H NMR (CDCl3): 8.04
[s, 1H, CH=N], 8.11 [d, 8 Hz, 2H, Hꢀ3], 7.81 [d, 8 Hz, 2H, Hꢀ4], 7.65ꢀ7.75 [m, 6H, Hꢀ2* (SnꢀPh)], 7.30ꢀ
7.40 [m, 9H, Hꢀ3* and Hꢀ4* (SnꢀPh)], 7.15 [d, 8 Hz, 2H, Hꢀ8], 6.81 [d, 8 Hz, 2H, Hꢀ9], 3.93 and 1.30 [q,
7Hz, 2H and t, 6 Hz, 3H, Hꢀ11] ppm. 13C NMR (CDCl3): δC; 172.2 [Cꢀ1], 158.1, 157.0 [Cꢀ6], 144.2, 138.1,
132.5, 131.0, 128.3, 122.4, 114.9 [ArꢀC], 63.7 and 14.9 [Cꢀ11], SnꢀPh: 140.1 [1J(13Cꢀ119Sn) = 640 Hz, Cꢀ
1*], 137.0 [2J(13Cꢀ119Sn) = 48 Hz, Cꢀ2*], 130.3 [4J(13Cꢀ119Sn) = 13 Hz, Cꢀ4*], 129.0 [3J(13Cꢀ119Sn) = 62 Hz,
Cꢀ3*] ppm. 119Sn NMR (CDCl3); δSn: ‒ 105.7 ppm.
Synthesis of [Ph3Sn(L7)] (7). An analogous method to that used for the preparation of 2 was followed
using pꢀfluoroaniline (0.06 g, 0.540 mmol). The product was crystallized from acetonitrile/methanol (3:1
v/v) mixture, giving yellow crystals of compound 7 in 57% yield. M.p.: 171ꢀ173 °C. Anal. Found. C,
65.12; H, 4.45; N, 2.25. Calc. for C32H24FNO2Sn: C, 64.90; H, 4.08; N, 2.37 %. IR (cmꢀ1): 1634
1
ν(OCO)asym, 1623ν(C(H)=N), 1499, 1330, 1300, 832, 730, 695. H NMR (CDCl3): 8.41 [s, 1H, CH=N],
8.16 [d, 8 Hz, 2H, Hꢀ3], 7.86 [d, 8 Hz, 2H, Hꢀ4], 7.70ꢀ7.80 [m, 6H, Hꢀ2* (SnꢀPh)], 7.35ꢀ7.50 [m, 9H, Hꢀ3*
13
and Hꢀ4* (SnꢀPh)], 7.10ꢀ7.20 [m, 2H, Hꢀ8], 6.95ꢀ7.10 [m, 2H, Hꢀ9] ppm. C NMR (CDCl3): δC; 171.4 [Cꢀ
1], 162.7, 160.3, 159.1 [Cꢀ6], 147.7, 138.1, 131.2, 131.0, 128.5, 129.3, 128.5, 128.4, 122.5, 122.4, 116.1,
115.9 [ArꢀC], SnꢀPh: 139.6 [1J(13Cꢀ119Sn) = 640 Hz, Cꢀ1*], 137.0 [2J(13Cꢀ119Sn) = 48 Hz, Cꢀ2*], 130.3
[4J(13Cꢀ119Sn) = 13 Hz, Cꢀ4*], 129.0 [3J(13Cꢀ119Sn) = 62 Hz, Cꢀ3*] ppm. 119Sn NMR (CDCl3); δSn: ‒ 104.7
ppm.
Synthesis of [Ph3Sn(L8)] (8). An analogous method to that used for the preparation of 2 was followed
using N,Nꢀdimethylꢀpꢀphenylenediamine (0.06 g, 0.491 mmol). The product was crystallized from
acetonitrile, giving bright yellow crystals of compound 8 in 63% yield. M.p.: 167ꢀ169 °C. Anal. Found. C,
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65.83; H, 5.35; N, 4.75. Calc. for C34H30N2O2Sn: C, 66.15; H, 4.90; N, 4.54 %. IR (cmꢀ1): 1619
ν(OCO)asym, 1580 ν(C(H)=N), 1517, 1480, 1430, 1342, 1163, 1126, 857, 818, 777, 730, 696, 537. 1H NMR
(CDCl3): 8.47 [s, 1H, CH=N], 8.12 [d, 8 Hz, 2H, Hꢀ3], 7.83 [d, 8 Hz, 2H, Hꢀ4], 7.65ꢀ7.80 [m, 6H, Hꢀ2*
(SnꢀPh)], 7.30ꢀ7.45 [m, 9H, Hꢀ3* and Hꢀ4* (SnꢀPh)], 7.22 [d, 8 Hz, 2H, Hꢀ8], 6.67 [d, 8 Hz, 2H, Hꢀ9],
2.91 [s, 3H, Hꢀ11] ppm. 13C NMR (CDCl3): δC; 172.3 [Cꢀ1], 154.3 [Cꢀ6], 149.9, 140.6, 138.2, 132.0, 131.0,
127.9, 122.6, 112.7, [ArꢀC], 40.6 [Cꢀ11], SnꢀPh: 140.1 [1J(13Cꢀ119Sn) = 640 Hz, Cꢀ1*], 137.0 [2J(13Cꢀ119Sn)
= 48 Hz, Cꢀ2*], 130.2 [4J(13Cꢀ119Sn) = 13 Hz, Cꢀ4*], 129.0 [3J(13Cꢀ119Sn) = 62 Hz, Cꢀ3*] ppm. 119Sn NMR
(CDCl3); δSn: ‒ 107.1 ppm.
Synthesis of [Ph3Sn(L9)(H2O)] (9). An analogous method to that used for the preparation of 1 was
followed except that 4ꢀformylbenzoic acid was replaced by 2ꢀformylbenzoic acid. The product was
crystallized from acetonitrile, giving colorless crystals of compound 9 in 91% yield. M.p.: 120ꢀ122 °C.
Anal. Found. C, 60.98; H, 3.85. Calc. for C26H22O4Sn: C, 60.36; H, 4.29 %. IR (cmꢀ1): 1663 ν(OCO)asym
,
1636, 1589, 1389, 1341, 1262, 1109, 729, 697. 1H NMR (CDCl3): 10.71 [s, 1H, Hꢀ8], 8.05 [br d, 1H, Hꢀ3],
7.65ꢀ7.90 [m, 7H, Hꢀ2* (SnꢀPh) and Hꢀ6], 7.50ꢀ7.60 [m, 2H, Hꢀ4 and Hꢀ5], 7.35ꢀ7.45 [m, 9H, Hꢀ3* and
H4* (SnꢀPh)] ppm. 13C NMR (CDCl3): δC; 193.1 [Cꢀ8], 172.2 [Cꢀ1], 137.5, 132.8, 132.2, 131.7, 127.9 [Arꢀ
C], SnꢀPh: 137.8 [1J(13Cꢀ119Sn) = 640 Hz, Cꢀ1*], 136.9 [2J(13Cꢀ119Sn) = 48 Hz, Cꢀ2*], 130.5 [4J(13Cꢀ119Sn)
= 13 Hz, Cꢀ4*], 129.1 [3J(13Cꢀ119Sn) = 62 Hz, Cꢀ3*] ppm. 119Sn NMR (CDCl3); δSn: ‒ 98.3 ppm.
Synthesis of [Ph3Sn(L10)] (10). A toluene solution (2 mL) of aniline (0.046 g, 0.490 mmol) was added to a
hot clear toluene solution (40 mL) containing 9 (0.25 g, 0.500 mmol) and then heated to reflux for 4 h
using a DeanꢀStark apparatus, whereupon the solution turned pale yellow. The reaction mixture was
filtered while hot and the filtrate concentrated to dryness, affording a viscous mass that was triturated with
iceꢀcold hexane (soluble in hexane) until free pale yellow powder was obtained. The solid was dissolved in
hexane/benzene (3:1 v/v) mixture, filtered and allowed to evaporate slowly at room temperature, which
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afforded bright yellow crystals of 10 in 58 % (0.17 g) yield. M.p.: 114ꢀ116 °C. Anal. Found. C, 66.90; H,
4.80; N, 2.50. Calc. for C32H25NO2Sn: C, 66.93; H, 4.39; N, 2.44 %. IR (cmꢀ1): 1626 ν(OCO)asym, 1610
ν(C(H)=N), 1480, 1431, 1340, 1189, 1142, 1076, 769, 731, 697. 1H NMR (CDCl3): 9.41 [s, 1H, Hꢀ8], 8.21
[br d, 2H, Hꢀ3 and Hꢀ6], 7.52ꢀ7.90 [m, 7H, Hꢀ2* (SnꢀPh) and Hꢀ6], 7.35ꢀ7.55 [m, 12H, Hꢀ3*, H4* (SnꢀPh),
13
remaining ArH], 7.15ꢀ7.35 [m, 3H, Hꢀ11 and Hꢀ12] ppm. C NMR (CDCl3): δC; 173.3 [Cꢀ1], 160.8 [Cꢀ8],
137.3, 132.3, 131.8, 131.3, 129.1, 128.1, 126.0, 121.3 [ArꢀC], SnꢀPh: 138.1 [1J(13Cꢀ119Sn) = 640 Hz, Cꢀ1*],
136.9 [2J(13Cꢀ119Sn) = 48 Hz, Cꢀ2*], 130.3 [4J(13Cꢀ119Sn) = 13 Hz, Cꢀ4*], 129.0 [3J(13Cꢀ119Sn) = 62 Hz, Cꢀ
3*] ppm. 119Sn NMR (CDCl3); δSn: ‒ 103.7 ppm.
Synthesis of [Ph3Sn(L11)] (11). An analogous method to that used for the preparation of 10 was followed
except that aniline was replaced by pꢀfluoroaniline (0.06 g, 0.540 mmol). The product was crystallized
from hexane/benzene (3:1, v/v) mixture giving bright yellow crystals of compound 11 in 49% yield. M.p.:
89ꢀ91 °C. Anal. Found. C, 65.44; H, 4.88; N, 2.52. Calc. for C32H24FNO2Sn: C, 64.90; H, 4.08; N, 2.37 %.
IR (cmꢀ1): 1627 ν(OCO)asym, 1590 ν(C(H)=N), 1501, 1480, 1430, 1350, 1232, 1185, 1080, 836, 733, 698.
1H NMR (CDCl3): 9.24 [s, 1H, Hꢀ8], 8.00ꢀ8.20 [m, 2H, Hꢀ3 and Hꢀ6], 7.51ꢀ7.53 [m, 6H, Hꢀ2* (SnꢀPh) ],
7.35ꢀ7.55 [m, 11H, Hꢀ3*, H4* (SnꢀPh), Hꢀ4 and Hꢀ5], 7.00ꢀ7.10 [m, 2H, Hꢀ10], 6.90ꢀ7.00 [m, 2H, Hꢀ11]
ppm. 13C NMR (CDCl3): δC; 173.2 [Cꢀ1], 162.5, 160.5 [Cꢀ8], 160.1, 148.1, 132.2, 131.7, 131.3, 128.0,
122.8, 122.7, 115.9, 115.7 [ArꢀC], SnꢀPh: 138.1 [1J(13Cꢀ119Sn) = 640 Hz, Cꢀ1*], 136.9 [2J(13Cꢀ119Sn) = 48
Hz, Cꢀ2*], 130.3 [4J(13Cꢀ119Sn) = 13 Hz, Cꢀ4*], 129.0 [3J(13Cꢀ119Sn) = 62 Hz, Cꢀ3*] ppm. 119Sn NMR
(CDCl3); δSn: ‒ 103.2 ppm.
X-ray crystallography
Crystals of compounds suitable for Xꢀray crystalꢀstructure determination were obtained by slow
evaporation of acetonitrile (5, 8 and 9), acetonitrile/methanol (7), DMF/acetonitrile (HL3 and HL6), hexane
(10), hexane/benzene (11) and methanol (HL5) solutions of the respective compounds at room temperature.
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Diffraction data were recorded at ambient temperature on an Agilent Technologies Gemini areaꢀdetector
diffractometer44 using Mo Kα radiation (λ = 0.71073 Å). The structures were solved by direct methods
using the SIRꢀ97 program45 and refined with SHELXLꢀ2014/7.46 Calculations were performed using the
WinGX SystemꢀVersion 2014.1.47 All nonꢀhydrogen atoms were refined anisotropically. Hydrogen atoms
bonded to carbon atoms were included in calculated positions and refined using the ridingꢀmodel
approximation with Uiso(H) defined as 1.2Ueq of the parent carbon atoms for phenyl and methyne residues
and 1.5Ueq of the parent carbon atoms for the methyl group. Hydrogen atoms attached to oxygen have been
located from the final difference Fourier map and their isotropic thermal parameter set as 1.5 times the
average thermal parameter of the belonging atoms; in some cases their coordinates were blocked during the
refinement process by means of DFIX instruction. One of the molecules of HL5 was highly disordered and
the atoms of one of the aromatic rings were difficult to locate, and thus they were included in the model by
means of the AFIX instruction. SIMU and DELU restrains had to be used in this case to make the ADP
values of the atoms more reasonable. The data collection and refinement parameters are given in Tables S1
and S2, while a comparison of selected bond distances and angles are shown in Table 1. The perspective
views of the molecular structures are shown in Figs. 1 and 2. No publishable results could be derived from
the observed diffraction data for compounds 2 and 6, however the raw data appear to indicate a tetrahedral
structure.
Experimental protocol and cytotoxicity tests
Cell line maintenance and determination of IC50 value
HeLa, MDAꢀMBꢀ231 and HEK293 (human embryonic kidney) cells were obtained from National Centre
for Cell Science (NCCS), Pune, India and were grown in Dulbecco Modified Eagle Medium (DMEM) with
Lꢀglutamine which was supplemented with penicillin, streptomycin and 10% FBS (Fetal Bovine Serum).
Cells were maintained at 37˚C in a humidified atmosphere containing 5% CO2. Cells were harvested at 80ꢀ
90% confluence and plated for subsequent experiments.
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The cell viability was checked by the MTT assay (colorimetric assay) based on the conversion of
the yellow tetrazolium salt MTT to purple formazan crystals after reaction with mitochondrial
dehydrogenase of metabolically active cells.48 Stock solutions (1 mM) of proꢀligands HLn (n = 1ꢀ8), 3ꢀ
(phenylamino)isobenzofuranꢀ1(3H)ꢀone and 3ꢀ((4ꢀfluorophenyl)amino)isobenzofuranꢀ1(3H)ꢀone, and
compounds 1ꢀ11 were prepared in DMSO and diluted with DMEM (a culture medium comprising 10%
fetal bovine serum, supplemented with 20 mM Lꢀglutamine, 100 units per mL penicillin and 100 ꢁg mLꢀ1
streptomycin) such that the final concentration of DMSO did not exceeded 0.1% v/v. CDDP stock solution
(1 mM) was prepared in normal saline (0.9% sodium chloride).
The cytotoxic activities of HLn, PhthalideꢀH, PhthalideꢀF and 1ꢀ11 were tested against HeLa,
MDAꢀMBꢀ231 and HEK293 cells at varying concentrations ranging from 0.2 to 2.0 ꢁM. Cells were seeded
in three different 96ꢀwell flatꢀbottom plates, keeping a similar cell density of around 8×103 in each well,
supplemented with complete media and incubated overnight to adhere under a humidified atmosphere at
5% CO2.
The adhered cells were further treated with predefined concentrations of compounds and CDDP,
then incubated further for 24 h in 5% CO2 humidified atmosphere. The medium was then discarded and
100 ꢁL of fresh medium and 10 ꢁL (5 mg mLꢀ1) MTT in phosphate buffered saline, PBS (pH 7.4) added to
each well and incubated further for 2 h. Finally, 100 µL of DMSO was added to each well to dissolve the
insoluble purple MTT formazan crystals followed by incubation for 30 min. Similarly; the MDAꢀMBꢀ231
and HeLa cells were exposed to various concentrations of CDDP as the drug control. The absorbance of
samples was measured after 30 min at 570 nm using an ELISA plate reader. The per cent cell inhibition
was calculated with respect to control and IC50 (inhibitory concentration) values obtained were represented
as mean ± SD for triplicates.
Hoechst 33342/PI assay
Hoechst 33342 dye is cell permeable and binds to DNA in live or dead cells, while PI is cell membrane
impermeable so is excluded from the viable cells and typically used to identify dead cells. For this
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experiment, HeLa cells (2 × 105) were seeded in 6 well plates and kept for 24 h at 37 °C in a humidified
atmosphere of 5% CO2. Thereafter, cells were treated with 0.2, 0.4 and 0.6 ꢁM concentrations of 1 and 5
for 24 h at 37 °C. Subsequently, the medium was removed and cells were washed with 1 × PBS, stained
with Hoechst 33342 (10 ꢁg mLꢀ1) and PI (15 ꢁg mLꢀ1) solutions and incubated at 37 °C for 30 min in the
dark. After incubation, the cells were washed with PBS and images of nuclear morphology of living and
apoptotic cells were captured using an inverted fluorescent microscope in red and blue channels as well as
in phase contrast.
ROS generation assay
The ROS assay was carried out to determine the influence of the triphenyltin compounds 1 and 5 on the
production of ROS levels in treated cells. The intracellular ROS level was assessed using DCFHꢀDA in
HeLa and HEK 293 cells. DCFHꢀDA is a cell permeable dye, which is hydrolyzed by cellular esterase to
nonꢀfluorescent form and is oxidized and converted to fluorescent DCF in presence of ROS. Briefly, HeLa
and HEK 293 cells were seeded in two different 6 well plates at a density of around 4 × 105 cells per well
for 24 h at 37 °C in a humidified atmosphere of 5% CO2. Then, both HeLa and HEK 293 cells were treated
with concentrations of 0.2, 0.4 and 0.6 µM (within the IC50 range) of compounds 1 and 5 for 24 h at 37 °C
maintaining the humidified atmosphere of 5% CO2. The treated cells were washed with PBS and then
exposed in DCFHꢀDA dye (10 µM) for 25 min at 37 °C. The treated cell samples, along with control, were
subjected to inverted fluorescence microscopy and DCF fluorescence was detected (λex = 485 nm; λem
=
530 nm) and then images were captured.
Cell cycle analysis
The effect of the triphenyltin(IV) compounds 1 and 5 on cell cycle distribution was evaluated by flow
cytometry analysis of cellular DNA content through the PI staining. HeLa cells (4 × 105) were seeded in 6
well plates as described above, and then treated with IC50 concentrations of 1 and 5 for 24 h in DMEM with
10% FBS. Cells were then washed, trypsinized and fixed in iceꢀcold 70% ethanol and kept overnight at ꢀ20
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°C. The cells were washed twice in iceꢀcold PBS, then stained by 500 ꢁL of staining solution (0.1% (v/v)
Triton Xꢀ100 solution, PI (1 mg mLꢀ1) solution and RNase (10 mg mLꢀ1 in PBS) and incubated for 30 min
at 37 ºC in the dark. After the staining procedure, cell samples were assessed and the cell cycle distribution
was analyzed using a FACS Aria II flow cytometer and CELLQUEST software (Becton Dickinson).
Results and discussion
Synthesis and general aspects
The stereochemistry of the metal ions in Schiff base complexes can be tuned by introducing suitable
groups into the ligand precursors. Accordingly, triphenyltin(IV) compounds 2ꢀ8 were prepared either by
reacting (E)ꢀ4ꢀ((phenylimino)methyl)benzoic acid (HL2ꢀHL8) with Ph3SnOH or by condensing
triphenylstannyl 4ꢀformylbenzoate [Ph3Sn(L1)] (1) with appropriate anilines. In the present investigation,
the synthetic conveniences led to the choice of the later method. In contrast to paraꢀ derivatives, synthesis
of (E)ꢀ2ꢀ((phenylimino)methyl)benzoic acid (HL11) and (E)ꢀ2ꢀ(((4ꢀfluorophenyl)imino)methyl)benzoic
acid (HL12) could not be accomplished because equimolar reactions of aniline and pꢀfluoroaniline with 2ꢀ
formylbenzoic acid in refluxing toluene proceeded via cyclization to give 3ꢀ(phenylamino)isobenzofuranꢀ
1(3H)ꢀone (PhthalideꢀH) and 3ꢀ((4ꢀfluorophenyl)amino)isobenzofuranꢀ1(3H)ꢀone (PhthalideꢀF),
respectively (refer to note in the experimental section and see refs. 42 and 43). Therefore, compounds 10
and 11 were prepared by reacting aquaꢀtriphenylstannyl 2ꢀformylbenzoate [Ph3Sn(L9)(H2O)] (9) with
appropriate anilines. Apparently, the generation of iminobenzoate ligands, e.g., (E)ꢀ2ꢀ
((phenylimino)methyl)benzoate (L11) and (E)ꢀ2ꢀ(((4ꢀfluorophenyl)imino)methyl)benzoate (L12) can be
promoted by the reactions of 9 with aniline and pꢀfluoroaniline, respectively, which prevented the
formation of cyclized product phthalides. Synthetic avenues towards the preparation of the aforementioned
compounds 1ꢀ11 are detailed in Scheme 1.
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8
9
11
R
4
3
7
10
NH2
N
R
OH
5
6
2
1
+ H2O
(HL2ꢀHL8)
Toluene, Reflux
O
Ph3SnOH Toluene
8
9
R
H
HLn
HL2
Compound No.
11
R
2
3
4
3
7
10
OH
O
N
OSnPh3
+ H2O
Me HL3
Et
HL4
4
5
6
7
8
5
6
2
1
OMe HL5
OEt HL6
(2ꢀ8)
O
O
F
HL7
4ꢀformylbenzoic acid (HL1)
NMe2 HL8
NH2 Toluene
R
4
3
OSnPh3
Ph3SnOH
5
6
1
2
+ H2O
Toluene, Reflux
O
O
(1)
O
O
NH2
R
(R = H: 3ꢀ(phenylamino)isobenzofuranꢀ1(3H)ꢀone; R =
F: 3ꢀ((4ꢀfluorophenyl)amino)isobenzofuranꢀ1(3H)ꢀone))
O
Toluene, Reflux
R
HN
O
OH
O
3
7
4
6
OSnPh3
.
H2O
10
11
Ph3SnO
1
Ph3SnOH
Toluene, Reflux
1
2
NH2
13
R
R
2
5
3
5
9
12
N
2ꢀformylbenzoic acid (HL9)
O
7
8
4
ꢀ2H2O
8
O
(R = H: 10, F: 11)
(9)
6
Scheme 1. The synthetic methodologies for obtaining proꢀligands and triphenyltin compounds produced from the
reactions thereof (1ꢀ11), along with numbering protocol of ligand framework used for NMR signal assignment.
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The triphenyltin(IV) compounds 1ꢀ11 are soluble in common organic solvents, furnishing single
crystals of the representative compounds suitable for diffraction studies and thecongruence of all analytical
data served to identify the composition. Behavior of the ligands in the presence of metal centres with
different coordination geometries and numbers of available coordination sites was assessed from the results
1
of spectroscopic and Xꢀray diffraction data. Proꢀligands have been characterized by IR, H and 13C
spectroscopic techniques, while additionally 119Sn NMR was used for the triphenyltin compounds. IR bands
of the compounds along with the assignment of ν(OCO)asym and ν(C(H)=N) have been presented in the
experimental section. In the IR spectra of 2ꢀ8, the asymmetric stretching ν(OCO)asym vibration for the
ligands were detected in the range 1675ꢀ1685 cmꢀ1, which is ∼ 60 cmꢀ1 lower than those found for the
respective proꢀligands due to coordination of the carboxylate group to the tin atoms.49 The shift of
ν(OCO)asym vibration is more pronounced in the case of compounds of orthoꢀanalogues 10 and 11. All
compounds displayed anticipated 1H and 13C signals for the ligand and SnꢀPh moieties, which are given in
the experimental section. The 1H and 13C chemical shift assignment of the phenyltin moiety is
n
straightforward from the multiplicity patterns, resonance intensities and also by examining the J(13Cꢀ
119/117Sn) coupling constants.49ꢀ51 The 119Sn NMR spectra of compounds 1ꢀ11 displayed a single sharp 119Sn
resonance in the range at ca. –98 to –107 ppm, indicative of a fourꢀcoordinated tin coordination geometry
in CDCl3 solution, in accordance with the literature precedents.50,51 This observation suggests that the Snꢀ
atom geometries observed in the solidꢀstate for compounds 8, 10 and 11 (tetragonal) and 9 (transꢀtrigonal
bipyramidal) dissociate in solution to give rise to a tetrahedral geometry (see Xꢀray discussion, vide infra).
Description of the crystal structures
The proꢀligands (HL3, HL5 and HL6) and representative triphenyltin compounds 5, 7ꢀ11 were
authenticated by singleꢀcrystal Xꢀray diffraction. Crystal data and structure refinement parameters are
given in Tables S1 and S2, while Tables 1 and 2 present a comparison of selected geometrical parameters.
Figs. 1 and 2 display the molecular structures of the proꢀligands and triphenyltin compounds. Relevant
intermolecular interactions for 5, 7, 8, 9, 11 and HL3 are shown in Figs. S1ꢀS5, ESI.†
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Fig. 1 Perspective views of the molecular structures of HL3, HL5 and HL6 with partial atom labeling
schemes.
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Fig. 2 Perspective views of the asymmetric units of [Ph3Sn(L5)] (5), [Ph3Sn(L7)] (7), [Ph3Sn(L8)] (8),
[Ph3Sn(L9)(H2O)] (9), [Ph3Sn(L10)] (10) and [Ph3Sn(L11)] (11) with partial atom labeling schemes.
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The asymmetric units of 5 and 9 contain one molecule of the complex but those of 7, 8, 10 and
11 comprise two crystallographically independent molecules. The metal cations in 5 and 7 present slightly
distorted tetrahedral geometries (τ4 of 0.89 and 0.92, respectively)52 while those of 8ꢀ11 are better
described as distorted tetragonal (τ =
5 between 0.46 and 0.56 for 8, 10 and 11)53 or trigonal bipyramid (9, τ5
0.90). The criterion to judge between these two geometries was based on the Sn−Ocarboxylate bond distances;
while the shorter distances range from 2.047(4) to 2.096(8) Å and achieve 2.1656(14) Å in 9 (Table 1), the
longer distances vary between 2.567(9) and 2.772(2) Å [9 is the exception, with 2.3804(15) Å]. In
compounds 5ꢀ7 the dimensions range from 2.803(3) to 2.855(4) and were thus treated as Sn···O contact
distances. The Sn−C bond distances are in the usual range for Sn(IV) compounds54ꢀ58 and the Cimino−N
lengths [1.242(13)ꢀ1.390(13) Å] prove the double bond character of the bond.
The phenyliminomethyl benzoate or benzoic groups are generally not planar as measured by the
CiminoNCArCAr torsion angle (Tables 1 and 2), which assume values as low as ‒142.3º in one of the
molecules of HL3, ‒149.6º in HL6 or even ‒139.6º in one of the molecules of 7. In the remaining
triphenyltin compounds, such values range from 153º (in 7) to 173º (in 8). The carboxylic groups and
attached aromatic rings are coplanar in the proꢀligands, however the carboxylate moieties and aromatic
rings can be highly twisted in the compounds. For example, in 9 such groups are nearly orthogonal
(OSnCCArCAr torsion angle of 118.9º), but this geometric parameter increases to close to 170º in some cases
(Table 1).
Structures of the compounds are stabilized by intermolecular nonꢀcovalent interactions, such as π···π
stacking. In 5, the molecules are gathered in pairs by means of almost perfectly aligned aromatic rings of
the L− ligands, whose centroids are 3.742 Å apart (Fig. S1, ESI.†). Faceꢀtoꢀface orientations were also
observed in 8, though less intense (centroid···centroid distance of 3.923 Å, Fig. S2, ESI.†) and involving
the phenyl groups bound to tin, and in 9 (centroid···centroid distance of 3.747 Å, Fig. S3, ESI.†) linking
the formylbenzoate rings. In 7, the aromatic rings are parallel displaced and comprise the L− ligand and a
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phenyl group (centroid···centroid distance of 3.937 Å, Fig. S2, ESI.†), respectively. C−H···π contacts in 8
are intense and reach values of 2.866 and 2.937 Å in the latter (Figs. S2, ESI.†). Resulting from the Fꢀ
substituted aromatic ring in the L− ligand of 11, the Sn1 and the Sn2 containing molecules are coupled by
means of C−F···π connections involving the benzoate rings (C−F···centroid of 3.726 and 3.630 Å,
respectively; Fig. S4, ESI.†). Only one of such type of contact was found in 7 (Fig. S2, ESI.†) covering a
longer distance (3.916 Å) and involving one of the Snꢀbound phenyl groups. In the structure of HL3, two
types of molecules are assembled by means of both the π···π and the C−H···π interactions
(centroid···centroid and H···centroid distances of 4.007 and 2.856 Å, in this order), the latter resulting
from the relative orientations of the aromatic rings (Fig. S5, ESI.†). Concerning the intermolecular Sn···Sn
distance, the compounds follow the order (Table 2): 7 [8.3258(5) Å] > 11 [8.0131(7) Å] > 5 [7.827(1) Å] >
9 [7.4569(4) Å] > 10 [7.2296(5) Å]> 8 [7.173(1) Å].
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Table 1 Sn coordination geometry and selected geometrical parameters for the triphenyltin compounds 5, 7ꢀ11
Compounds
Parameters
5
7
8
9
10
11
Tin coordination number
4
4
5
5
5
5
Tin coordination spherea and
geometry indices
Tetrahedral
(τ4 = 0.91) (Sn1)
(τ4 = 0.92) (Sn2)
Dist. tetragonal
(τ5 = 0.48) (Sn1)
(τ5 = 0.52) (Sn2)
Dist. tetragonal
(τ5 = 0.56) (Sn1)
(τ5 = 0.48) (Sn2)
Dist. tetragonal
(τ5 = 0.49) (Sn1)
(τ5 = 0.46) (Sn2)
Tetrahedral
(τ4 = 0.89)
Trigonal
bipyramid
(τ5 = 0.90)
Sn–O [Sn···O] (Å)
Sn–C (º)
2.058(3)
[2.803(3)]
2.062(4) (Sn1)
[2.831(4)]
2.047(4) (Sn2)
[2.855(4)]
2.096(8) (Sn1)
2.567(9) Sn1)
2.072(7) (Sn2)
2.725(8) (Sn2)
2.1656(14)
2.3804(15)
2.076(2) (Sn1)
2.647(2) (Sn1)
2.058(2) (Sn2)
2.772(2) (Sn2)
2.081(3) (Sn1)
2.726(3) (Sn1)
2.087(3) (Sn2)
2.674(3) (Sn2)
2.121(5) ꢀ
2.130(5)
2.108(7) ꢀ
2.137(6) (Sn1)
2.121(6) ꢀ
2.125(13) ꢀ
2.136(13) (Sn1)
2.123(11) ꢀ
2.118(2) ꢀ
2.1341(19)
2.121(3) ꢀ
2.139(3) (Sn1)
2.115(3) ꢀ
2.119(4) ꢀ
2.122(4) (Sn1)
2.117(4) ꢀ
2.134(6) (Sn2)
2.127(13) (Sn2)
2.130(3) (Sn2)
2.125(4) (Sn2)
N=C (Å)
1.249(7)
178.1
1.266(8)
1.253(7)
1.242(13)
1.390(13)
ꢀ
1.256(4)
1.270(5)
1.252(5)
ꢀ164.3 (Sn1)
ꢀ167.4 (Sn2)
Avg. 168 (Sn1)
Avg. 163 (Sn2)
118.6
Avg. 155 (Sn1 and ꢀ144.8, ꢀ138.9
Sn2)
∠ OSnCCArCAr (º)
(Sn1)
145.9, 138.8
(Sn2)
163.0
ꢀ153.0 (Sn1)
ꢀ139.6 (Sn2)
173 (Sn1)
168 (Sn2)
ꢀ
ꢀ155.1 (Sn1)
158.9 (Sn2)
157.8 (Sn1)
ꢀ154.0 (Sn2)
∠ CiminoNCArCAr (º)
Intermolecular Sn···Sn
(minimum)
7.827(1)
8.3258(5)
7.173(1)
7.4569(4)
7.2296(5)
8.0131(7)
a For the definition of τ4 and τ5, see references [52,53].
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Table 2 Selected geometrical parameters for the proꢀligands HL3, HL5 and HL6
Parameters
Pro-ligands
HL3
HL5
HL6
N=C (Å)
1.259(3)
1.243(3)
1.281(10)
1.19(4)
1.198(5)
ꢀ149.6
ꢀ142.3
174.1
160.6
ꢀ159
∠ CiminoNCArCAr (º)
D−H···A
O1−H1O···O3
O1−H1···O4
[2.646(17); 168]
O5−H5···O2
[2.58(2); 171]
O1−H1O···O2
[2.633(3); 171(5)]
[dD···A (Å);
[2.618(2); 173(3)]
O4−H4O···O2
∠( D−H···A) (º)]
[2.636(2); 175(3)]
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Solubility and stability assessment of triphenyltin(IV) compounds 1-11
The triphenyltin(IV) compounds (1ꢀ11) are soluble in acetonitrile, DMF and dimethylsulfoxide
(DMSO), acetone, methanol, ethanol, dichloromethane, chloroform, xylene and toluene but insoluble in
hexane. The solution stability of a drug under physiological conditions is an important preꢀrequisite for
its in vitro/ in vivo applications. Usually, organotin(IV) compounds are dissolved in DMSO and diluted
with test medium prior to in vitro testing and hence the stabilities of the triphenyltin(IV) compounds 1ꢀ
11 were assessed by UVꢀvisible spectroscopy in DMSO prior to the cytotoxic studies. The compounds
were found to be stable, as evidenced from the unchanged basic pattern of absorption spectra even after
21 days (Fig. S6, ESI†).
Evaluation of in vitro cytotoxicity
Effective concentrations to affect cell viability
The effectiveness of triphenyltin(IV) compounds in suppressing tumor cells and advancing apoptosis
has been well established.8ꢀ12,22 The overall goal of the present investigation was to synthesize
chemopreventive agents that could potentially lead to their use in clinical evaluation. Having now the
availability of a wellꢀcharacterized series of proꢀligands (HLn) and triphenyltin compounds 1ꢀ11, it is
possible to make a direct comparison of their antiꢀcancer efficacy. To this end, the antiꢀ
proliferative/apoptotic activity of compounds 1ꢀ11 described above was evaluated against human HeLa,
MDAꢀMBꢀ231 cancer cells and normal HEK 293 cells. Explicitly, to first determine in which
concentration range these compounds mediate cytotoxic effects; we conducted an in vitro cytotoxicity
screen in HeLa, MDAꢀMBꢀ231 and HEK 293 cells (Figs. S7ꢀS9 ESI†) and compared the effects with an
untreated control, triorganotin(IV) precursor Ph3SnOH (Fig. S10, ESI†) and CDDP using the MTT
assay after incubation of 24 h. IC50 values (ꢁM) for proꢀligands (HLn), PhthalideꢀH and PhthalideꢀF and
triphenyltin compounds 1ꢀ11 in studied cells are given in Table 3. As shown in Fig. S11, ESI†, all
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Table 3 IC50 values (ꢁM) for triphenyltin compounds 1ꢀ11 and CDDP after 24 h
exposure in cancer cells (HeLa, MDAꢀMBꢀ231) and normal HEK 293 cells
Test compoundsa
IC50 values (µM) ± SEb
MDAꢀMBꢀ231
0.76±0.25
HeLa
HEK 293
1.28±0.04
1.15±0.03
0.71±0.02
0.36±0.04
1.46±0.03
2.3±0.02
0.72±0.02
0.74±0.04
0.41±0.02
1.35±0.03
1.22±0.03
1.96±0.02
c
Ph3Sn(L1) (1)
Ph3Sn(L2) (2)
Ph3Sn(L3) (3)
Ph3Sn(L4) (4)
Ph3Sn(L5) (5)
Ph3Sn(L6) (6)
Ph3Sn(L7) (7)
Ph3Sn(L8) (8)
Ph3Sn(L9) (9)
Ph3Sn(L10) (10)
Ph3Sn(L11) (11)
Ph3SnOH
0.51±0.02
0.23±0.03
0.19±0.00
0.63±0.05
0.41±0.08
0.24±0.09
0.27±0.01
0.45±0.01
0.41±0.01
0.72±0.08
0.53±0.09
0.52±0.04
51.3±1.19
0.77±0.06
0.97±0.14
0.62±0.12
0.78±0.03
0.75±0.05
0.75±0.02
0.51±0.09
0.44±0.03
0.43±0.00
0.39±0.12
0.42±0.09
CDDP
23.63±0.20
aCytotoxicity of the proꢀligands HL1ꢀHL9, PhthalideꢀH and PhthalideꢀF were found to be nonꢀ
toxic up to tested concentration of 2 ꢁM as the viability of cells were 90%.
bStandard error and the value represents the average of three sets of independent experiments.
cNot determined.
29