Synthesis and some physicochemical properties of the aqua complexes of covalent conjugates of platinum(II) with octacarboxy-substituted cobalt phthalocyanine

Article abstract of DOI:10.1134/S1070328407020066

Aqua complexes of the covalent conjugates of octacarboxy-substituted cobalt phthalocyanine with platinum, which are of interest as components of a catalytic system for cancer therapy, were synthesized. For the tetraplatinated product, elemental analysis data and the data from electronic absorption, IR, and mass spectra are given. Nauka/Interperiodica 2007.

Full text of DOI:10.1134/S1070328407020066

ISSN 1070-3284, Russian Journal of Coordination Chemistry, 2007, Vol. 33, No. 2, pp. 111–115. © Pleiades Publishing, Ltd., 2007.
Original Russian Text © O.V. Dolotova, O.L. Kaliya, 2007, published in Koordinatsionnaya Khimiya, 2007, Vol. 33, No. 2, pp. 116–120.
Synthesis and Some Physicochemical Properties
of the Aqua Complexes of Covalent Conjugates of Platinum(II)
with Octacarboxy-Substituted Cobalt Phthalocyanine
O. V. Dolotova and O. L. Kaliya
NPO Organic Intermediates and Dyes (NIOPIK), ul. Bol’shaya Sadovaya 1/4, Moscow, 103787 Russia
Received February 9, 2006
Abstract—Aqua complexes of the covalent conjugates of octacarboxy-substituted cobalt phthalocyanine with plat-
inum, which are of interest as components of a catalytic system for cancer therapy, were synthesized. For the tetra-
platinated product, elemental analysis data and the data from electronic absorption, IR, and mass spectra are given.
DOI: 10.1134/S1070328407020066
During the last decade, studies aimed at combining
in one preparation of the cytotoxic activity of platinum
complexes with photodynamic activity of porphyrins
and their ability to selectively accumulate in a tumor
have occupied a prominent place in the research con-
cerned with anticancer therapy [1–8]. It is known
[9−11] that platinum complexes are fairly efficient in
the therapy of malignant neoplasms at some sites; how-
ever, side effects caused by their toxicity create a num-
ber of grave problems in the clinical use of these com-
plexes. Studies dealing with combination of the useful
properties of platinum-containing preparations and
porphyrins resulted in the synthesis of a number of
compounds representing platinum complexes (covalent
conjugates) with hematoporphyrin and tetraphenylpor-
phyrin derivatives [2, 3, 12–16] and with zinc phthalo-
cyanine [4]. A study of the effect of conjugates on liv-
ing cells showed an additive effect of porphyrin photo-
dynamic activity and platinum cytotoxic activity.
A new approach to the therapy of cancer [17] (so-
called catalytic therapy) makes use of the cytotoxic
properties of free radicals formed as intermediate prod-
ucts in the catalytic oxidation of ascorbic acid with oxy-
gen in the presence of transition metal phthalocyanines.
During the development of efficient drugs for the cata-
lytic therapy of cancer and the ways of their applica-
tion, it was shown that combined use of the best cata-
lysts with standard cytostatics often gives an over-addi-
tive therapeutic effect [18], which thus allows one to
decrease the therapeutic dose of, in particular, platinum
drugs. This mitigates the problem of toxicity of these
drugs but does not solve it radically.
The purpose of this study is an attempt to prepare a
platinum complex with octacarboxy-substituted cobalt
phthalocyanine (covalent conjugate) (II) by the follow-
ing reaction:
H O
OH
Pt
2
Na+
Na+
O–
2
O
O
O
O
H O Pt
O
2
O–
O
OH
2
Na+
Na+
O–
O–
O
O
O
N
Co
N
O
O
N
O
N
N
N
N
N
N
N
N
K2[PtCl4]
H2O, MeOH, EtOH
(1)
N
N
N
Co
N
O
O
O
O
O
O
N
O–
O–
Na+
Na+
O–
Na+
O–
Na+
O Pt OH
2
O
O
H O Pt
O
O
O
2
(I)
(II)
OH
2
OH
2
111

112
DOLOTOVA, KALIYA
The sodium salt of cobalt 2,3,9,10,16,17,23,24-octacar- 48 h, the precipitate was filtered off, washed with dis-
boxyphthalocyanine OCPcCoNa8 (Teraphthal, I) is tilled water and dried in air. The yield was 0.27 g.
now under the second phase of clinical tests as a com-
ponent of a catalytic system for the therapy of cancer.
As judged from the dependence of the elemental
analysis data on the particular reactant ratio, the precip-
itate formed in this reaction is not an individual sub-
stance but a mixture of mono-, di- and trisubstituted
complexes.
EXPERIMENTAL
Teraphthal produced at the pilot plant of the Federal
Unitary Enterprise, State Scientific Center, Organic
Intermediates and Dyes (NIOPIK) and high-purity
grade potassium hexachloroplatinate K2[PtCl6] were
used in the syntheses.
IR spectra of were recorded on a FSM-1201 FT
spectrometer in the 400–4000 cm–1 range (KBr pellets).
Mass spectra were measured on an LCQ Finnigan spec-
trometer. The electronic absorption spectra (UV/Vis) of
I and II were measured on a Hewlett Packard 82341C
HP spectrometer.
Step 2. A solution of K2[PtCl4] (0.24 g, 0.58 mmol)
in 50% ethanol (285 ml) was added to a suspension of
the product obtained in step 1 (0.27 g) in a mixture of
water (50 ml) with methanol (210 ml). The subsequent
operations were similar to those described in step 1 of
the synthesis. The solid product was washed with dis-
tilled water, ethanol, acetone, and ether and dried in air.
The air-dry product was a dark violet-colored crystal-
line compound with a metallic luster soluble in dimeth-
ylformamide and dimethyl sulfoxide. The yield was
0.29 g (81%).
Potassium tetrachloroplatinate was synthesized by a
modification of a reported procedure [19]. N2H4 · H2SO4
(0.27 g, 2.06 mmol) was added to K2[PtCl6] (2 g,
4.12 mmol) dissolved in distilled water (20 ml), and the
mixture was brought to boiling and heated on a water
bath for 40 min. The resulting solution was filtered, and
K2[PtCl4] was precipitated by an acetone–diethyl ether
mixture (1 : 1). The product was washed with acetone
and ether. The yield was 1.46 g (86%).
According to elemental analysis data, the composi-
tion of the compound can be described by the formula
OCPcCoPt4(H2O)8.
For C40H24N8CoO24Pt4
anal. calcd. (%): C, 26.11; H, 1.31; N, 6.09; Co,
3.20; Pt, 42.40.
Found (%): C, 26.84; H, 1.50; N, 6.94; ash, 46.71.
(with the assumption that the ash consists of Pt and
equal amounts of CoO and Co2O3, the calculated over-
all percentage of Pt and Co is 45.55).
Analysis for platinum was carried out by a known
procedure [20]. A sample (18 mg) was dissolved in a
buffer solution (20 ml) of a Na2HPO4 and Kç2PO4 mix-
The Beilstein test and the elemental analysis of the
ture (pH 8). A 30% aqueous solution of formaldehyde reaction product showed the absence of residual chlo-
and 10 ml of a 50% aqueous solution of NaOH were rine in the sample.
added to the resulting solution. After a while, platinum
black precipitated, which was filtered through a porous
glass filter. The filtrate was intensively aquamarine-col-
RESULTS AND DISCUSSION
ored, i.e., the phthalocyanine chromophore was not
destroyed. The platinum black precipitate was washed
on a filter with distilled water to pH 7 and dried in a dry-
ing oven at 150°ë for 2 h. The yield of platinum black
was 7.53 mg, which is in good agreement with the ele-
mental analysis data for ash.
As found experimentally when testing the condi-
tions of the synthesis, the preparation of a covalent con-
jugate containing four platinum atoms requires that the
initial cobalt phthalocyanine and a platinum salt be
taken in 1 : 7 molar ratio. Since one-time addition of a
large excess of K2[PtCl4] results in the formation of
platinum black during the reaction, probably via the
reaction of the initial potassium tetrachloroplatinate
with methanol, a two-step synthetic procedure was
elaborated.
The introduction of platinum at the periphery of
cobalt octacarboxyphthalocyanine changes essentially
the physicochemical properties of complex I. For
example, the replacement of the ionic bond, Na+O–, by
the Pt–O covalent bond eliminates almost completely
the solubility of the tetraplatinated product II in water.
The initial complex I can be chromatographed on silica
gel with a Na2HPO4 – Kç2PO4 buffer solution (pH 8);
no eluent was selected for the final product II, which
was sorbed irreversibly on the stationary phase.
A comparison of the UV/Vis spectra of complex II
and initial salt I (Fig. 1) reveals significant changes in
the spectral pattern with the general structure being
retained. These changes (especially those in the 230–
260 nm range) can serve for monitoring the formation
of complex II.
Synthesis of OCPcCoPt4(H2O)8 (II). Step 1. Ter-
The presence of platinum in product II was con-
aphthal OCPcCoNa8 (I) (0.21 g, 0.19 mmol) was dis- firmed by a qualitative test for Pt(II) with photometric
solved in distilled water (25 ml), and methanol (210 ml) detection [21]. The procedure included the extraction
was added. A solution of K2[PtCl4] (0.32 g, 0.77 mmol) of Pt(II) from an aqueous suspension of a sample of II
in 50% ethanol (380 ml) prepared immediately prior to with a diphenylthiocarbazone (dithizone HDz) solution
the synthesis was added to the solution of salt I, and the in carbon tetrachloride containing SnCl2 and 2 N HCl.
mixture was stirred for 3 h at room temperature. After This resulted in a transition of the green color typical of
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SYNTHESIS AND SOME PHYSICOCHEMICAL PROPERTIES
113
D
0.6
678
239
1
0.4
0.2
0
683
255
2
300
400
500
600
700
800
900
1000
1100
λ, nm
–5
Fig. 1. UV/Vis spectrum of the (1) initial OCPcCoNa and (2) final OCPcCoPt (H O) compounds in water (Ò = 10 mol/l, l = 1 cm).
8
4
2
8
II
D
0.6
1
0.4
0.2
0
2
300
400
500
600
700
800
900
λ, nm
–5
Fig. 2. UV/Vis spectrum of (1) dithizone and (2) the product of its reaction with OCPcCoPt (H O) in CCl (Ò = 10 mol/l, l = 1 cm).
4
2
8
4
II
a dithizone solution in CCl4 to brownish-yellow color
The IR spectrum of II (Fig. 3, 1) in the 1400–
typical of platinum dithizonate Pt(HDz)2 and was 1700 cm–1 range differs considerably from the spec-
accompanied by a change in the UV/Vis spectrum trum of the initial Teraphthal (Fig. 3, 2), which has two
(Fig. 2).
characteristic bands, namely, at 1380 cm–1 due to
RUSSIAN JOURNAL OF COORDINATION CHEMISTRY Vol. 33 No. 2 2007

114
DOLOTOVA, KALIYA
1
2
3
500
1000
1500
2000
2500
3000
3500
4000
ν, cm
–1
Fig. 3. IR spectra of (1) OCPcCoPt (H O) , (2) Teraphthal, and (3) OCPcCoH .
4
2
8
8
νs(ëéé–) and at 1570 cm–1 due to νas(ëéé–), and also induces the elimination of platinum and the recovery of
from the spectrum of OCPcCoH8 (Fig. 3, 3) in which initial OCPcCoNa8, which is accompanied by a charac-
the strongest band at 1704 cm–1 is due to the C=O mode teristic change in the UV/Vis spectrum. The addition of
of the carboxy group. The 1600–1700 cm–1 range is acids to complex II also results in the elimination of
known to be rather ambiguous for interpretation platinum to give the acid OCPcCoH8.
[22, 23]. This range includes the C=O vibrations of the
carboxy groups of carboxylic acids, their salts, or other
compounds. According to published data [15, 16, 24, 25],
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