University of Kragujevac, Faculty of Science, Department of Chemistry
Serbia
Introduction
Transition metals and their reactions are in general important in the environment, in
technical processes (catalysis, extraction and purification of metal complexes) and in biology
and medicine (biological electron transfer, toxicology and use of metal complexes as drugs).
Moreover, nonessential metal ions are very often used in biological systems either for
therapeutic application or as diagnostic aids. For instance, metal complexes have been used
for the treatment of many diseases (cancer, arthritis, diabetes, Alzheimer, etc.), but with little
understanding of their mechanism of action in biological systems.(Ronconi & Sadler, 2007;
Bruijnincx & Sadler, 2009) Biochemical studies have not clearly established the molecular
basis for the activity and mechanism of action. The growing field of bioinorganic chemistry
is presently dealing with the clarification of the mechanisms of action of metal complexes in
biological systems.(Ronconi & Sadler,2007; Bruijnincx & Sadler, 2009; Jakupec et al., 2008)
Research in the area of application of metal complex compounds in medicine began with the
discovery of antitumor properties of cisplatin. (Rosenberg, 1965, 1967, 1969, 1970) Today
cisplatin is in routine use as therapeutics worldwide. Following the success of cisplatin a
large number of analogous compounds were synthesized. All these compounds have a
several common characteristics:
1. bifunctional complex compounds with cis-geometry
2. PtX2(amin)2 is general formula of this compounds, where X2 are two labile monodentate
or one labile bidentate ligand, and (amine)2 are inert nitrogen-donor ligands
3. nitrogen-donor ligands have to containe at least one NH bond.
Despite the large number of synthesized compounds only a few of them entered the
medicinal use and most are still in preclinical investigation. (Jakupec et al., 2003; Reedijk,
2009) At the Fig. 1. are presented some of platinum complexes that are in the medicinal use
worldwide.
Chronic lymphocytic leukemia is the most frequent type of leukemia and it accounts for
approximately 25% of all leukemias. (Chiorazzi et al., 2005) Although at the present there is
no curative treatment, combinations of cytotoxic agents and of immunotherapies that
generate high complete remission rates hold promise for altering the natural history of this
340 Chronic Lymphocytic Leukemia
disease. (Wierda et al., 2005) Fludarabine (9-beta-D-arabinofuranosyl-2-fluoroadenine 5’-
phosphate) is the most effective purine nucleoside analogue for the treatment of indolent
lymphoproliferative disorders, including Chronic lymphocytic leukemia, low-grade
lymphoma, and prolymphocytic leukemia. (Eichhorst et al., 2005)
The studies show that among the best drugs in the treatment of Chronic lymphocytic
leukemia are the combination of Pt(II) complexes (cisplatin and oxaliplatin) and alkylating
agents and nucleoside analogues such as fluradabine. (Zecevic et al., 2011) The
nonoverlapping side effect profiles of oxaliplatin and fludarabine and their different but
potentially complementary mechanisms of action provide a basis for investigation of the
activity of the drugs in combination. The rationale for combining oxaliplatin with
fludarabine is based on preclinical data showing synergistic cytotoxicity between cisplatin
in combination with the nucleoside. (Wang et al., 1991; Yamauchi et al., 2001)
Consequently, knowledge of the interaction of the different Pt(II) complexes and nitrogenand
sulfur-bonding bio-molecules, and the results obtained from in vitro studies of this type
of interactions will help in finding of good antitumor drug for the treatment of many tumors
including the Chronic lymphocytic leukemia. The main topic of this chapter will be to show
the results obtained in numerous studies of the interactions of the potential antitumor Pt(II)
complexes and different biomolecules.
Platinum(II) has a high affinity for sulphur, so after administrating Pt(II) complex in the
human body there is a strong possibility for binding with sulphur-donor bio-molecules.
Sulphur-donor bio-molecules are present in large amounts in the form of peptides, proteins
and enzymes. Binding of platinum complexes with sulphur-donor bio-molecules are
responsible for the occurrence of toxic effects. (Lippert, 1999; Reedijk, 1999) However, a
certain amount of platinum complexes being bound to nitrogen-donor bio-molecules (amino
acids or DNA). Today it is generally accepted that the anti-tumor activity of platinum drugs
can be ascribed to interactions between the metal complex and DNA, primarily with the
genetic DNA, which is located in the nucleus. The interactions with mitochondrial DNA are
less responsible for the antitumor activity of the platinum complexes. (Fuertes et al., 2003)
When the Pt(II) complexe reach the DNA, the possibilities for coordination are different.
Binding of Pt(II) complexes to DNA primarily occurs through the N7 atoms of guanine,
while a binding to N7 and N1 of adenine and N3 of cytosine occurs in small amount.
(Lippert, 1999; Reedijk, 1999) Since the DNA molecule containing a different sequence of
purine and pyrimidine bases, it was found that with 60% represented the coordination of
the type 1,2-(GPG), i.e., the coordination realizes via two molecules of guanosine-5’-
monophosphate (5’-GMP), which are located on opposite strands of DNA. About 25% is
represented by coordination of the type 1,2-(APG), i.e. coordination with adenosine-5'-
monophosphate (5’-AMP) and 5’-GMP placed on opposite DNA strands. Other ways of
coordinations (monofunctional binding of the type 1,3-(GPG), coordination via guanosine
located on the same chain of DNA, etc.) are less frequent. On the Fig. 2. is shown the
different ways of coordination of cisplatin to DNA. (Jakupec et al., 2003; Kozelka et al., 1999)
However, as noted above, the cells contain other bio-molecules which can also react with
platinum complexes. High affinities for the platinum complexes show the bio-molecules that
contain sulphur, as the thiols and the thioethars. Namely, Pt(II) as "soft" acid forms very stable
compounds with sulphur donor ("soft" bases). The resulting compounds are responsible for
the occurrence of toxicity (nephrotoxicity, neurotoxicity, resistance, etc.). Since the
concentration of thiols, including glutathione (GSH) and L-cysteine, in intracellular liquid is
about 10 mM, it is assumed that most of the platinum complex bound to sulphur before it
comes to the molecules of DNA. (Jakupec et al., 2003; Reedijk, 2009; Lippert, 1999; Reedijk,
1999) Binding of platinum complexes to sulphur from thioethars are the kinetically favored
process. The resulting Pt-S(thioethar) bond may be terminated in the presence of DNA, i.e. N7
atom of 5’-GMP can substitute the molecule of thioethar. (Reedijk, 1999; Soldatović & Bugarčić,
2005) For these reasons the compounds of the type Pt-S(thioethers) are believe to be the
reservoirs of “platinum complexes’’ in the body, i.e. they are suitable intermediates in the
reaction of Pt(II) complexes and DNA. Pt-S(thioethers) bond can be terminated in the presence
of thiol molecules. The product of this substitution is thermodynamically stable. Also, Pt(II)
complex can direct bind to sulphur from thiol molecules and the resulting Pt-S(thiol) bond is
very stable and can not be easy broken. It is believed that compounds of the type Pt-S(thiol)
are responsible for the occurrence of toxic effects during the use of Pt(II) complexes as
anticancer reagents. The Pt-S(thiol) bond can be terminated in the presents of compounds
known as "rescue agents″, which are compounds with sulphur and they are very strong
nucleophiles (diethyldithiocarbamate, thiourea, thiosulfate, GSH, cysteine, biotin, etc.).
(Jakupec et al., 2003; Fuertes et al., 2003; Soldatović & Bugarčić, 2005)
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