Synthesis and cancer cell cytotoxicity of gold(III) tetraarylporphyrins with a C5-carboxylate substituent

Article abstract of DOI:10.3184/174751911X13230815130502

Gold(III) tetraarylporphyrins with a C5-carboxylate substituent have been synthesised and their in vitro cytotoxic activity against SGC-7901 human gastric cancer cell line panel evaluated. The compound 5-[4-(4-ethoxycarbonylbut oxy)phenyl]-10,15,20-tri(4-

Full text of DOI:10.3184/174751911X13230815130502

698 RESEARCH PAPER
DECEMBER, 698–702
JOURNAL OF CHEMICAL RESEARCH 2011
Synthesis and cancer cell cytotoxicity of gold(III) tetraarylporphyrins with
a C5-carboxylate substituent
Jinliang Liua, Huasheng Chenb, Yan Lia, Ying Chenb, Leilei Maob, Aihua Xub and Cunde Wanga*
aSchool of Chemistry and Chemical Engineering and bSchool of Medicine, Yangzhou University, Yangzhou 225002, P. R. China
Gold(III) tetraarylporphyrins with a C5-carboxylate substituent have been synthesised and their in vitro cytotoxic
activity against SGC-7901 human gastric cancer cell line panel evaluated. The compound 5-[4-(4-ethoxycarbonylbut
oxy)phenyl]-10,15,20-tri(4-methoxyphenyl)porphyrinatogold(III) chloride exhibited significant growth inhibitory
properties against SGC-7901 human gastric cancer cells and afforded an IC50 value of 29 µM for 69.73% of the cell
lines in the panel.
Keywords: gold(III) substituted porphyrins, C5 carboxylate, tetraaryl porphyrins, in vitro cytotoxicity
Cis-diamminedichloroplatinum(II) (cisplatin) and its deriva-
tives carboplatin and oxaliplatin have been in clinical use for a
number of years. However, although they have demonstrated
excellent anti-cancer activity in the treatment of several forms
of cancer, including cervical, ovarian, head and neck, and
cell lung cancers,1–4 the main problem in their use is their
low selectivity for cancer cells and their often high toxicity to
the body.5,6 Hence the search for improved complexes with
platinum or other noble metals with less toxicity has been a
major goal in pharmaceutical research and development in
recent years. Many platinum-based compounds have been syn-
thesised and evaluated successfully as potential anti-cancer
agents.7–10 In contrast, and despite gold(III) possessing the
same isoelectronic configuration (d8) and structural (square
planar) characteristics as platinum(II),11–13 relatively few
studies have examined the potential therapeutic properties of
gold(III) compounds.14–17 Recently, Che et al. have reported
the synthesis and antitumor efficacy of gold(III) tetraphenyl-
porphyrin.18 Subsequently, great efforts have been made in
elucidating the mechanisms of gold(III) tetraphenylporphyrin
action and in synthesising modified gold(III) tetraphenylpor-
phyrins. These gold(III) porphyrin compounds, which behave
as organic lipophilic cations with a planar structure, are stable
against demetallation under physiological conditions. Further
in vitro and in vivo studies revealed that gold(III) porphyrin
is a promising anticancer agent for the treatment of colon
and liver cancer,19–27 because the porphyrin ligand in these
compounds can efficiently stabilise the gold(III) centre and
drastically reduces its redox reactivity and oxidising character.
The use of gold(III) porphyrin complexes may be advatageous
for clinical application, but, until now, although gold(III) tetra-
phenylporphyrin shows a high anti-cancer activity, it is not a
clinical gold drug. Therefore, the main focus is still aimed at
the discovery of gold(III) analogues with improved pharmaco-
logical properties. As part of these analogue studies, important
structure–activity rules to define the requirements for antitu-
mour activity of gold(III) compounds have been established.
According to these principles, the main strategy to achieve this
goal is to modulate the aqueous solubility and liposolubility of
potential gold(III) complexes by altering the substituents of
the ligands in gold(III) porphyrins, which previous reports18,21
suggest can affect the electrochemical properties and in vitro
cytotoxicity of the corresponding gold(III) porphyrins. These
results showed that the introduction of a methoxycarbonyl- or
methoxy-substituted group into a structure can dramatically
change the physical and chemical properties of the gold(III)
porphyrin, including its potential pharmaceutical behaviour,28
and indicated that gold(III) multi-substituted tetraarylporphy-
rin chlorides could produce specific diastereoisomeric
interactions and increase the activity spectrum. Based on these
previous studies, we report here the synthesis and evaluation of
new gold(III) substituted tetraarylporphyrin chloride analogues
of the type C5-carboxylate tetraarylporphyrin. The C5-carbox-
ylate, with a linear alkyl group, was expected to provide a
balanced lipo/hydrophilicity of the gold(III) complex and
anti-cancer activity.
Experimental
All reagents and solvents were commercially available analytical
grade and used as received. Further purification, drying and distilla-
tion by standard method were employed prior to use when necessary.
All evaporations of organic solvents were carried out with a rotary
evaporator in conjunction with a water aspirator. Melting points were
1
taken on a hot-plate microscope apparatus and are uncorrected. H
NMR spectra were recorded with a Bruker AV-600 spectrometer. IR
spectra were obtained on a Bruker Tensor 27 spectrometer (KBr disc).
MS spectra were obtained on a ZAB-HS mass spectrometer with
70 eV; TPPAuCl [5,10,15,20-tetraphenylporphyrinatogold(III) chlo-
ride] was synthesised by the reported method.18,29 Elemental analytical
data were obtained using a model 240 elementary instrument.
Mycoplasma-free newborn calf serum was purchased from Hangzhou
Sijiqing Biological Engineering Materials Co., Ltd. Cisplatin (Cis)
was the product of Jiangsu Hansen Pharmaceutical Co., Ltd. RPMI
1640, MTT, DMSO were purchased from Sigma-Aldrich Chemical
Co.
SGC-7901 human gastric carcinoma cell (SGC-7901) was purcha-
sed from Shanghai Institute of Cell Biology, Chinese Academy
of Science. The cell line was cultured in RPMI 1640 medium with
10% newborn calf serum serum. It was maintained in a humidified
incubator with an atmosphere of 95% air and 5% CO2 at 37 °C. The
cells were continuously passaged once every 3–4 days. Growing cells
were collected for experiments.
Preparation of substituted porphyrins 1–4
Compounds 1–4 were synthesised from the appropriate various sub-
stituted benzaldehydes and freshly distilled pyrrole in propionic acid
utilising the reported method.28
5,10,15-Tri(4-methylphenyl)-20-(4-methoxy)phenyl porphyrin (1):
9.5% yield, m.p. >250 °C; IR (KBr, cm−1): υ 3021, 2914, 2857, 1605,
1
1505, 1467, 1346, 1244, 1175, 1030, 965, 797, 736, 593; H NMR
(CDCl3, 600 MHz) δ (ppm): 8.85 (s, 8 H), 8.13–8.08 (m, 8H), 7.56–
7.54 (d, J = 7.2Hz, 6 H), 7.29–7.28 (d, J = 7.2 Hz, 2 H), 4.10 (s, 3 H),
2.70 (s, 9H), –2.77 (s, 2 H); MS (EI): 687 (M+1, 90%). Anal. Calcd
for C48H38N4O:C, 83.94; H, 5.58; N, 8.16. Found: C, 83.80; H, 5.44;
N, 8.09%.
5,10,15-Tri(4-bromophenyl)-20-(4-methoxy)phenyl porphyrin (2):
8.6% yield, m.p. >250 °C; IR (KBr, cm−1): υ 2922, 2853, 1603, 1506,
1469, 1345, 1244, 1172, 1010, 963, 798, 732; 1H NMR (CDCl3,
600 MHz) δ (ppm): 8.83 (s, 2H), 8.76 (s, 6H), 8.04 (d, J = 7.8 Hz, 2H),
8.00 (d, J = 7.2 Hz, 6H), 7.83 (d, J = 7.2 Hz, 6H), 7.23 (d, J = 7.8 Hz,
2H), 4.03 (s, 3H), –2.91 (s, 2H); MS (EI): 883 (M+1, 72%). Anal.
Calcd for C45H29Br3N4O:C, 61.32; H, 3.32; N, 6.36. Found: C, 61.27;
H, 3.48; N, 6.20%.
5,10,15-Tri(4-chlorophenyl)-20-(4-methoxy)phenyl porphyrin (3):
8.9% yield, m.p. >250 °C; IR (KBr, cm−1): υ 3312, 1664, 1602, 1466,
1345, 1255, 1167, 1088, 1013, 963, 795; 1H NMR (CDCl3, 600 MHz)
δ (ppm): 8.80 (s, 2H), 8.74 (s, 6H), 8.00 (d, J = 7.8 Hz, 2H), 7.94 (d,
* Correspondent. E-mail: wangcd@yzu.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2011 699
Scheme 1 Preparation of compounds 5–8.
Table 1 Preparation of compounds 5–8
8.84 (s, 8H), 8.04–8.05 (m, 8H), 7.55 (d, J = 7.2 Hz, 6H), 7.19 (d,
J = 7.8 Hz, 2H), 5.42 (s, 1H), 2.70 (s, 9H), –2.71 (s, 2H); MS (EI): 673
(M+1, 39%). Anal. Calcd for C47H36N4O:C, 83.90; H, 5.39; N, 8.33.
Found: C, 83.71; H, 5.34; N, 8.58%.
5,10,15-Tri(4-bromophenyl)-20-(4-hydroxyphenyl)porphyrin (6):
Following the above procedure using compound 2 as a starting mate-
rial, compound 6 (90% yield) was obtained as a purple solid, m.p.
>250 °C; IR (KBr, cm−1): υ 3308, 3022, 1604, 1555, 1467, 1345, 1254,
1165, 1020, 963, 799, 732; 1H NMR (CDCl3, 600 MHz) δ (ppm): 8.90
(s, 2H), 8.83 (s, 6H), 8.07 (d, J = 7.2 Hz, 8H), 7.90 (d, J = 7.8 Hz, 6H),
7.23 (d, J = 7.8 Hz, 2H), 5.45 (s, 1H), −2.85 (s, 2H); MS (EI): 867
(M+1, 82%). Anal. Calcd for C44H27Br3N4O: C, 60.92; H, 3.14; N,
6.46. Found: C, 60.84; H, 2.98; N, 6.50%.
Compd R1
R2
Reaction conditions
Yield/%
5
6
7
8
CH3
OCH3
BBr3/CH2Cl2/r.t./3 h
BBr3/CH2Cl2/r.t./3 h
BBr3/CH2Cl2/r.t./3 h
NaOH/DMF/r.t./12 h
91
90
94
85
Br
OCH3
Cl
OCH3
OCH3
OCOCH3
J = 7.2 Hz, 6H), 7.82 (d, J = 7.2 Hz, 6H), 7.22 (d, J = 7.8 Hz, 2H), 4.02
(s, 3H), –2.90 (s, 2H); MS (EI): 747 (M+1, 68%). Anal. Calcd for
C45H29Cl3N4O: C, 72.25; H, 3.91; N, 7.49. Found: C, 72.52; H, 3.88;
N, 7.32%.
5,10,15-Tri(4-chlorophenyl)-20-(4-hydroxyphenyl)porphyrin (7):
Following the above procedure using compound 3 as a starting mate-
rial, compound 7 (94% yield) was obtained as a purple solid, m.p.
>250 °C; IR (KBr, cm−1): υ 3312, 1664, 1602, 1466, 1345, 1255, 1167,
1088, 1013, 963, 795; 1H NMR (CDCl3, 600 MHz) δ (ppm): 8.90 (s,
2H), 8.82 (s, 6H), 8.00 (d, J = 7.2 Hz, 8H), 7.92 (d, J = 7.8 Hz, 6H),
7.22 (d, J = 7.8 Hz, 2H), 5.40 (s, 1H), −2.87 (s, 2H); MS (EI): 733
(M+1, 79%). Anal. Calcd for C44H27Cl3N4O: C, 71.99; H, 3.71; N,
7.63. Found: C, 71.82; H, 3.88; N, 7.48%.
5,10,15-Tri(4-methoxyphenyl)-20-(4-acetoxylphenyl) porphyrin (4):
7.8% yield, m.p. >250 °C; IR (KBr, cm−1): υ 2955, 2925, 2855, 1731,
1
1603, 1503, 1463, 1349, 1246, 1169, 1033, 962, 803, 735; H NMR
(CDCl3, 600 MHz) δ (ppm): 8.88 (s, 8H), 8.14 (d, J = 7.2 Hz, 2H),
8.05 (d, J = 6.6 Hz, 6H), 7.22 (d, J = 6.0 Hz, 8H), 4.05 (s, 9H), 2.42
(s, 3H), −2.84 (s, 2H); MS (EI): 763 (M+1, 86%). Anal. Calcd for
C49H38N4O5: C, 77.15; H, 5.02; N, 7.34. Found: C, 77.02; H, 5.26;
N, 7.40%.
Preparation of compounds 5–8
5,10,15-Tri(4-methoxyphenyl)-20-(4-hydroxyphenyl) porphyrin (8):
A mixture of compound 4 (360 mg, 0.5 mmol), sodium hydroxide
(600 mg, 15 mmol) and water (0.5 mL) in DMF (10 mL) was stirred
at room temperature for 12 h. After completion of the reaction was
checked by TLC, ice-water (20 g) was poured into the mixture. The
crude product was filtered and the filter cake was extracted thoroughly
with dichloromethane (50 mL). The resulting organic phase was
washed with water (30 mL × 3) and was dried over anhydrous sodium
sulfate. After removal of Na2SO4, the filtrate was concentrated and the
crude product was purified by column chromatography (silica gel,
CH2Cl2/n-hexane: 1/1 V/V); recrystallisation from CH2Cl2/methanol
gave the pure product. 5,10,15-Tri(4-methoxyphenyl)-20-(4-hydro-
xyphenyl) porphyrin (8): 0.27 g, 85% yield; m.p. >250 °C; IR (KBr,
cm−1): υ 3207, 2923, 2852, 1606, 1506, 1466, 1350, 1247, 1174, 1033,
5,10,15-Tri(4-methylphenyl)-20-(4-hydroxyphenyl)porphyrin (5): BBr3
(50 mg, 0.2 mmol) was added to a solution of compound 1 (0.27 g,
0.4 mmol) in dried dichloromethane (30 mL) in an ice-water bath.
The resultant mixture was stirred for 2 h at room temperature. After
completion of the reaction was checked by TLC, ice-water (10 g) was
poured into the mixture. The crude product was filtered and the filter
cake was extracted thoroughly with dichloromethane (50 mL). The
resulting organic phase was washed with water (30 mL × 3) then dried
over anhydrous sodium sulfate. After removal of Na2SO4, the filtrate
was concentrated and the crude product was purified by column chro-
matography (silica gel, CH2Cl2/n-hexane: 1/1 V/V); re-crystallisation
from CH2Cl2/ethanol gave pure product. 5,10,15-Tri(4-methylphenyl)-
20-(4-hydroxyphenyl)porphyrin (5): 0.24 g, 91% yield; m.p. >250 °C;
IR (KBr, cm−1): υ 3107, 2928, 2854, 1600, 1510, 1463, 1352, 1237,
1
965, 802, 737; H NMR (CDCl3, 600 MHz) δ (ppm): 8.85 (s, 8H),
1
1171, 1033, 967, 801, 739; H NMR (CDCl3, 600 MHz) δ (ppm):
8.12 (d, J = 8.4 Hz, 2H), 8.07 (d, J = 7.8 Hz, 6H), 7.28 (d, J = 7.8 Hz,
Scheme 2 Preparation of multi-substituted tetraarylporphyrins with C5 carboxylate.

700 JOURNAL OF CHEMICAL RESEARCH 2011
Table 2 Preparation of compounds 9–12
(t, J = 7.2 Hz, 3H), –2.90 (s, 2H); MS (EI): 861 (M+1, 38%). Anal.
Calcd for C51H39Cl3N4O3: C, 71.04; H, 4.56; N, 6.50. Found: C, 71.22;
H, 4.30; N, 6.62%.
Compd.
R1
Yield/%
5-[4-(4-Ethoxycarbonylbutoxy)phenyl]-10,15,20-tri(4-methoxyphenyl)
porphyrin (12): Following the above procedure using compound 8 as
a starting material, compound 12 (71% in yield) was obtained as a
purple solid, m.p. >250 °C; IR (KBr, cm−1): υ 3335, 2921, 2851, 1728,
1602, 1505, 1464, 1382, 1346, 1243, 1173, 1029, 962, 840, 799, 737;
1H NMR (CDCl3, 600 MHz) δ (ppm): 8.86 (s, 8H), 8.13–8.10 (m, 8H),
7.28 (d, J = 7.2 Hz, 8H), 4.26 (t, J = 5.4 Hz, 2H), 4.20 (q, J = 7.2 Hz,
2H), 4.09 (s, 9H), 2.52 (t, J = 6.6 Hz, 2H), 2.04–2.00 (m, 4H), 1.32
(t, J = 7.2 Hz, 3H), –2.74 (s, 2H); MS (EI): 849 (M+1, 54%). Anal.
Calcd for C54H48N4O6:C, 76.39; H, 5.70; N, 6.60. Found: C, 76.53; H,
5.77; N, 6.48%.
9
10
11
12
CH3
Br
80
73
67
71
Cl
OCH3
6H), 7.21(d, J = 8.4 Hz, 2H), 5.14 (s, 1H), 4.09 (s, 9H), 2.42 (s, 3H),
–2.74 (s, 2H); MS (EI): 721 (M+1, 90%). Anal. Calcd for C47H36N4O4:
C, 78.31; H, 5.03; N, 7.77. Found: C, 78.08; H, 5.30; N, 7.90%.
Preparation of 5-[4-(4-ethoxycarbonylbutoxy)phenyl]-10,15,20-tri-
arylporphyrins (compounds 9–12)
Preparation of 5-[4-(4-ethoxycarbonylbutoxy)phenyl]-10,15,20-triaryl
porphyrinato gold(III) chloride (compounds 13–16)
5-[4-(4-Ethoxycarbonylbutoxy)phenyl]-10,15,20-tri(4-methylphenyl)
porphyrin (9): Ethyl 5-bromopentanoate (62 mg, 0.30 mmol) was
added to a mixture of compound 5 (168 mg, 0.25 mmol) and sodium
hydroxide (100 mg, 2.5 mmol) in DMF (5 mL) under nitrogen gas at
room temperature for 0.5 h. The resultant mixture was stirred at room
temperature for 12 h. After completion of the reaction was checked by
TLC, ice-water (20 g) was poured into the mixture. The crude product
was filtered and the filter cake was extracted thoroughly with dichlo-
romethane (50 mL). The resulting organic phase was washed with
water (20 mL x 3) and was dried over anhydrous sodium sulfate.
After removal of Na2SO4, the filtrate was concentrated and the crude
product was purified by column chromatography (silica gel, CH2Cl2/
n-hexane: 1/1 V/V); recrystallisation from CH2Cl2/methanol gave
pure (9). (161 mg, 80% yield), m.p. >250 °C; IR (KBr, cm−1): υ 3331,
3022, 2917, 2848, 1731, 1603, 1558, 1505, 1468, 1371, 1346, 1241,
A mixture of substituted porphyrin 9–12 (2.5 mmol), K[AuCl4]
(2.82 g, 7.5 mmol) and sodium acetate (2.05 g, 25 mmol) in acetic
acid (15 mL) was refluxed for 10–13 h. After completion of the
reaction was checked by TLC, the crude product was obtained by
removing the acetic acid. Next the purple solid product was extracted
thoroughly with dichloromethane and the organic phase was washed
water (20 mL × 3). The organic phase was dried over anhydrous
sodium sulfate.After removal of Na2SO4, the filtrate was concentrated,
then the crude product was purified by column chromatography (silica
gel, DCM/methanol: 5/1 V/V). The purified product was dissolved in
acetone, and after filtering the mixture, the solution was treated with
LiCl in aqueous acetone to give the analytically pure gold(III) porphy-
rin compounds 13–16 as chloride salts in 68–82% yields (Scheme 3,
Table 3).
1
1173, 1025, 985, 963, 841, 799, 734; H NMR (CDCl3, 600 MHz)
5-[4-(4-Ethoxycarbonylbutoxy)phenyl]-10,15,20-tri(4-methylphe-
nyl)porphyrinato gold(III) chloride (13): M.p. 119–121 °C; IR: (KBr,
cm−1): υ 2918, 2849, 1729, 1602, 1500, 1466, 1358, 1243, 1176, 1031,
δ (ppm): 8.85 (s, 8H), 8.11–8.08 (m, 8H), 7.55 (d, J = 7.2 Hz, 6H),
7.26 (d, J = 7.8 Hz, 2H), 4.26 (t, J = 5.4 Hz, 2H), 4.20 (q, J = 7.2 Hz,
2H), 2.70 (s, 9H), 2.46 (t, J = 6.6 Hz, 2H), 2.04–1.99 (m, 4H), 1.32
(t, J = 7.2 Hz, 3H), –2.77 (s, 2H); MS (EI): 801 (M+1, 35%). Anal.
Calcd for C54H48N4O3: C, 80.97; H, 6.04; N, 6.99. Found: C, 80.82; H,
6.23; N, 7.16%.
5-[4-(4-Ethoxycarbonylbutoxy)phenyl]-10,15,20-tri(4-bromophenyl)
porphyrin (10): Following the above procedure using compound 6 as
a starting material, compound 10 (73% yield) was obtained as a purple
solid, m.p. >250 °C; IR (KBr, cm−1): υ 3312, 2918, 2849, 1731, 1604,
1
802, 722; H NMR (CDCl3, 600 MHz) δ (ppm): 9.25–9.22 (m, 8H),
8.07–8.03 (m, 8H), 7.60 (d, J = 7.8 Hz, 6H), 7.30 (d, J = 8.4 Hz, 2H),
4.23 (t, J = 5.4 Hz, 2H), 4.13 (q, J = 7.2 Hz, 2H), 2.67 (s, 9H), 2.51
(t, J = 6.6 Hz, 2H), 1.99–1.93 (m, 4H), 1.32 (t, J = 7.2 Hz, 3H);
MS(EI): (M+1-Cl): 996.19 (100%). Anal. Calcd for C54H46N4O3ClAu:
C, 62.88; H, 4.50; N, 5.43. Found: C, 62.73; H, 4.40; N, 5.68%.
5-[4-(4-Ethoxycarbonylbutoxy)phenyl]-10,15,20-tri(4-bromophenyl)
porphyrinato gold(III) chloride (14): M.p. 116–118 °C; IR: (KBr,
cm−1): υ 2917, 2849, 1733, 1602, 1468, 1359, 1245, 1175, 1032, 805,
713; 1H NMR (CDCl3, 600 MHz) δ (ppm): 9.32 (s, 2H), 9.23 (s, 6H),
8.16–8.15 (m, 8H), 8.00 (d, J = 6.0 Hz, 6H), 7.36 (d, J = 5.4 Hz, 2H),
4.29 (t, J = 5.4 Hz, 2H), 4.21 (q, J = 7.2 Hz, 2H), 2.52 (t, J = 6.6 Hz,
2H), 2.07–2.00 (m, 4H), 1.35 (t, J = 7.2 Hz, 3H); MS(EI): (M+1-Cl):
1191.83 (100%). Anal. Calcd for C51H37N4O3AuBr3Cl: C, 49.96; H,
3.04; N, 4.57. Found: C, 49.82; H, 3.18; N, 4.66%.
1
1559, 1470, 1347, 1242, 1172, 1090, 1015, 986, 964, 843, 799; H
NMR (CDCl3, 600 MHz) δ (ppm): 8.90 (s, 2H), 8.83 (s, 6H),
8.10–8.06 (m, 8H), 7.90 (d, J = 6.6 Hz, 6H), 7.73 (s, 1H), 7.54 (s, 1H),
4.27 (t, J = 5.4 Hz, 2H), 4.21 (q, J = 7.2 Hz, 2H), 2.52 (t, J = 6.6 Hz,
2H), 2.06–1.99 (m, 4H), 1.30 (t, J = 7.2 Hz, 3H), –2.84 (s, 2H); MS
(EI): 995 (M+1, 29%). Anal. Calcd for C51H39Br3N4O3: C, 61.53; H,
3.95; N, 5.63. Found: C, 61.38; H, 3.70; N, 5.72%.
5-[4-(4-Ethoxycarbonylbutoxy)phenyl]-10,15,20-tri(4-chlorophenyl)
porphyrin (11): Following the above procedure using compound 7 as
a starting material, compound 11 (67% yield) was obtained as a purple
solid, m.p. >250 °C; IR (KBr, cm−1): υ 3312, 2913, 2849, 1731, 1604,
Table 3 Preparation of compounds 13–16
Compd.
R1
Yield/%
1
1558, 1473, 1347, 1242, 1175, 1085, 1015, 986, 964, 850, 799; H
13
14
15
16
CH3
Br
82
73
68
78
NMR (CDCl3, 600 MHz) δ (ppm): 8.83 (d, J = 4.2 Hz, 2H), 8.75–8.74
(m, 6H), 8.07–8.05 (m, 6H), 8.03 (d, J = 8.4 Hz, 2H), 7.67 (d, J =
7.2 Hz, 6H), 7.21 (d, J = 8.4 Hz, 2H), 4.20 (t, J = 5.4 Hz, 2H), 4.13
(q, J = 7.2 Hz, 2H), 2.45 (t, J = 6.6 Hz, 2H), 1.97–1.92 (m, 4H), 1.31
Cl
OCH3
Scheme 3 Preparation of gold(III) substituted tetraarylporphyrins with C5 carboxylate.

JOURNAL OF CHEMICAL RESEARCH 2011 701
5-[4-(4-Ethoxycarbonylbutoxy)phenyl]-10,15,20-tri(4-chlorophe-
nyl) porphyrinato gold(III) chloride (compounds 15): M.p. 113–115
°C; IR: (KBr, cm−1): υ 2917, 2849, 1738, 1603, 1466, 1359, 1244,
(5–8) and ethyl 5-bromopentanoate under dinitrogen promoted
by sodium hydroxide in 67–80% yield (Scheme 2, Table 2).
Gold(III) porphyrin compounds (13–16) were synthesised by
treatment of K[AuCl4] with the porphyrin ligand (9–12) in the
presence of NaOAc in acetic acid. After purification with
column chromatography and metathesis reaction with LiCl in
aqueous acetone, gold(III) porphyrin compounds are obtained
as chloride salts in 68–82% yields (Scheme 3, Table 3).
To analyse the potential of compounds (13–16) as antitu-
mour agents, their cytotoxicity was evaluated (Table 4) towards
the SGC-7901 human tumor and for comparison purposes the
cytotoxicity of cisplatin and TPPAuCl18,29 were also evaluated
under the same experimental conditions. From the data shown
in Table 4, the new compounds (13–16) showed a measurable
anti-cancer activity against SGC-7901 human tumour cell lines
tested. Although this is a preliminary screening, the results
showed that the cytotoxicity of (16) against SGC-7901 human
tumor cells was higher than cisplatin, but less than TPPAuCl.
Compounds 13–15, with the same 4-(4-ethoxycarbonylbutoxy
)phenyl structure and different types of substituent group in the
10,15,20-postions of the aromatic rings, showed a distinct dif-
ference in their cytotoxicity against SGC-7901 human tumour
cells. They showed a lower anticancer activity than TPPAuCl,
cisplatin, and compound 13. Comparing the activity of
compounds 13–16 in the in vivo study, the inhibitory effect
of complex 13 on the tumour growth was dose dependent,
while compounds 14–16 showed different sensitivities towards
the human cancer tested. These results indicate that the
gold(III) substituted porphyrins with a methoxycarbonyl- or
methoxy-substituted group have greater anticancer activity
than compounds containing such groups as methyl and halides.
In our previous study,28 we found previously that gold(III)
substituted porphyrin compounds (MeOTPPAuCl and
MeO2CTPPAuCl), exhibited high cytotoxicity against the
tumor cell lines in vitro. Here our in vivo study of the four
compounds (13–16) showed that compound 16 displayed high
antitumor activities and these complexes had better aqueous
solubility compared with cisplatin and TPPAuCl. These results
suggest that C5 alkoxycarboxylate, a long chain and polar
group, could conspicuously promote the aqueous solubility of
gold(III) substituted porphyrins, thus causing improvement of
the bioavailabilty of the compounds. At the same time, the
long-chain alkoxycarboxylate group could balance the lipo-
solubility with aqueous solubility, which could be helpful in
transport of drugs into target cells and improve antitumour
activity.
1
1174, 1032, 804, 722; H NMR (CDCl3, 600 MHz) δ (ppm): 9.33–
9.32 (d, J = 4.8 Hz, 2H), 9.23 (d, J = 8.4 Hz, 6H), 8.21 (d, J = 7.2 Hz,
6H), 8.15 (d, J = 7.2 Hz, 2H), 7.85 (d, J = 7.2 Hz, 6H), 7.36 (d, J =
7.8 Hz, 2H), 4.29 (t, J = 5.4 Hz, 2H), 4.22 (q, J = 7.2 Hz, 2H), 2.53 (t,
J = 6.6 Hz, 2H), 2.04–2.01 (m, 4H), 1.32(t, J = 7.2 Hz, 3H); MS(EI):
(M+1-Cl): 1057.87 (100%). Anal. Calcd for C51H37N4O3Cl4Au (%): C,
56.06; H, 3.41; N, 5.13. Found: C, 56.19; H, 3.20; N, 5.40%.
5-[4-(4-Ethoxycarbonylbutoxy)phenyl]-10,15,20-tri(4-methoxyphenyl)
porphyrinato gold(III)chloride (16): M.p. 127–129 °C; IR: (KBr,
cm−1): υ 2910, 2850, 1738, 1602, 1500, 1465, 1357, 1249, 1175, 1020,
1
805, 723; H NMR (CDCl3, 600 MHz) δ (ppm): 9.31 (s, 8H), 8.17–
8.14 (m, 8H), 7.39 (d, J = 7.8 Hz, 6H), 7.37 (d, J = 8.4 Hz, 2H),
4.30 (t, J = 4.8 Hz, 2H), 4.21 (q, J = 7.2 Hz, 2H), 4.13 (s, 9H), 2.53
(t, J = 7.2 Hz, 2H), 2.05–2.00 (m, 4H), 1.34 (t, J = 7.2 Hz, 3H);
MS(EI): (M+1-Cl): 1044.18 (100%).Anal. Calcd for C54H46N4O6ClAu:
C, 60.09; H, 4.30; N, 5.19. Found: C, 60.16; H, 4.13; N, 5.10%.
Cytotoxicity assay of the effect of compounds 13–16 on SGC-7901
human cell proliferation30
Compounds 13–16 were prepared at the concentrations of
6.4×10−5 mol L−1, 3.2×10−5 mol L−1, 1.6×10−5 mol L−1, 8×10−6 mol L−1,
4×10−6 mol L−1 and 2×10−6 mol L−1 respectively. DMSO was used as
latent solvent with the highest concentration less than 0.1% in solution
of tetraarylporphyrin complex. The control groups of cisplatin, blank
(1640) and DMSO solvent were set up at the same time. The cytotox-
icities of 13–16 were determined by MTT cytotoxic assay. SGC-7901
human gastric carcinoma cell was plated in 96-well plates at
1×105 mL and 100 µL/well in complete media. Then the prepared and
various amounts of 13–16 and cisplatin were plated in 96-well plates
contain SGC-7901 human gastric carcinoma cell and incubated
commonly for 44 h. 100 µL supernatant liquid was sucked from each
hole, 10 µL of MTT (5 mg mL−1) was added in and cultured for 4 h,
the media was then removed and hydrochloric acid/isopropanol added
at 100 µL/well. Following agitating for 5 minutes using the micro
oscillator to dissolve MTT crystals, the OD value was measured at
570 nm using a Model Elx 800Autoplate reader (Bio-Tek Instruments,
USA).
Statistical analysis of experimental data
All the data of the experiments were compiled and analysed according
to SPSS 15.0 software. Measurement data were expressed as the
mean.
Results and discussion
First, according to our previous reported method,28 tetraaryl-
porphyrins 1–4 were synthesised in 7.8–9.5% yield by treating
the appropriate, freshly distilled pyrrole with various
substituted benzaldehydes in propionic acid. Zeisel reaction of
triaryl(4-methoxyphenyl) porphyrins (1–3) with BBr3 at room
temperature for 2 h afforded triaryl(4-hydroxyphenyl) porphy-
rins (5–7) (90–94% in yield) (Scheme 1, Table 1). Hydrolysis
of 5,10,15-tri(4-methoxyphenyl)-20-(4-acetoxylphenyl) por-
phyrin (4) in the presence of sodium hydroxide at room
temperature for 12 h gave 5,10,15-tri(4-methoxyphenyl)-20-
(4-hydroxyphenyl) porphyrin (8) in 85% yield (Scheme 1,
Table 1). 5-[4-(4-ethoxycarbonylbutoxy)phenyl]-10,15,20-
triarylporphyrins (9–12) were readily obtained by reaction of
Conclusions
In this study, compound 16 not only exhibited better antitu-
mour activity than cisplatin against the tested tumours, but also
possesses desirable physico-chemical properties, such as rather
good solubility in both water and organic solvents. Compound
16 also presents quite high antitumor activity and fairly low
toxicity. Therefore, it might be worth further investigation as a
potential antitumour agent.
The authors are grateful to the National Natural Science
Foundation of China (Projects No. 20872125).
Table4 Cytotoxicityofgold(III)substitutedtetra-arylporphyrin
chlorides against SGC-7901 human tumor cell line in vitro
Received 7 September 2011; accepted 28 November 2011
Paper 1100881 doi: 10.3184/174751911X13230815130502
Published online: 27 December 2011
Entry
Compound
Maximum
IC50/µmol L−1
inhibition rate/%a
a
b
c
d
e
f
TPPAuCl[18]
74.42
54.32
50.68
48.73
69.73
56.86
9.87
>100
75.08
>100
29.18
31.23
13
14
15
16
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