Synthesis, characterization, photoluminescence and electrochemical properties of Pt(II) and Ag(I) complexes of tetradentate aminomethylphosphine ligands and antiproliferative activities on HT-29 human colon cancer

Article abstract of DOI:10.1002/aoc.3550

Novel N¹,N¹,N⁴,N⁴-tetrakis((diphenylphosphino)methyl)benzene-1,4-diamine (L1), N¹,N¹,N⁵,N⁵-tetrakis((diphenylphosphino) methyl)naphthalene-1,5-diamine (L2) and 4,4′-me

Full text of DOI:10.1002/aoc.3550

Full paper
Received: 12 April 2016
Revised: 30 May 2016
Accepted: 7 June 2016
Published online in Wiley Online Library: 25 July 2016
(wileyonlinelibrary.com) DOI 10.1002/aoc.3550
Synthesis, characterization, photoluminescence
and electrochemical properties of Pt(II) and Ag
(I) complexes of tetradentate
aminomethylphosphine ligands and
antiproliferative activities on HT-29 human
colon cancer
Serhan Uruşa,b*, Mahmut İncesua, Seda Köşkera, Akif Hakan Kurtc
and Gökhan Ceyhanb
Novel N1,N1,N4,N4-tetrakis((diphenylphosphino)methyl)benzene-1,4-diamine (L1), N1,N1,N5,N5-tetrakis((diphenylphosphino)
methyl)naphthalene-1,5-diamine (L2) and 4,4′-methylenebis(N,N-bis((diphenylphosphino)methyl)aniline) (L3) ligands and their
Pt(II) and Ag(I) complexes have been synthesized under nitrogen atmosphere using the Schlenk technique. The ligands and the
complexes were characterized using 1H NMR, 31P NMR and Fourier transform infrared spectroscopies,
thermogravimetric/differential thermal analysis, elemental analysis (C, H, N), inductively coupled plasma optical emission spec-
trometry (metal content), cyclic voltammetry and photoluminescence. All the complexes were investigated as anticancer agents
on HT-29 human colon cancer cell line. HT-29 cells were treated with various concentrations (10, 25, 50, 100, 250 μM) of Pt(II)
and Ag(I) tetrakisditertiaryaminomethylphosphine complexes. Cisplatin was tested at the same concentrations in order to com-
pare the antiproliferative activities of the synthesized Pt(II) and Ag(I) complexes. Pt(II) complexes of L1 and L3 and Ag(I) complexes
of L1, L2 and L3 showed a similar inhibition effect of cancer cell proliferation when compared to cisplatin up to 50 μM; at 100 μM
and higher concentrations, L1–Pt(II) and L3–Ag(I) complexes showed a much greater effect than cisplatin. Copyright © 2016 John
Wiley & Sons, Ltd.
Additional supporting information may be found in the online version of this article at the publisher’s web site.
Keywords: phosphine; anticancer; HT-29; cyclic voltammetry; photoluminescence
activities of metal–aminophosphine complexes, there have not
been enough studies up to now on the biological activities of
Introduction
Pt(II) complexes have been used as used in tumour chemotherapy
for about three decades. However, they have severe side effects on
human cells and the applicability of them is limited because of in-
creasing drug resistance. These problems have not been resolved
yet. Studies of antimicrobial and antitumoral activities of Ag(I) and
Au(I) complexes using phosphines have reported them to show a
wide spectrum of antimicrobial activities.[1,2] Some AgN, AgP, NAgP
and AgC types of silver(I) complexes were synthesized and cyto-
toxic activity was found against some Gram-positive and Gram-
negative bacteria.[1–3]
It has also been reported that Au(I) bis(diphosphine) complexes
such as [Au(dppe)2]+ (where dppe is 1,2-bis(diphenylphosphino)
ethane) and optically active phosphine–Au(I) complexes are active
against some types of cancer.[4]
Functionalized chelating ditertiary aminomethylphosphines of
the type (R2PCH2)2NR′ can be obtained by treating phosphonium
salts [R2P(CH2OH)2]Cl with primary amines R′NH2.[5–10] Even though
there has been much research on the chemistry and catalytic
aminomethylphosphines having P–C–N linkages. Thus, we have fo-
cused on the synthesis of novel aminomethylphosphine–metal
complexes of Au(I), Ag(I), Cu(I) and Co(II) and have explored some
of the biological properties of these complexes.[6,11–16] Ditertiary
aminomethylphosphine ligands having soft NCPPh2 donor atoms
coordinated to metal centres have a significant trans effect. Chloro
*
Correspondence to: Serhan Uruş, Chemistry Department, Faculty of Science and
Letters, Kahramanmaras Sütçü İmam University, 46100 Kahramanmaraş,
Turkey. E-mail: serhanurus@yahoo.co.uk
a Chemistry Department, Faculty of Science and Letters, Kahramanmaras Sütçü
İmam University, 46100 Kahramanmaraş, Turkey
b Research and Development Centre for University-Industry-Public Relations,
Kahramanmaras Sütçü İmam University, 46100 Kahramanmaras, Turkey
c
Department of Pharmacology, School of Medicine, Kahramanmaras Sütçü İmam
University, 46050 Kahramanmaras, Turkey
Appl. Organometal. Chem. 2017, 31, e3550
Copyright © 2016 John Wiley & Sons, Ltd.

Uruş S. et al.
ligands located at the trans position of NCPPh2 groups can easily
leave the metal centres and trans-labilization is increased for DNA
coordination to the metal centres. If comparing the trans effect of
the phosphorus donor atom of NCPPh2 groups with either nitro-
gen or oxygen, several phosphine-based complexes inhibit tumour
growth.[1,17,18]
Our synthesized Pt(II) complexes of L1 and L3 and Ag(I) com-
plexes of L1, L2 and L3 showed a similar inhibition effect on cancer
cell proliferation compared to cisplatin up to a concentration of 50
μM; at 100 μM and higher concentrations, L1–Pt(II) and L3–Ag(I)
complexes showed a much greater effect than cisplatin.
procedures and immediately distilled under nitrogen atmosphere
prior to use.
Synthesis of Tetrakis(aminomethylphosphine) Ligands (L1, L2,
L3)
[PPh2(CH2OH)2]Cl salt was obtained according to the
literature.[6,7,9,13] The novel tetrakis(aminomethylphosphine)
ligands were synthesized using the reaction of 1,4-
phenylenediamine,
4,4′-diaminodiphenylmethane,
1,5-
naphthalenediamine and [PPh2(CH2OH)2]Cl with NEt3 using the
Schlenk technique under nitrogen atmosphere.[5–9,12–16] An
amount of 0.1 g (0.3537 mmol) of [Ph2P(CH2OH)2]Cl was dissolved
in EtOH–water (1:1) and 1.0 ml of triethylamine (99%) and 0.088
mmol of aryldiamine were added to this solution respectively. After
Experimental
General
refluxing this mixture for
1 h, the synthesized tetrakis
1H NMR and 31P NMR spectra were recorded at 25°C in CDCl3 using
an Avance III HD Ascend 600 ULH NMR spectrometer. Fourier trans-
form infrared (FT-IR) spectra were recorded with a PerkinElmer
Spectrum 400 FT-IR system. Elemental analyses were performed
using a LECO CHNS 932 instrument. Mass spectra of the ligands
were recorded with a Zivak Tandem Gold LC-MSMS spectrometer
(ESI). The positive and negative ion modes were used simulta-
neously in MS analyses. The complexes were digested with HNO3
+ H2O2 solution using a Berghof MWS 3+ microwave oven and
metal contents were determined with a PerkinElmer Optima 2100
DV inductively coupled plasma optical emission spectrometer. Cal-
ibration standards of Pt(II) and Ag(I) ions were prepared from Inor-
ganic Ventures (USA) calibration stocks (about 1000 mg lÀ1).
Ultrapure water obtained from a Milli-Q purifier system (Millipore
Corp., Bedford, MA) was used for the calibration standards. The
thermal properties of the ligands were investigated with a SII ther-
mal system under nitrogen atmosphere at a heating rate of 10°C
minÀ1 in the range 30–1000°C.
(aminomethylphosphine) ligands were extracted with 10 ml of di-
chloromethane. The dichloromethane phase were washed three
times with appropriate amount of water and dried with anhydrous
Na2SO4. An oily product was obtained when the dichloromethane
phase was evaporated.
N1,N1,N4,N4-Tetrakis((diphenylphosphino)methyl)benzene-1,4-diamine (L1)
Yield 0.06537 g (81%). Molecular formula C58H52N2P4. Anal. Calcd
(%): C, 77.32; H, 5.82; N, 3.11. Found (%): C, 77.34; H, 5.84; N, 3.08.
FT-IR (KBr, ν, cmÀ1): 3054 (aromatic C C for PPh2 and disubstituted
benzene), 2918 (aliphatic C H), 1607, 1510 (aromatic C C for PPh2
and disubstituted benzene), 1432 (P Ph), 1094 (tert-amine C N). 1H
NMR (CDCl3, δ, ppm): 7.20–7.44 (m, 40H, P Ph2), 6.72 (br, 4H, N Ar N),
3.90 (s, 8H, N CH2 PPh2). 13C{1H} NMR (CDCl3, δ, ppm): 154.72
(PhC N), 149.21, 142.14, 137.85 (PPh2 carbons), 130.07 (central
ArC), 57.64 (N CH2 P). 31P{1H} NMR (CDCl3, δ, ppm): À27.12 (s,
PPh2). MS-ESI: m/z 900 ([M À 1]+, 25%), 901 ([M]+, 54%), 902 ([M +
1]+, 50%).
Dimethylformamide (DMF) stock solutions (1 × 10À4 M) of the
phosphine ligands and their metal complexes were used for elec-
trochemical studies. Cyclic voltammograms were recorded using
an Iviumstat electrochemical workstation equipped with a low cur-
rent module (BAS PA-1) recorder. The electrochemical cell was
equipped with a BAS glassy carbon working electrode (area of 4.5
mm2), a platinum coil auxiliary electrode and an Ag+/AgCl reference
electrode filled with tetrabutylammonium tetrafloroborate (0.1 M)
in DMF solution and adjusted to 0.00 V versus SCE. Cyclic
voltammetric measurements were performed at room temperature
in an undivided cell (BAS model C-3 cell stand) with a platinum
counter electrode and an Ag+/AgCl reference electrode (BAS). All
potentials are reported with respect to Ag+/AgCl. The solutions
were deoxygenated by passing dry nitrogen through them for 15
min prior to the experiments, and during the experiments the flow
was maintained over the solution. Digital simulations were per-
formed using DigiSim 2.0 for windows (BAS Inc.). Experimental cy-
clic voltammograms used for the fitting process had the
background subtracted and were corrected electronically for ohmic
drop. A Hanna pH meter was used for the pH measurements using
a combined electrode (glass reference electrode) with an accuracy
of 0.01.
N1,N1,N5,N5-Tetrakis((diphenylphosphino)methyl)naphthalene-1,5-diamine (L2)
Yield 0.0724 g (86%). Molecular formula C62H54N2P4. Anal. Calcd (%):
C, 78.30; H, 5.72; N, 2.96. Found (%): C, 78.24; H, 5.74; N, 3.01. FT-IR
(KBr, ν, cmÀ1): 3052 (aromatic C H), 2915 (aliphatic C H), 1602, 1525
(aromatic C C for PPh2 and disubstituted naphthalene), 1432 (P Ph),
1
1114 (tert-amine C N). H NMR (CDCl3, δ, ppm): 7.82–7.33 (m, 40H,
P Ph2), 7.28 (br, 2H, α-H of naphthalene), 6.95 (d, J = 7.8 Hz, 2H, β-H
of naphthalene), 6.75 (d, J = 7.8 Hz, 2H, γ-H of naphthalene), 4,20
(s, 8H, N CH2 PPh2). 13C{1H} NMR (CDCl3, δ, ppm): 155.62, (naphtha-
lene C N), 150.96, 143.01, 139.18 (PPh2 carbons), 152.84, 137.88,
133.24, 130.13 (other naphthalene carbons), 58.45 (N CH2 P). 31P
{1H} NMR (CDCl3, δ, ppm): À26.06 (s PPh2). MS-ESI: m/z 950 ([M À
1]+, 32%), 951 ([M]+, 54%), 952 ([M + 1]+, 60%), 953 ([M + 2]+, 35%).
4,4′-Methylenebis(N,N-bis((diphenylphosphino)methyl)aniline) (L3)
Yield 0.0746 g (85%). Molecular formula C65H58N2P4. Anal. Calcd
(%): C, 78.77; H, 5.90; N, 2.83. Found (%): C, 78.74; H, 5.84; N, 2.84.
FT-IR (KBr, ν, cmÀ1): 3051 (aromatic C H), 2910 (aliphatic C H),
1610, 1512 (aromatic C C for PPh2 and disubstituted benzene),
1
1433 (P Ph), 1119 (tert-amine C N). H NMR (CDCl3, δ, ppm): 7.85–
7.12 (m, 40 H, P Ph2), 6.98 (d, J = 8.6 Hz, 4H, ortho-H of N Ar N),
6.72 (d, J = 8.6 Hz, 4H, meta-H of N Ar N), 4.80 (s, 2H, Ph CH2 Ph),
3.92 (s, 8H, N CH2 PPh2). 13C{1H} NMR (CDCl3, δ, ppm): 151.91 (ArC N),
150.20, 145.15, 138.01 (PPh2 carbons), 148.01, 141.22, 139.24
(central-Ph carbons), 57.66 (N CH2 P), 42.19 (Ph CH2 Ph). 31P{1H}
NMR (CDCl3, δ, ppm): À27.57 (s, PPh2). MS-ESI: m/z 990 ([M À 1]+,
32%), 991 ([M]+, 44%), 992 ([M + 1]+, 20%), 993 ([M + 2]+, 12%).
UV–visible spectra in the range 200–1000 nm were obtained with
samples in DMF solvent using a PerkinElmer Lambda 45 spectro-
photometer. Photoluminescence properties were investigated with
a PerkinElmer LS55 instrument.
All chemicals and reagents were purchased from Merck, Fluka,
Sigma or Aldrich and all solvents were dried using established
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Tetrakis(aminomethylphosphine) complexes effective on HT-29 cells
Synthesis of Metal Complexes
[Pt2(L3)Cl4]Á(NEt3)(H2O) (3). Yield 0.1193 g (82%). Molecular for-
mula C71H75Cl4N3OP4Pt2. Anal. Calcd (%): C, 51.93; H, 4.60; N, 2.56;
Pt, 23.76. Found (%): C, 51.92; H, 4.63; N, 2.54; Pt, 23.71. FT-IR (KBr,
ν, cmÀ1): 3338 (OH), 3053 (aromatic C H ), 2901 (aliphatic C H),
1612, 1514 (aromatic C C for PPh2 and disubstituted benzene),
1435 (P Ph), 1101 (tert-amine C N). 1H NMR (CDCl3, δ, ppm):
6.9–8.0 (m, 48H, Ar-H), 4.9 (s, 2H, Ph CH2 Ph), 4.27 (s, 8H, N CH2 PPh2
), 3.12 (q, J = 7.3 Hz, 6H, N CH2 CH3), 1.42 (t, J = 7.3 Hz, 9H,
N CH2 CH3). 13C{1H} NMR (CDCl3, δ, ppm): 152.23 (ArC N), 150.75,
145.34, 137.12 (PPh2 carbons), 148.54, 142.13, 138.59 (PPh2
carbons), 57.89 (N CH2 P), 42.11 (Ph CH2 Ph). 31P{1H} NMR (CDCl3, δ,
ppm): 53.06 (JPPt = 10.6 Hz, PPh2 Pt PPh2).
Pt(II) complexes
Tetrakis(aminomethylphosphine) ligand L1, L2 or L3 (0.088 mmol)
was dissolved in dichloromethane and a solution of 0.156 mmol
of [Pt(COD)Cl2] in EtOH–water (1:1) was added to the solution.
The mixture was stirred under refluxed for 6 h under nitrogen atmo-
sphere. Addition of diethyl ether, the complexes precipitated which
was then filtered off and dried at 60°C.
[Pt2(L1)Cl4]Á(NEt3)(H2O) (1). Yield 0.1113 g (81%). Molecular for-
mula C64H69Cl4N3OP4Pt2. Anal. Calcd (%): C, 49.52; H, 4.48; N, 2.71;
Pt, 25.14. Found: C, 49.48; H, 4.41; N, 2.74; Pt, 25.18. FT-IR (KBr, ν,
cmÀ1): 3332 (OH), 3050 (aromatic C H), 2962 (aliphatic C H), 1611,
1512 (aromatic C C for PPh2 and disubstituted benzene), 1434
Ag(I) complexes
1
(P Ph), 1099 (tert-amine C N). H NMR (CDCl3, δ, ppm): 6.8–7.9 (m,
Tetrakis(aminomethylphosphine) ligand L1, L2 or L3 (0.088 mmol)
was dissolved in dichloromethane and a solution of 0.156 mmol
of AgNO3 in EtOH–water (1:1) was added into the ligand solution.
The mixture was stirred under refluxed for 6 h under nitrogen
atmosphere in the dark. Addition of diethyl ether, the complexes
precipitated which was then filtered off and dried at 60°C.
44H, Ar-H), 4.37 (s, 8H, N CH2 PPh2), 3.08 (q, J = 7.7 Hz, 6H,
N CH2 CH3), 1.3 (t, J = 7.7 Hz, 9H, N CH2 CH3). 13C{1H} NMR (CDCl3,
δ, ppm): 154.21 (PhC N), 149.10, 142.24, 136.98 (PPh2 carbons),
130.92 (central ArC), 57.25 (N CH2 P). 31P{1H} NMR (CDCl3, δ, ppm):
53.01 (JPPt = 10.9 Hz, PPh2 Pt PPh2).
>[Pt2(L2)Cl4]Á(NEt3)(H2O) (2). Yield 0.1107 g (78%). Molecular for-
mula C68H71Cl4N3OP4Pt2. Anal. Calcd (%): C, 50.98; H, 4.47; N, 2.62;
Pt, 24.35. Found (%): C, 50.93; H, 4.43; N, 2.64; Pt, 24.30. FT-IR (KBr, ν,
cmÀ1): 3387 (OH), 3063 (aromatic C H), 2987 (aliphatic C H), 1613,
1526 (aromatic C C for PPh2 and disubstituted naphthalene), 1434
[Ag2(L1)(NO3)2(NEt3)2]ÁH2O (4). Yield 0.1023 g (79%). Molecular
formula C70H84Ag2N6O7P4. Anal. Calcd (%): C, 57.54; H, 5.80; N,
5.75; Ag, 14.77. Found (%): C, 57.59; H, 5.78; N, 5.81; Ag, 14.71. FT-
IR (KBr, ν, cmÀ1): 3296 (OH), 3040 (aromatic C H), 2987 (aliphatic
C H), 1309 (N O), 1610, 1514 (aromatic C C for PPh2 and disubsti-
tuted benzene), 1434 (P Ph), 1098 (tert-amine C N). 1H NMR (CDCl3,
δ, ppm): 7.8–6.8 (m, 44H, Ar-H), 4.29 (s, 8H, N CH2 PPh2), 3.12 (q, J =
7.5 Hz, 6H, N CH2 CH3), 1.38 (t, J = 7.5 Hz, 9H, N CH2 CH3). 13C{1H}
NMR (CDCl3, δ, ppm): 153.98 (PhC N), 150.11, 143.01, 137.14 (PPh2
carbons), 129.34 (central ArC), 57.42 (N CH2 P). 31P{1H} NMR (CDCl3,
δ, ppm): 30.76 (s-br, PPh2 Ag PPh2).
1
(P Ph), 1101 (tert-amine C N). H NMR (CDCl3, δ, ppm): 8.1–6.9 (m,
46H, Ar-H), 4.47 (s, 8H, N CH2 PPh2), 1.38 (t, J = 7.3 Hz, 9H, N CH2 CH3),
3.1 (q, J = 7.3 Hz, 6H, N CH2 CH3). 13C{1H} NMR (CDCl3, δ, ppm): 155.01
(Naphthalene C N), 148.97, 150.77, 150.83 (PPh2 carbons), 155.22,
141.46, 140.90, 138.25 (other naphthalene carbons), 58.22 (N CH2 P).
31P{1H} NMR (CDCl3, δ, ppm): 53.04 (JPPt = 10.6 Hz, PPh2 Pt PPh2).
Figure 1. Synthesis of the ligands and their Pt(II) and Ag(I) complexes. [PPh2(CH2OH)2]Cl salt was synthesized according to the literature.[6,7,9,13]
Appl. Organometal. Chem. 2017, 31, e3550
Copyright © 2016 John Wiley & Sons, Ltd.
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Uruş S. et al.
[Ag2(L2)(NO3)2(NEt3)2]ÁH2O (5). Yield 0.1094 g (78%). Molecular
formula C74H94Ag2N6O11P4. Anal. Calcd (%): C, 58.52; H, 5.74; N,
5.56; Ag, 14.28. Found (%): C, 58.48; H, 5.79; N, 5.52; Ag, 14.24. FT-
IR (KBr, ν, cmÀ1): 3306 (OH), 3071 (aromatic C H), 2987 (aliphatic
C H), 1325 (N O), 1604, 1532 (aromatic C C for PPh2 and disubsti-
tuted benzene), 1433 (P Ph), 1098 (tert-amine C-N). 1H NMR (CDCl3,
δ, ppm): 6.8–7.8 (m, 46H, Ar-H), 4.38 (s, 8H, N CH2 PPh2), 3.18 (q, J =
7.3 Hz, 12H, N CH2 CH3), 1.41 (t, J = 7.3 Hz, 9H, N CH2 CH3). 13C{1H}
NMR (CDCl3, δ, ppm): 155.56 (naphthalene C N), 150.89, 142.76,
139.55 (PPh2 carbons), 123.22, 137.38, 133.22, 130.37 (PPh2 car-
synthesized Pt(II) and Ag(I). Cells were placed in 96-well plates and
incubated for 48 h. Following incubation, MTT solution
(Sigma-Aldrich) was added controlled to each well at a concentra-
tion of 0.5 mg mlÀ1, and incubated for 4 h at 37°C. At the end of this
period, 100 μl of DMSO solvent was added to each well. The
absorbance values (optical density) at 570 nm for the solution in
each well were read using
a spectrophotometer (ELx800
Absorbance Reader; BioTek Instruments Inc., Winooski, VT, USA).
bons), 58.32 (N CH2 P). 31P{1H} NMR (CDCl3, δ, ppm): 30,06 (JPAg
54.7 Hz, PPh2 Ag PPh2).
=
[Ag2(L3)(NO3)2(NEt3)2]ÁH2O (6). Yield 0.1107 g (77%). Molecular
formula C77H98Ag2N6O11P4. Anal. Calcd (%): C, 59.62; H, 5.85; N,
5.42; Ag, 13.91. Found (%): C, 56.99; H, 5.92; N, 5.23; Ag, 13.88. FT-
IR (KBr, ν, cmÀ1): 3321 (OH), 3062 (aromatic C H), 2987 (aliphatic
C H), 1307 (N O), 1611, 1514 (aromatic C C for PPh2 and disubsti-
tuted benzene), 1434 (P Ph), 1098 (tert-amine C N). 1H NMR (CDCl3,
δ, ppm): 7.1–8.2 (m, 48H, Ar-H), 4.9 (s, 2H, Ph CH2 Ph), 4.1 (s, 8H,
N CH2 PPh2), 3.20 (q, J = 7.3 Hz, 12H, N CH2 CH3), 1.39 (t, J = 7.3 Hz,
9H, N CH2 CH3). 13C{1H} NMR (CDCl3, δ, ppm): 152.15 (ArC N),
150.02, 145.23, 138.25 (PPh2 carbons), 148.17, 140.95, 139.61
(PhC R), 57.75 (N CH2 P), 42.21 (Ph CH2 Ph). 31P{1H} NMR (CDCl3, δ,
ppm): 31.55 (br, PPh2 Ag PPh2).
Antiproferative Activity on HT-29 Human Colon Cancer
Human colon cancer cell culture
The culturing of cancer cells was performed at the Laboratory of
Tissue Culture and Stem Cells (Department of Pharmacology,
School of Medicine, Kahramanmaras Sütçü İmam University,
Kahramanmaras, Turkey). Human colon cancer cell line (HT-29)
was obtained from the American Type Cell Collection (Manassas,
VA, USA). Cells were cultured in McCoy’s 5a Medium (Gibco Life
Technologies, Carlsbad, CA, USA) supplemented with 10% foetal
bovine serum (Gibco Life Technologies) and 100 U mlÀ1 penicillin
(Sigma-Aldrich, St Louis, MO, USA) at 37°C in a humidified atmo-
sphere of 5% CO2. For three days prior to the experiment, HT-29
cells were cultured with phenol red free medium (Gibco Life Tech-
nologies). The negative control condition for all assays was
untreated medium containing vehicle (0.1% dimethylsulfoxide
(DMSO)). Cisplatin and DMSO were purchased from Sigma-Aldrich.
MTT assay
HT-29 cells were treated with various concentrations (10, 25, 50,
100, 250 μM) of Pt(II) and Ag(I) complexes of L1, L2 and L3. Cisplatin
was used at the same concentrations in order to compare with the
Table 1. 31P NMR data for the complexes
Ligand δP (ppm)
Complex
δP (ppm) JPMP Δδ (ppm)a
L1 À27.12 [Pt2(L1)Cl4]ÁN(Et)3(H2O)
53.01 10.86 80.13
[Ag2(L1)(NO3)2(N(Et)3)2]ÁH2O 30.76
L2 À27.68 [Pt2(L2)Cl4]ÁN(Et)3(H2O) 53.03 10.66 80.71
[Ag2(L2)(NO3)2(N(Et)3)2]ÁH2O 30.05 57.73
L3 À27.57 [Pt2(L3)Cl4]ÁN(Et)3(H2O) 53.06 10.63 80.63
[Ag2(L3)(NO3)2(N(Et)3)2]ÁH2O 31.55 59.12
—
57.88
—
—
aCoordination shift values of the complexes: Δδ = δ(complex) À δ(free
ligand).[13]
Figure 2. TG analysis curves.
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Tetrakis(aminomethylphosphine) complexes effective on HT-29 cells
Statistical analysis
The ligands and their Pt(II) and Ag(I) complexes were character-
1
ized using NMR (31P and H) and FT-IR spectroscopies, elemental
Statistical analysis was performed using GraphPad Prism 3.0
(GraphPad, San Diego, CA, USA). For all data, statistical analysis
was performed using repeated measurements of ANOVA followed
by post hoc analysis with the Bonferroni test to detect differences
between the groups. Results are expressed as mean standard errors
of the mean. A P value of less than 0.05 was considered significant.
analysis (C, H, N and metal content), thermogravimetric/differential
thermal analysis (TG/DTA), cyclic voltammetry (CV) and
photoluminescence. In FT-IR spectra of the ligands, aromatic C H
stretches of P aryl and aromatic backbone were assigned to the band
at about 3050 cmÀ1 as a medium peak. Aliphatic C H stretches of
P CH2 N groups appeared at about 2940 cmÀ1. Aromatic C C bending
for PPh2 and disubstituted aromatic backbone was observed at
about 1510–1610 cmÀ1. C N stretches of tertiary amine were seen
at about 1100 cmÀ1. Sharp peaks at about 1430 cmÀ1 were assigned
to P Ph stretches according to the literature. There are no significant
differences between the ligands and Pt(II) and Ag(I) complexes in FT-
IR spectra.[1,6–26]
All the tetrakis ditertiary aminomethylphosphine ligands have
symmetric structures and have similar proton resonances in 1H
NMR spectra. The 1H NMR signals of the aromatic protons were ob-
served at two different areas for L1 and three different areas for L2
and L3. The backbone protons resonances of L1 were recorded at
6.72 ppm as a broad signal. Two phenyl rings bound to one phos-
phorus have multiple proton signals at about 7.20–7.44 ppm. A sin-
glet peak at 3.90 ppm was from N CH2 P proton resonance.
Symmetric aminophosphine ligand L1 has a single 31P NMR peak
at À27.12 ppm in the 31P NMR spectrum (supporting information).
Results and Discussion
Synthesis and Characterization
The novel ligands L1, L2 and L3 have been synthesized using the re-
action of 1,4-phenylenediamine, 4,4′-diaminodiphenylmethane
and 1,5-naphthalenediamine, respectively, with [PPh2(CH2OH)2]Cl
salt under nitrogen atmosphere using the Schlenk technique ac-
cording to a modified method in the literature (Fig. 1).[5–9,11–17]
[PPh2(CH2OH)2]Cl phosphonium salt was obtained according to
the literature.[6,7,9,13] Pt(II) and Ag(I) complexes of these tetradentate
ditertiary aminomethylphosphine ligands have been obtained from
the reactions of the synthesized ligands and [Pt(COD)Cl2] and
AgNO3 complexes by refluxing for 6 h under nitrogen atmosphere
(Fig. 1).
Table 2. Electrochemical data for the metal complexes in DMFa
Compoud
Scan rate (mV sÀ1
)
Epa (V)
Epc (V)
Epa/Epc
E1/2 (V)
ΔEp (V)
L1–Ag(I)
100
250
500
750
1000
100
250
500
750
1000
100
250
500
750
1000
100
250
500
750
1000
100
250
500
750
1000
100
250
500
750
1000
À0.71, 0.31
À0.72, 0.32
À0.73, 0.33
À0.74, 0.34
À0.75, 0.35
À0.60, 0.20
À0.61, 0.21
À0.62, 0.22
À0.63, 0.23
À0.64, 0.24
À0.40, 1.10
À0.41, 1.09
À0.42, 1.08
À0.43, 1.07
À0.44, 1.06
À0.69, 0.90
À0.70, 0.91
À0.71, 0.92
À0.72, 0.93
À0.73, 0.94
À0.40, 0.30
À0.41, 0.31
À0.42, 0.32
À0.43, 0.34
À0.44, 0.35
À0.31
1.00, 0.15, À0.50
1.01, 0.16, À0.52
1.02, 0.17, À0.54
1.03, 0.18, À0,56
1.04, 0.19, À0.58
0.21, 0.61
1.42
1.38
1.33
1.32
1.29
0.95
0.95
0.95
0.95
0.96
0.97
0.97
0.97
0.97
0.97
1.97
1.94
1.91
1.89
1.87
0.50
0.50
0.51
0.52
0.53
3.44
3.20
3.00
2.83
2.69
—
—
À0.21
À0.20
À0.19
À0.18
À0.17
À0.01
À0.01
À0.01
À0.01
À0.01
0.01
—
—
—
L2–Ag(I)
L3–Ag(I)
L1–Pt(II)
L2–Pt(II)
L3–Pt(II)
0.20
0.21
0.22
0.23
0.24
0.41
0.42
0.43
0.44
0.45
—
0.22, 0.62
0.23, 0.63
0.24, 0.64
0.25, 0.65
0.59, 0.08, À0.41
0.60, 0.09, À0.42
0.61, 0.10, À0.43
0.62, 0.11, À0.44
0.64, 0.12, À0.45
0.25, À0.35
0.26, À0.36
0.27, À0.37
0.28, À0.38
0.29, À0.39
0.10, À0.80
0.10, À0.81
0.11, À0.82
0.12, À0.82
0.13, À0.83
0.09
0.01
0.01
0.01
0.01
À0.34
À0.34
À0.34
À0.34
À0.34
À0.40
À0.40
À0.40
À0.39
À0.39
À0.40
À0.42
À0.44
À0.46
À0.48
—
—
—
—
0.60
0.61
0.62
0.63
0.64
—
À0.32
0.10
—
À0.33
0.11
—
À0.34
0.12
—
À0.35
0.13
—
aSupporting electrolyte: tetrabutylammonium tetrafluoroborate (Bu4NBF4) (0.1 M); concentration of compound: 1 × 10À3 M. All potentials referenced to
Ag+/AgCl (0.03 M AgNO3). Epa and Epc are anodic and cathodic potentials, respectively. E1/2 = 0.5 × (Epa + Epc). ΔEp = Epa À Epc
.
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Uruş S. et al.
Naphthalene protons had signals as three different doublet
peaks in H NMR spectra. Phosphorus-bound phenyl ring proton
signals were at 7.33–7.82 ppm as a multiplet peak for L2. α-H of
naphthalene was observed at 7.28 ppm as a broad signal. Doublet
proton resonances of β-H and γ-H of naphthalene were seen at 6.95
ppm (J = 7.8 Hz) and 6.75 ppm (J = 7.8 Hz), respectively. N CH2 P
protons were detected as a singlet peak at 4.20 ppm. Phosphorus
resonance was assigned at À26.06 ppm as a singlet peak in the
31P NMR spectrum (supporting information).
Aromatic proton resonances of L3 were observed at three differ-
ent regions in the 1H NMR spectrum. Mono-substituted phenyl
protons bound to phosphorus showed signals at 7.12–7.85 ppm
1
Figure 3. Cyclic voltammograms of the metal complexes in the presence of 0.1 M NBu4BF4–DMF solution at various scan rates.
Table 3. UV–visible absorption, emission and excitation spectral data of metal complexes
λmax
λ (ɛ)
Excitation (nm)
Intensity
Emission (nm)
Intensity
L1–Ag(I)
L2–Ag(I)
L3–Ag(I)
L1–Pt(II)
L2–Pt(II)
L3–Pt(II)
587
544
543
544
390
546
920
980
935
975
945
930
729
718
720
716
547
717
955
1000
995
335 (0.64 × 104), 436 (0.18 × 104)
340 (0.95 × 104), 440 (0.39 × 104)
342 (0.56 × 104), 444 (0.14 × 104)
355 (0.76 × 104), 450 (0.24 × 104)
360 (0.53 × 104), 460 (0.18 × 104)
365 (0.53 × 104), 470 (0.36 × 104)
990
1000
980
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Tetrakis(aminomethylphosphine) complexes effective on HT-29 cells
as a multiplet. Ortho and meta proton signals of di-substituted ben-
zene of symmetric L3 ligand were observed at 6.98 ppm (J = 8.6 Hz)
and 6.72 ppm (J = 8.6 Hz), respectively. Other singlet peaks of L3
appeared at 4.80 and 3.92 ppm assigned to Ph CH2 Ph and N CH2 P
magnetic anisotropic effect of aromatic structures and the phos-
phorus binding effect.
1
Although H NMR and 13C NMR spectra of the Pt(II) and Ag(I)
complexes of the ligands are similar to those of the ligands, 31P res-
onance peaks of the complexes were shifted from À27 ppm to
about 53 ppm for Pt(II) complexes and to about 31 ppm for Ag(I)
complexes in 31P NMR spectra. These shifts of 31P resonances were
due to the metal–phosphorus binding.[6–16] Additionally, M–P spin–
spin coupling effects were observed because of the NMR-active Pt
(II) and Ag(I) nuclei. Especially, Pt(II) complexes showed doublet
31P peaks at about 53 ppm. Accordingly, these shifts of 31P reso-
nances and phosphorus–metal spin–spin couplings were proof of
the synthesized complexes (Table 1).
protons, respectively. As the other ligands, L3 showed a singlet 31
P
resonance at À27.27 ppm in the 31P NMR spectrum (supporting
information).
Additionally to 1H NMR spectra, symmetric structures were
observed in proton decoupled 13C NMR spectra for all the com-
pounds. Ligands L1 and L2 showed three types of resonances
in the 13C NMR spectra. These were backbone aromatic structure,
PPh2 and N CH2 P resonances. L3 showed a fourth 13C resonance
because of methylene groups of Ph CH2 Ph structure. All the li-
gands and complexes showed similar 13C peaks in 13C NMR spec-
tra. While PPh2 carbons showed signals at about 137–150 ppm as
three peaks, N CH2 P showed one peak at about 58 ppm. N CH2 P
carbon signal shifted to low field due to N and P binding. PPh2
carbon signals also shifted to low-field region because of the
All 1H NMR and 31P NMR signals prove that the novel ligands and
their Pt(II) and Ag(I) complexes have been synthesized
successfully.[5–26]
All the ligands have one degradation band between 100 and
1000°C. Pt(II) and Ag(I) complexes have four endothermic peaks in
Figure 4. Photoluminescence of the metal complexes at the solid state.
Appl. Organometal. Chem. 2017, 31, e3550
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Uruş S. et al.
TG analyses. Hydrated water decomposed between 40 and 100°C
for all Pt(II) complexes. The second peak at about 100–205°C was at-
tributed to chloro ligand and trimethylamine degradation and the
largest band between 205 and 510°C was because of the degrada-
tion of aminophosphine ligands. After 600°C, metal oxide formation
was observed for Pt(II) complexes. Hydrated water decomposition
was observed at about 40–100°C for all Ag(I) complexes as well as
Pt(II) complexes. Trimethylamine degradation followed the hy-
drated water loss. Aminophosphine ligands decomposed between
200 and 550°C and metal oxide formation began after 550°C (Fig. 2).
Electrochemical properties of the phosphine ligands and their
metal complexes were investigated in DMF–3 M Bu4NBF4 as
supporting electrolyte at 293 K. All potentials quoted refer to mea-
surements run at scan rates of 100, 250, 500, 750 and 1000 mV sÀ1
range and against an internal ferrocene–ferrocenium standard. The
electrochemical studies were conducted in 1 × 10À4 M DMF solu-
tions and the obtained data are summarized in Table 2. The poten-
tials for reduction or oxidation of phosphine containing strongly
electron-withdrawing groups at the phosphine positions of the
macrocycle will depend upon the electronic properties of the
diamine. In addition, the shift in redox potentials between neutral
and positively or negatively charged ligands (L1–L3) depends on
the conjugation between the positively or negatively charged
group at the phosphine and the π-ring system. The phosphine
ligands are planar and show conjugation by π-electrons. The
ligands contain strongly electron-withdrawing groups such as
P C N linkage. Metallophosphines containing electro-inactive Pt(II)
and Ag(I) metal ions undergo only reactions involving the π-ring
system (see Table 2). In the CV curves of ligands L1 and L2 (Fig. 3),
all redox processes at scan rates of 100-1000 mV sÀ1 in 1 × 10À3
M solutions are reversible. But ligand L3 shows a quasi-reversible
redox process at all scan rates. The L2–Ag(I) and L3–Ag(I) complexes
show reversible redox couples at all scan rates. The L2–Pt(II)
complex shows quasi-reversible couples at 0.50/0.53 V at all scan
rates. The L1–Ag(I), L1–Pt(II) and L3–Pt(II) complexes show irrevers-
ible redox processes (Fig. 3).
concentrations (10, 25, 50, 100, 250 μM) of the Pt(II) and Ag(I) com-
plexes in 96-well plates and incubated for 48 h. Cisplatin was used
at the same concentrations in order to compare with the synthe-
sized Pt(II) and Ag(I) complexes. When comparing cisplatin with
the synthesized Pt(II) and Ag(I) complexes, the Pt(II) complexes of
L1 and L3 and Ag(I) complexes of L1, L2 and L3 significantly de-
creased cell proliferation at a concentration of 100 μM, whereas
L2–Pt(II) and control did not significantly differ (Figs 5 and 6). While
the Pt(II) complexes of L1 and L3 and Ag(I) complexes of L1, L2 and
L3 showed similar inhibition effect of cancer cell proliferation com-
pared to cisplatin up to 50 μM concentration, at 100 μM and higher
concentrations, L1–Pt(II) and L3–Ag(I) complexes showed a much
greater effect than cisplatin (Figs 5-7). It is possible that the sterically
hindered ligands labilize the trans leaving of cis-positioned chloro
ligands in these complexes and the ligands prevent the axial bind-
ing of any ligands to the metal which would inhibit the formation of
five-coordinated metal complex intermediates that would lead to a
ligand substitution.[1] L2–Pt(II) and L2–Ag(I) complexes did not
show anticancer activities because of the too bulky structure of
naphthalene tetrakis ditertiary aminomethylphosphine ligands
coordinating to metal centres. This structure does not labilize
cis-chloro leaving from metal centres and this steric hindrance
would not permit high selectivity to DNA binding.[1,27–30] Because
phosphine compounds are strong-field ligands, Pt(II) complexes
have dsp2 and Ag(I) complexes have sp3 hybridization. Thus, Pt(II)
complexes have square planar structure with cis-chloro ligands
The single-photon fluorescence spectra of the phosphine ligands
and their metal complexes were collected with a PerkinElmer LS55
luminescence spectrometer. Photoluminescence properties of the
ligands and their metal complexes were investigated in the solid
state and obtained data are summarized in Table 3. The
photoluminescence spectra of the metal complexes are shown in
Fig. 4. The excitation bands of L1–Ag(I), L2–Ag(I) and L3–Ag(I) were
in the range 543–587 nm in the excitation spectra. The group (NOÀ3 )
bound to the metal did not affect the excitation bands for Ag(I)
complexes. The excitation bands of the L1–Pt(II), L2–Pt(II) and L3–
Pt(II) complexes were in the range 390–546 nm in the excitation
spectra. Highest red shift was seen in the spectrum of L3–Pt(II).
The emission bands of the L1–Ag(I), L2–Ag(I) and L3–Ag(I) metal
complexes were observed in the range 718–729 nm as one band
in the emission spectra. Additionally, in the spectra of the L1–Pt(II),
L2–Pt(II) and L3–Pt(II) complexes, the emission bands were in the
range 647–664 nm. The emission and excitation bands were shifted
to lower wavelengths than those of L1–Ag(I), L2–Ag(I) and L3–Ag(I).
Depending on the reduction of the concentration, the band inten-
sities of the compounds decreased. As a result, a concentration
change has a slight effect on the emission and excitation bands.
Antiproferative Activity on HT-29 Human Colon Cancer
Figure 5. HT-29 human colon cancer cells treated with Pt(II) complexes (10,
25, 50, 100, 250 μM, n = 8), assessed by MTT assay (*p < 0.05, **p < 0.01
versus vehicles).
All the complexes were used as anticancer agents on the HT-29
human colon cancer cell line. HT-29 cells were treated with various
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Copyright © 2016 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2017, 31, e3550

Tetrakis(aminomethylphosphine) complexes effective on HT-29 cells
Conclusions
Pt(II) and Ag(I) complexes of tetradentate ditertiary
aminomethylphosphine complexes have been synthesized using
Schlenk techniques. All the ligands and their metal complexes were
1
characterized using H NMR, 31P NMR and FT-IR spectroscopies,
TG/DTA, elemental analysis, CV and photoluminescence tech-
niques. All the complexes were used as anticancer agents on the
HT-29 human colon cancer cell line. Cisplatin was used at the same
concentrations in order to compare with the synthesized Pt(II) and
Ag(I) complexes. When comparing cisplatin with the synthesized Pt
(II) and Ag(I) complexes, Pt(II) complexes of L1 and L3 and Ag(I)
complexes of L1, L2 and L3 significantly decreased cell proliferation
at a concentration of 100 μM, whereas L2–Pt(II) and control did not
significantly differ. L1–Pt(II) and L3–Ag(I) complexes showed a
much greater effect than cisplatin at 100 μM and higher concentra-
tions. These efficient results on the antiproliferative activity on hu-
man colon cancer cells indicate that the novel synthesized L1–
Pt(II) and L3–Ag(I) complexes are worth focusing on in pharmaco-
logical studies in order to verify their ability to reach cancer tissues.
Acknowledgements
We thank the Scientific & Technological Research Council of Turkey
(TÜBİTAK, project no. 111T211) and Kahramanmaraş Sütçü İmam
University (project nos. 2013/6-33 M and 2015/2-13 YLS) for their
financial support.
Figure 6. HT-29 human colon cancer cells treated with Ag(I) complexes (10,
25, 50, 100, 250 μM, n = 8), assessed by MTT assay (*p < 0.05, **p < 0.01
versus vehicles).
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Supporting information
Additional supporting information may be found in the online ver-
sion of this article at the publisher’s web site.
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