See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/5437260

Synthesis, Spectroscopic, and Anticancerous Properties of Mixed Ligand

Palladium(II) and Silver(I) Complexes with 4,6-Diamino-5-hydroxy-2-
mercaptopyrimidine and 2,2′-Bipyridyl

Article  in  Metal-Based Drugs · February 2008

DOI: 10.1155/2008/723634 · Source: PubMed

CITATIONS READS

31 186

2 authors:

Sahar I. Mostafa Farid Abd Elreheem Badria

Mansoura University Mansoura University
77 PUBLICATIONS   943 CITATIONS    193 PUBLICATIONS   3,273 CITATIONS   

SEE PROFILE SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Evaluation of the anticancer activity of synthesized compounds or semi-synthesized natural products against different cancer cell lines and normal cells View project

sle TREATMENT View project

All content following this page was uploaded by Sahar I. Mostafa on 23 May 2014.

The user has requested enhancement of the downloaded file.

Hindawi Publishing Corporation
Metal-Based Drugs
Volume 2008, Article ID 723634, 7 pages
doi:10.1155/2008/723634

Research Article
Synthesis, Spectroscopic, and Anticancerous Properties
of Mixed Ligand Palladium(II) and Silver(I) Complexes with
4,6-Diamino-5-hydroxy-2-mercaptopyrimidine and
2,2-Bipyridyl

Sahar I. Mostafa1 and Farid A. Badria2

1 Chemistry Department, Faculty of Science, Mansoura University, 35516 Mansoura, Egypt
2 Liver Research Laboratory, Faculty of Pharmacy, Mansoura University, 35516 Mansoura, Egypt

Correspondence should be addressed to Sahar I. Mostafa, sihmostafa@yahoo.com

Received 27 May 2007; Revised 30 October 2007; Accepted 13 February 2008

Recommended by Rafael Moreno-Sanchez

Synthesis of two new water-soluble mixed ligand [Pd(bpy)(dahmp)]Cl and [Ag(bpy)(Hdahmp)]NO3 complexes (dahmp and
Hdahmp are the deprotonated monoanion and the protonated neutral 4,6-diamino-5-hydroxy-2-mercaptopyrimidine, resp.) is
reported. The composition of the reported complexes was discussed on the bases of IR, 1 H NMR, and mass spectra, as well as
conductivity and thermal measurements. The reported complexes display a significant anticancer activity against Ehrlich ascites
tumor cells (EACs). The higher activity of these complexes with their higher conductivity values corresponds to their complete
ionization in aqueous solution.

Copyright © 2008 S. I. Mostafa and F. A. Badria. This is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.

1. INTRODUCTION and S-analogy of pyrimidinic bases on oral epidermoid hu-

man carcinoma (KB) have been reported [10, 11].
As a continuation of our research in 4,6-diamino-5-
Currently, cisplatin is being used as an anticancer agent hydroxy-2-mercaptopyrimidine complexes and their biolog-
in several human cancers, particularly, testicular and ovar- ical activities [12], in this research, we report the com-
ian cancers [1, 2]. Side effects, especially nephrotoxicity, of plexes obtained from the reaction of 4,6-diamino-5-hydroxy-
this drug limit its widespread use in high dose [3]. The 2-mercaptopyrimidine (Hdahmp) with [Pd(bpy)Cl2 ] and
need to develop new complexes with reduced nephrotox- [Ag(bpy)(H2 O)2 ]NO3 . They have been investigated using IR,
icity and higher activity has stimulated the synthesis of 1 HNMR, and mass spectra, conductivity and thermal mea-
many new complexes. Over the past years, a renewed inter- surements. In addition, the anticancer activity of these com-
est in Pd(II) complexes as potential anticancer agents has plexes against Ehrlich ascites tumor cells (EACs) has been re-
developed. Though a number of interesting Pd(II) targets ported.
have been investigated [4–7], the biological utility of such
agents continues to be questioned, this may be due to the
2. EXPERIMENTAL
poor solubility of common Pd(II) complexes under physio-
logic conditions. Many studies, including nucleic and amino 2.1. Material and methods
acid derivatives, showed that 2-mercaptopyrimidine and 2-
mercapto-4-aminopyrimidine are able to inhibit the synthe- All manipulations were performed under aerobic conditions
sis of t-RNA [8]. Thus, they may act as valuable substrates using 4,6-diamino-5-hydroxy-2-mercaptopyrimidine and all
in the synthesis of antitumor chemotherapeutic agents [9]. other reagents (Merck) as received. [Pd(bpy)Cl2 ] was synthe-
Also, the effect of 2-mercaptopyrimidine-5-carboxylic acid sized by the literature method [13].
2 Metal-Based Drugs

The cells of Ehrlich ascites (EACs) tumor were obtained 2.5. Anticancer activity against Ehrlich ascites
from National Cancer Institute (Cairo, Egypt). After harvest- carcinoma in mice
ing and preparation of the cells, their total number and via-
bility were determined by counting using Trypan blue [14]. All the compounds were screened for their anticancer
activity by dissolving samples in minimum amount of
DMSO (Hdahmp) or water (complexes) and diluting with
2.2. Instrumentation phosphate-buffered saline (PBS; pH = 7.2). The anticancer
studies using Ehrlich ascites tumor cells (EACs) were car-
Microanalyses were determined by the Micro Analytical Unit ried out by incubating 0.2 mL of cells IP. All the treat-
(Cairo University, Cairo, Egypt). Electronic spectra were ments started 24 hours after inoculation for 45 days. The
recorded using a Unicam UV2–100 U.V.-vis. Spectrometer. IR tumor-bearing mice were divided into three groups. Group
spectra were measured as KBr discs on a Matson 5000 FT- (1) is the standard one that received the 5-florouracil
IR spectrometer (Cairo University). 1 H NMR spectra were [16] (5-fu; 20 mg/kg/day of mice) for comparison. Group
measured on a Varian Gemini WM-200 spectrometer (Laser (2) received Hdahmp, [Pd(bpy)(dahmp)]Cl, [Ag(bpy)-
Centre, Cairo University). Thermal analysis measurements (Hdahmp)]NO3 complexes (0.01 mg/mice/day). Group (3)
were made in the 20–800◦ C range at the heating rate of 10◦ C is the control one received physiological saline (0.9% sodium
min−1 , using α-Al2 O3 as a reference, on a Shimadzu Ther- chloride).
mogravimetric Analyzer TGA-50. Conductimetric measure-
ments were carried out at room temperature on a YSI Model
3. RESULTS AND DISCUSSION
32 conductivity bridge. Mass spectra were recorded on a
Matson MS 5988 spectrometer (Micro Analytical Unit, Cairo 3.1. Synthesis of complexes
University).
Table 1 lists two new complexes of 4,6-diamino-5-hydroxy-
2-mercaptopyrimidine (Hdahmp). The elemental analyses of
2.3. Synthesis of complexes
the isolated complexes agree with the assigned formula. The
2.3.1. [Pd(bpy)(dahmp)]Cl·H2 O conductivities (ΛM ) in DMF at room temperature showed
the electrolytic character of these complexes [4, 16].
To a stirred suspension of [Pd(bpy)Cl2 ] (0.17 g, 0.5 mmol) The complex [Pd(bpy)(dahmp)]Cl was prepared from
in methanol-benzene (3 : 2, V/V) (15 cm3 ), was added a [Pd(bpy)Cl2 ] and Hdahmp in methanol-benzene in presence
methanolic solution of KOH (0.055 g, 1 mmol) contain- of aqueous base, while [Ag(bpy)(Hdahmp)]+ was made from
ing Hdahmp (0.08 g, 0.5 mmol). The resulting suspension aqueous AgNO3 with bpy and Hdahmp in methanol.
was stirred for two days and a brown complex was ob- The complexes are powder-like, stable in the normal lab-
tained. It was filtered off, washed with water and methanol, oratory atmosphere, and soluble in water, DMF, or DMSO.
and then air-dried. Conductivity data (10−3 M in DMF): We had hoped to characterize the structure of one of the
ΛM = 97.0 ohm−1 cm2 mol−1 . Elemental Anal. Calc. for complexes by single X-ray crystallography, but were thwarted
C14 ClH15 N6 O2 SPd: C, 35.53; H, 3.17; N,17.76; S, 6.77; Cl, on numerous occasions by very small crystal dimensions.
7.51. Found C, 35.72; H, 3.11; N, 17.71; S, 6.85; Cl, 7.63. Thus, the characterization of these complexes was based on
the physical and spectroscopic techniques.
2.3.2. [Ag(bpy)(Hdahmp)]NO3
3.2. Vibration spectra
Silver nitrate (0.087 g, 0.5 mmol) in water (2 cm3 )was The characteristic IR bands observed and the vibration as-
added to bpy (0.078 g, 0.5 mmol) in methanol (35 cm3 ) to signments of 4,6-diamino-5-hydroxy-2-mercaptopyrimidine
produce a colorless solution, to which Hdahmp (0.08 g, (Hdahmp) complexes are reported in Table 1. The spectrum
0.5 mmol) was added. The reaction mixture was stirred in of Hdahmp supports the existence of the thione form in
dark for 3 hours to produce a pale brown solid. It was fil- the solid phase (Scheme 1). This can be attributed to the
tered off, washed with little water, methanol, and diethyl presence of ν(NH) stretch at 2970 cm−1 [17], the absence of
ether, then dried in vacuo. Conductivity data (10−3 M in ν(SH) near 2600 cm−1 , and the production of the character-
DMF): ΛM = 60.0 ohm−1 cm2 mol−1 . Elemental Anal. Calc. istic thioamide bands due to extensive coupling of δ(NH),
for C14 H14 N7 O4 SAg: C, 34.72; H, 2.89; N, 20.25; S, 6.61. ν(C=N), ν(NCS), and ν(C=S) at 1652, 1562, 1455, and (1375,
Found C, 34.54; H, 2.78; N, 20.00; S, 6.42. 1268, 1177) cm−1 , respectively [18–20].
In the spectrum of [Pd(bpy)(dahmp)]Cl, the stretching
2.4. Conductivity measurements vibration ν(OH) at 3305 cm3 in the free ligand is missing in
the complex [21]. The bands at 3390 and 3185 cm−1 , aris-
The conductivity values for [Pd(bpy)(dahmp)]Cl and [Ag- ing from νs (NH2 ) and νas (NH2 ), respectively [21], in the
(bpy)(Hdahmp)]NO3 were determined. The compounds free ligand are shifted to lower wave numbers upon com-
were dissolved in water and the measurements were done at plexation [21, 22]. The bands arising from ν(C=N), ν(NCS),
concentrations; 1, 0.8, 0.6, 0.4, and 0.2 mM. The conductance and ν(C=S) are not affected while the bands arising from
values (ΛM ) were calculated and plotted against concentra- ν(NH) and δ(NH) stretches are slightly shifted to lower
tion [15]. wave number in the complexes. This suggests that Hdahmp
S. I. Mostafa and F. A. Badria 3

Table 1: Spectral data of Hdahmp and its complexes.

IR spectral data
ν(CN)
ν(C=C) ν(M–N)
Complexes ν(OH) νs (NH2 ) νas (NH2 ) δ(NH) ν(NCS) ν(NCS) ν(M–O)
ν(C=N)
ν(CS)
1362
3397
[Pd(bpy)(dahmp)]Cl — 3165 1640 1556 1450 1255 524 409
3360
1176
1396
412
[Ag(bpy)(Hdahmp)]NO3 3308 3396 3171 1650 1543 1479 1277 —
372∗
1207
∗
ν(Ag–S).

NH2 +
NH2
3 4 OH
3 4
N OH
5 N N
5
2 NO3 −
Ag 2
S N 6 NH2
1 S N 6
NH2
N 1
1
H H

Scheme 1: 4,6-diamino-5-hydroxy-2-mercaptopyrimidine (Hdah-

mp). Scheme 3: Structure of [Ag(bpy)(Hdahmp)2 ]NO3 .

NH2 +
The spectrum of [Ag(bpy)(Hdahmp)]NO3 shows new
3 4 N
strong band near 1370 cm−1 assigned to the ionic uncoor-
O
N
5
dinated NO−3 [16, 26, 27].
Pd Cl−
2
S N 6 N 3.3. Electronic spectra
1 N
H2
H The electronic spectrum of [Pd(bpy)(dahmp)]+ complex
shows bands at 475 and 326 nm due to 1 A1g → 1 B1g and
1g → E1g , transitions in a square-planar configuration
1A 1
Scheme 2: Structure of [Pd(bpy)(dahmp)]Cl.
[4, 23, 27]. Also, the spectrum of [Ag(bpy)(Hdahmp)]+
shows bands at 467, 382, and 277 nm; the latter two may arise
from charge transfer of the type ligand (π) → b1g (Ag+ ) and
acts as a mononegative bidentate ligand, coordinating the ligand (σ) → b1g (Ag+ ), respectively, in a typically distorted
metal ion through the deprotonated hydroxyl and amino square planar environment around the metal ion [4, 28, 29].
N(6)H2 groups, without any participation of the thione sul-
fur or cyclic nitrogen atoms in coordination [23]. This fea- 3.4. 1 H NMR spectra
ture is further supported by the observation that a band
near 1178 cm−1 arises from ν(C=S) stretch that remains The 1 H NMR spectrum of Hdahmp in d6 -DMSO shows
unchanged [18] (Scheme 2). The vibrational spectrum of two singlets at δ6.07 and 6.18 ppm arising from N(4)H2 and
[Ag(bpy)(Hdahmp)]NO3 suggests the participation of the N(6)H2 , respectively (Scheme 1). The proton of the hydroxyl
thione sulphur and the cyclic N(3) in coordination due to the group O(5)H appears as a broad singlet at δ9.13 ppm and the
shift observed in the ν(C=S) and ν(N–C=S) stretching vibra- N(1)H proton gives a singlet at δ7.43 ppm. In the 1 H NMR
tions (Scheme 3). This suggestion is supported by the slight spectrum of [Pd(bpy)(dahmp)]+ , the proton of the hydroxyl
shift of ν(NH) and δ(NH) to lower wave number with the group is not observed while the resonance arising from
existence of νs (NH2 ), νas (NH2 ), and ν(OH) stretches more N(6)H2 is shifted to lower field [24, 30]. Also, the resonances
or less in the same position as in the free ligand [18, 22, 24]. arising from N(4)H2 and N(1)H are slightly shifted to lower
Also, the bands of the free bpy ligand near 740 cm−1 are field. This is probably due to the decrease in the electron
shifted to higher frequencies in the complexes (773 cm−1 ) density caused by the withdrawing of electrons by the metal
[4, 25]. ions from the pyrimidine ring coordination centers [13, 23].
4 Metal-Based Drugs

Table 2: 1 H NMR spectral data of Hdahmp and its complexes.

Compounds N(1)H N(4)H2 O(5)H N(6)H

Hdahmp 7.43 6.07 9.13 6.18
[Pd(bpy)(dahmp)]+ —∗ 6.08 — 6.46
[Ag(bpy)(Hdahmp)]+ —∗ 6.16 9.20 6.24
∗
Signal interefered with Ph or bpy protons.

The 1 H NMR spectrum of [Ag(bpy)(Hdahm)]+ confirms the 140

neutral bidentate behavior of Hdahmp through the thione
sulfur and the cyclic N(3) center, as there is a slight shift 120
from the free ligand spectrum (Table 2). Also, the bpy lig-
and, in the complexes, shows upfield shifts as compared with
[Pd(bpy)Cl2 ] or [Ag(bpy)(H2 O)2 ]+ . This is interpreted in 100
terms of strong binding of dahmp− to Pd(II) or Ag(I) in

Λm (Ω−1 cm 2 )
comparison to binding of chloride and aquo species, respec- 80
tively [4–6].
60
3.5. Mass spectra

The mass spectrum of [Pd(bpy)(dahmp)]Cl·H2 O shows a 40

signal at m/e 474 (Cacld. 472.9) with 2.60% abundance. The
spectrum shows signals at 355, 215, and 129 corresponding 20
the loss of (H2 O, C2 H3 N3 S), (Cl, Pd) [4], and (N2 , C2 H2 NO)
fragments, respectively.
0
0 0.2 0.4 0.6 0.8 1 1.2
3.6. Thermal measurements Concentration (M) ×10−3

The thermal decomposition of [Pd(bpy)(dahmp)]Cl·H2 O Ag(I)

and [Ag(bpy)(Hdahmp)]NO3 was studied by using the Pd(II)
thermogravimetry (TG) technique. The thermogram of
[Pd(bpy)(dahmp)]Cl·H2 O shows four TG inflections in the Figure 1: Conductance-concentration relationship of the com-
ranges 32–148, 150–360, 361–475, and 476–593◦ C. The first plexes.
weight loss may arise from the elimination of crystal lat-
tice water (Calcd. 3.81, Found 3.73%) [4]. The second step
may arise from the release of half Cl2 and C3 H5 N3 frag-
the complexes species [31]. Since the conductivity for Cl−
ments (Calcd. 25.06, Found 24.48%), the third step is due
and NO−3 is 76 and 71 ohm cm2 , respectively [31, 32], this
to the removal of CNS and half bpy (C5 H4 N) fragments
suggests that the complexes ionized completely in aqueous
(Calcd. 28.76, Found 29.22%) [27], while the fourth step
media [33].
is attributed to the removal of the other half of bpy species
(Calcd. 16.49, Found 16.55%) followed by the formation of
PdO at 665◦ C (Calcd. 25.88, Found 26.36%) [4, 27]. The 3.8. Anticancerous activity
thermogram of [Ag(bpy)(Hdahmp)]NO3 shows the first-
step weight loss of 9.29% between 198 and 252◦ C, which cor- The reliable criteria for judging the efficacy of any anticancer
responds to the release of NO2 species (Calcd. 9.51%). The drug are prolongation of life span, improving the clinical,
second decomposition step occurs between 253 and 352◦ C, hematological, and biochemical profile, as well as reduction
this weight loss is attributed the loss of C3 H6 N3 fragment in viable tumor cell count in the host [34, 35]. We have re-
(Calcd. 17.36, Found 17.89%). The third TG inflection be- ported that [PdL(pa)]+ , [PdL’(pa)Cl], and [Pd(bpy)(cdhp)]
tween 432–520◦ C, may arise from the elimination of bpy, CS, (L = 2, 2 -bipyridyl; L = 9,10-phenanthroline, 2-(2 -
three quarter species (Calcd. 49.18, Found 51.09 %), leaving pyridyl)quinoxaline); pa = anion of 2-pepiridine carboxylic
Ag2 O representing (Found 23.00%) [5, 27]. acid; cdhp = dianion of 5-chloro-2,3-dihydroxypyridine) in
water or DMSO exhibit potent cytotoxic activity against
3.7. Conductivity measurements Ehrlich ascites tumor cells [4, 5]. It is known that the an-
ticancer available drugs inhibit the hematological and bio-
Figure 1 shows the plots of the conductivities of [Pd(bpy)- chemical parameters (hemoglobin (Hb), red blood cells
(dahmp)]Cl and [Ag(bpy)(Hdahmp)]NO3 against concen- count (RBCs), and white blood cells count (WBCs); blood
trations. It is clear that as the concentration increases, the picture). The ultimate goal of this project is to develop mixed
conductivity increases, indicating the complete ionization of ligand complexes containing nitrogen bases effective against
S. I. Mostafa and F. A. Badria 5

Table 3: Haematological and biochemical parameters of Hdahmp and its complexes.

Parameters
RBCs(2)
Hb(1) (12– HCT(3) WBCs(4) (4000– EAC Count
Compound (4.0–6.0 × MSt/day(5)
16 g/dl) (35.0–50.0%) 11000 × 106 cell/cm3 ) (×106 cell/cm3 )
106 cell/cm3 )
Hdahmp 10.7 6.3 40.3 8800 44.8 13.2
[Pd(bpy)(dahmp)]Cl 11.4 6.4 40.3 12000 31.8 11.4
[Ag(bpy)(Hdahmp)]NO3 11.0 6.3 41 9000 30.4 11.2
5-fu 10.2 6.0 37.7 7600 80 13.6
Control (0.9% NaCl) 7.8 4.72 22.2 2400 220 9.0
(1)
Hb = hemoglobin, (2) RBCs = red blood cells count, (3) HCT = hemato crate value, (4) WBCs = white blood cells count values in normal mice are in paren-
theses, (5) the mean survival time.

cancer without side effects on the hematological and bio- mal unbound DNA. The results are prevention of DNA syn-
chemical parameters. thesis, inhibition of transcription, and induction of muta-
In order to detect the influence of Hdahmp, [Pd(bpy)- tions [5, 39].
(dahmp)]Cl, and [Ag(bpy)(Hdahmp)]NO3 on the hema- Regarding the tumor size and EAC count, in the control
tological status of EAC-bearing mice, a comparison study group was (220 × 106 cells/cm3 ), reduced in using 5-fu to
was made among three groups of mice (each group con- (80 × 106 cells/cm3 ) while the strong reduction to 44.8 × 106 ,
tains seven mice) from the second day after inoculation. 31.8 × 106 , and 30.4 × 106 cells per cm3 was observed in using
Group (1) tumor-bearing mice treated with 5-fu (stan- Hdahmp, [Pd(bpy)(dahmp)]+ , and [Ag(bpy)(Hdahmp)]+ ,
dard [36, 37]). Group (2) tumor-bearing mice treated with respectively. The strong reduction in EAC count and tumor
Hdahmp, [Pd(bpy)(dahmp)]Cl, [Ag(bpy)(Hdahmp)]NO3 . size may be due to the reductive nature of many tumors that
Group (3) is the control tumor-bearing mice. The an- contain significant regions at low oxygen tension. Thus, they
ticancer activity of Hdahmp, [Pd(bpy)(dahmp)]Cl, and initiate a catalytic auto-oxidation process involving genera-
[Ag(bpy)(Hdahmp)]NO3 shows remarkable efficacy man- tion of reactive oxygen species. The coordinated dahmp and
ifested by survival and activity, as well as reduction in bpy may reduce toxic effects caused by xenobiotic core of the
the tumor size. The hematological parameters including complexes, contribute to their anticancer action, and facili-
hemoglobin (Hb), red blood cells count (RBCs), and white tate their transport through cell membrane [40]. Our investi-
blood cells count (WBCs) data are reported in Table 3. gations have shown that glutathione content, in liver and kid-
It is clear that the hematological parameters of tumor- ney, and glutathione-S-transferase activity were decreased,
bearing mice treated with Hdahmp, [Pd(bpy)(dahmp)]Cl, suggesting that the partial reduction products of oxygen, in
and [Ag(bpy)(Hdahmp)]NO3 exhibits much better signifi- the presence of the complexes, yield very reactive species,
cant figures with the use of small doses of (0.01 mg/mice/day) which could start catalytic oxidation of substrates and show
compared with the standard (5-fu), the market drug antitumor action [41].
(∼0.4 mg/mice/day). In order to detect the influence of the solvent in the cy-
There are reports that complexes containing pyridine totoxicity of Hdahmp, [Pd(bpy)(dahmp)]+ , and [Ag(bpy)-
ring (cyclic nitrogen) display significant anticancer activity (Hdahmp)]+ . As expected, the water-soluble [Pd(bpy)-
[4, 38]. Thus, the presence of the pyrimidine ring increases (dahmp)]+ and [Ag(bpy)(Hdahmp)]+ are less kidney toxic.
the anticancer activity and activates the binding of metal ion
to the tumor DNA as it contains two cyclic nitrogen atoms 3.9. Effect of survival time
[5].
The hematological parameters show that [Pd(bpy)- The mean survival time (MST) of groups 1 and 2 was
(dahmp)]Cl and [Ag(bpy)(Hdahmp)]NO3 are more effec- compared with that of the control group using the fol-
tive than Hdahmp itself, as the presence of both bpy and lowing calculations [42]. Percentage (%) increase in lifes-
dahmp in the complexes possess a multiring planar area pan over control = [(MST of treated group × 100/MST
with nitrogen bases and hence higher hydrophobicity, which of control group) −100]; MST = days of each mice
would lead the intercalation more deeply into the tumor in the group/total number of mice. Percentage (%) in-
DNA [5]. crease in lifespan over control showed to be high in
In order to investigate the action of Pd(II) and Ag(I) mice treated with Hdahmp, [Pd(bpy)(dahmp)]Cl, and
complexes in the tumor DNA, the intercalated complexes [Ag(bpy)(Hdahmp)]NO3 (Table 3).
affecting the structure of the DNA prevent polymerase and
other DNA binding proteins from functioning properly. As 3.10. The side effects and toxicity
the complexes covantely bind to DNA with preferential bind-
ing to the N-7 position of guanine and adenine, they are able The side effects and toxicity of Hdahmp, [Pd(bpy)-
to bind two different sites on DNA, producing cross-links (dahmp)]+ , and [Ag(bpy)(Hdahmp)]+ have been detected.
that cause increase in the viscosity in comparison to the nor- After the first week of the treatment, the mice show flu-like
6 Metal-Based Drugs

attack and in the third week show spot dropping on the hair [11] S. D’Ancona, G. Magnolfi, G. Guidetti, et al., “Effects of
(alopecia). Fortunately, the solid organs have not been af- 6,6 -dithiodinicotinic acid (CPDS) and its metabolite 6-
fected. mercaptonicotinic acid (6-MNA) on murine and hamster fi-
The study of detailed mechanism and in vivo anticancer broblasts (3T3 and BHK) and murine metastatic melanoma
screens (phase II & III) using the studied complexes are un- cells (F10),” Chemioterapia, vol. 5, no. 4, pp. 219–227, 1986.
der way. [12] S. I. Mostafa and N. Hadjiliadis, “New biologically active
transition metal complexes of 2-mercapto-4,6-diamino-5-
hydroxypyrimidine,” Inorganic Chemistry: An Indian Journal,
4. CONCLUSION vol. 2, no. 3, pp. 186–192, 2007.
[13] W. P. Griffith and S. I. Mostafa, “Complexes of esculetin with
There are reports that complexes containing pyridine ring second and third row transition elements,” Polyhedron, vol. 11,
(cyclic nitrogen) display significant anticancer activity. The no. 8, pp. 871–877, 1992.
anticancer activity of the new water-soluble complexes, [14] K. R. Sheeji, G. Kuttan, and R. Kuttan, Amala Research Bul-
[Pd(bpy)(dahmp)]Cl and [Ag(bpy)(Hdahmp)]NO3 , shows letin, vol. 17, pp. 73–76, 1997.
remarkable efficacy against Ehrlich ascites tumor cells (EACs) [15] W. J. Geary, Coordination Chemistry Reviews, vol. 7, no. 81,
manifested by survival and activity, as well as reduction in the 1981.
tumor size. [16] A. Abdullah, F. Huq, A. Chowdhury, H. Tayyem, P. Beale, and
K. Fisher, “Studies on the synthesis, characterization, binding
ACKNOWLEDGMENT with DNA and activities of two cis-planaramineplatinum(II)
complexes of the formml: cis-PtL(NH3 )Cl2 where L = 3-
We wish to thank Professor W. P. Griffith (Imperial College hydroxypyridine and 2,3-diaminopyridine,” BMC Chemical
London, UK) for English corrections of the manuscript. Biology, vol. 6, article 3, pp. 1472–1484, 2006.
[17] Z. Popovic, D. M. Calogovic, J. Hasic, and D. V. Topic,
“Preparation and spectroscopic properties of the complexes of
REFERENCES
mercuric thiocyanate with pyridine-2-thione and pyridine-2-
[1] M. P. Hacker, E. B. Douple, and I. H. Krakoff, Platinium Co- carboxylic acid. Crystal and molecular structure of two poly-
ordination Complexes in Cancer Chemotherapy, Martinus Ni- morphs of Hg(SCN)2 (C5 H5 NS)2 ,” Inorganica Chimica Acta,
jhoff, Dordrecht, The Netherlands, 1984. vol. 285, no. 2, pp. 208–216, 1999.
[2] M. Coluccia, A. Nassi, F. Loseto, et al., “A trans-platinum [18] M. D. Gutierrez, R. Lopez, M. A. Romero, and J. M. Salas,
complex showing higher antitumor activity than the cis con- “Spectroscopic studies of some Pd(II), Pt(II), Ag(I), and
geners,” Journal of Medicinal Chemistry, vol. 36, no. 4, pp. 510– Au(III) complexes of 4,6-diamino-2-thiopyrimidine and 4,6-
512, 1993. diamino-2-methylthiopyrimidine. Structure and binding site
[3] F. P. T. Harmers, W. H. Gispen, and J. P. Neijt, “Neurotoxic determination,” Canadian Journal Chemistry, vol. 66, no. 2,
side-effects of cisplatin,” European Journal of Cancer, vol. 27, pp. 249–255, 1988.
pp. 372–376, 1991. [19] E. L. Torres and M. A. Mendiola, “Complexes of a triazine-
[4] S. I. Mostafa, “Mixed ligand complexes with 2-piperidine- 3-thione ligand with divalent metals crystal structure of
carboxylic acid as primary ligand and ethylene diamine, 2,2 - [CdL2 DMF2 ]2 2DMF 1/4H2 O,” Polyhedron, vol. 24, no. 12,
bipyridyl, 1,10-phenanthroline and 2(2 -pyridyl)quinoxaline pp. 1435–1444, 2005.
as secondary ligands: preparation, characterization and bio- [20] G. Glolub, H. Cohen, P. Paoletti, A. Bencini, and D.
logical activity,” Transition Metal Chemistry, vol. 32, no. 6, pp. Meyerstein, “Copper-(I) and -(II) complexes with tertiary
769–775, 2007. linear polyamines of the type Me2 NCH2 (CH2 NMeCH2 )n -
[5] S. I. Mostafa, “Synthesis, characterization and antineoplas- CH2 NMe2 (n = 1 − 4),” Journal of the Chemical Society, Dal-
tic activity of 5-chloro-2,3-dihydroxypyridine transition metal ton Transactions, no. 10, pp. 2055–2060, 1996.
complexes,” Journal of Coordination Chemistry, in press. [21] S. I. Mostafa and S. A. Abd El-Maksoud, “Synthesis and char-
[6] V. X. Jin and J. D. Ranford, “Complexes of platinum(II) or pal- acterization of some transition metal complexes of 2-amino-3-
ladium(II) with 1,10-phenanthroline and amino acids,” Inor- hydroxypyridine and its application in corrosion inhibition,”
ganica Chimica Acta, vol. 304, no. 1, pp. 38–44, 2000. Monatshefte für Chemie, vol. 129, no. 5, pp. 455–466, 1998.
[7] G. Cavigiolio, L. Benedetto, E. Boccaleri, D. Colangelo, H. [22] M. Guta and M. N. Srivastava, “Synthesis and characterization
Viano, and D. Osella, “Pt(II) complexes with different N- of complexes of copper(II), nickel(II), cobalt(II) and zinc(II)
donor aromatic ligands for specific inhibition of telomerase,” with alanine and uracil or 2-thiouracil,” Synthesis and Reac-
Inorganica Chimica Acta, vol. 305, no. 1, pp. 61–68, 2000. tivity in Inorganic, Metal-Organic, and Nano-Metal Chemistry,
[8] S. K. Hadjikakou, M. A. Demertzis, M. Kubicki, and D. Kovala- vol. 26, no. 2, pp. 305–320, 1996.
Demertzis, “Organotin adducts with pyrimidinethione: crys- [23] S. I. Mostafa, M. A. Kabil, E. M. Saad, and A. A. El-Asmy,
tal structure of dimethyldi(pyrimidine-2-thiolato)tin(IV) and “Ligational and analytical applications of a uracil derivative
diphenyldi(pyrimidine-2-thiolato)tin(IV),” Applied Organo- toward some transition metal ions,” Journal of Coordination
metallic Chemistry, vol. 14, no. 11, pp. 727–734, 2000. Chemistry, vol. 59, no. 3, pp. 279–293, 2006.
[9] V. N. Krishnamurthy, K. V. Naglowara Rao, P. L. Narasimha [24] C.-L. Ma, Y. Shi, Q.-F. Zhang, and Q. Jiang, “Synthe-
Rao, and B. Praphulla, “Some potential antiviral agents,” ses, characterization and crystal structures of diorganotin
British Journal of Pharmacology and Chemotherapy, vol. 31, compounds with 2-mercaptopyrimidine and 4-amino-2-
no. 1, pp. 1–10, 1967. mercaptopyrimidine,” Polyhedron, vol. 24, no. 10, pp. 1109–
[10] M. D. Couce, G. Faraglia, U. Russo, et al., “2-mercaptopyridine 1116, 2005.
derivatives as neutral or ionic donors towards tin tetrahalides,” [25] R. Castro, J. A. G. Vazquez, J. Romero, A. Sousa, R. Pritchard,
New Journal of Chemistry, vol. 21, no. 10, pp. 1103–1111, 1997. and C. A. McAuliffe, “4,6-dimethylpyrimidine-2-thionato
 S. I. Mostafa and F. A. Badria 7

(dmpymt− ) complexes of nickel(II) and cadmium(II). Crystal [40] S. Osinsky, Ukr Patent, Appl., no. 981 27 052, December 1998.
structure of [Cd(dmpymt)2 ]: a compound with a calixarene- [41] S. Osinsky, I. Levitin, L. Bubnovskaya, et al., in Proceedings
like structure,” Journal of the Chemical Society, Dalton Transac- of the 6th Internet World Congress for Biomedical Sciences (IN-
tions, no. 7, pp. 1115–1120, 1994. ABIS ’00), pp. 1–6, Ciudad Real, Spain, February 2000.
[26] M. A. Haj, M. Quiros, J. M. Salas, and R. Faure, “Silver com- [42] P. Sur and D. K. Ganguly, “Tea plant root extract (TRE) as
plexes with triazolopyrimidine ligands containing an exocyclic an antineoplastic agent,” Planta Medica, vol. 60, pp. 106–109,
oxygen atomml: X-ray evidence for an unusual tautomeric 1994.
form,” Journal of the Chemical Society, Dalton Transactions,
no. 11, pp. 1798–1801, 2001.
[27] S. I. Mostafa and M. M. Bekheit, “Synthesis and struc-
ture studies of complexes of some second row transition
metals with 1-(phenylacetyl and phenoxyacetyl)-4-phenyl-
3- thiosemicarbazide,” Chemical and Pharmaceutical Bulletin,
vol. 48, no. 2, pp. 266–271, 2000.
[28] F. Sabin, C. K. Ryu, P. Fork, and A. Vogler, “Photophysical
properties of hexanuclear copper(I) and silver(I) clusters,” In-
organic Chemistry, vol. 31, no. 10, pp. 1941–1946, 1992.
[29] M. A. Omary, T. R. Webb, Z. Assefa, G. E. Shankle, and
H. H. Patterson, “Crystal structure, electronic structure, and
temperature-dependent Raman spectra of Tl[Ag(CN)2 ]: evi-
dence for ligand-unsupported argentophilic interactions,” In-
organic Chemistry, vol. 37, no. 6, pp. 1380–1386, 1998.
[30] M. Calvo, A. M. Lanfredi, L. Oro, et al., “Synthesis and
properties of rhodium(I) chloranilate and 2,5-dihydroxy-1,4-
benzoquinonate complexes. Crystal structures of the binuclear
[Rh2 (μ-CA) (cod)2 ] and tetranuclear [Rh4 (μ-CA)2 (cod)4 ]
complexes (CA = cbloranilate anion),” Inorganic Chemistry,
vol. 32, no. 7, pp. 1147–1152, 1993.
[31] W. P. Griffith and S. I. Mostafa, “Complexes of 3-
hydroxypyridin-2-one and 1,2-dimethyl-3-hydroxypyridin-4-
one with second and third row elements of groups 6, 7 and 8,”
Polyhedron, vol. 11, no. 23, pp. 2997–3005, 1992.
[32] D. Aguado, T. Montoya, J. Ferrer, and A. Seco, “Relating
ions concentration variations to conductivity variations in a
sequencing batch reactor operated for enhanced biological
phosphorus removal,” Environmental Modelling & Software,
vol. 21, no. 6, pp. 845–851, 2006.
[33] G. W. Castellan, Physical Chemistry, edited by L. Rogers, The
Benjamin, Menlo Park, Calif, USA, 1983.
[34] B. D. Clarkson and J. H. Burchenal, “Preliminary screening of
antineoplastic drugs,” Progress in Clinical Cancer, vol. 1, pp.
625–629, 1965.
[35] C. Oberling and M. Guerin, “The role of viruses in the produc-
tion of cancer,” Advances in Cancer Research, vol. 2, pp. 353–
423, 1954.
[36] B. Ardalan, M. D. Buscagila, and P. S. Schein, “Tumor 5-
fluorodeoxyuridylate concentration as a determinant of 5-
fluorouracil response,” Biochemical Pharmacology, vol. 27,
no. 16, pp. 2009–2013, 1978.
[37] K. Yoshisue, Z. Hironaga, S. Yamaguchi, A. Yamamoto, S. Na-
gayama, and Y. Kawaguchi, “Reduction of 5-fluorouracil (5-
FU) gastrointestinal (GI) toxicity resulting from the protec-
tion of thymidylate synthase (TS) in GI tissue by repeated
simultaneous administration of potassium oxonate (Oxo) in
rats,” Cancer Chemotherapy and Pharmacology, vol. 46, no. 1,
pp. 51–56, 2000.
[38] A. Romerosa, P. Bergamini, V. Bertolasi, et al., “Biologically ac-
tive platinum complexes containing 8-thiotheophylline and 8-
(methylthio)theophylline,” Inorganic Chemistry, vol. 43, no. 3,
pp. 905–913, 2004.
[39] D. Lebwohl and R. Canerra, “Clinical development of plat-
inum complexes in cancer therapy: an historical perspective
and an update,” European Journal of Cancer, vol. 34, no. 10,
pp. 1522–1534, 1998.

View publication stats