JAB-56; No. of Pages 25
journal of applied biomedicine xxx (2015) xxx–xxx
Available online at www.sciencedirect.com
ScienceDirect
journal homepage: http://www.elsevier.com/locate/jab
Review Article
Coordination compounds in cancer: Past, present
and perspectives
Federica Trudu a,b,1,2, Filippo Amato a,1, Petr Vaňhara c,
Tiziana Pivetta b, E.M. Peña-Méndez d, Josef Havel a,*
a
Department of Chemistry, Faculty of Science, Masaryk University, Brno, Czech Republic
b
Department of Chemical and Geological Sciences, University of Cagliari, Monserrato (CA), Italy
c
Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
d
Department of Chemistry, Faculty of Science, University of La Laguna, La Laguna, Tenerife, Spain
article info abstract
Article history: Metal-based coordination compounds have been used throughout the history of human
Received 24 October 2014 medicine to treat various diseases, including cancer. Since the discovery of cisplatin in 1965,
Received in revised form a great number of metal coordination complexes, such as platinum, ruthenium, gold or
4 March 2015 copper have been designed, synthesized and tested in order to develop clinically effective
Accepted 9 March 2015 and safe drugs. Currently, many reviews cover applications of cytostatic metal complexes
Available online xxx pointing out the most promising examples of platinum- and non-platinum-based com-
pounds in preclinical and clinical trials. However, recent comprehensive reviews covering
Keywords: chemical and biological aspects of metal-based coordination compounds in cancer therapy
Cancer are still rare. In this review we wish to provide an overview of the coordination chemistry of
Coordination metal complexes current and novel cytostatic compounds, including an outline of their design and rationale
Cisplatin of synthesis, and summarize bio-chemical reactivity and physicochemical properties of
Omics candidate metal complexes.
Perspectives # 2015 Faculty of Health and Social Studies, University of South Bohemia in Ceske
Budejovice. Published by Elsevier Sp. z o.o. All rights reserved.
antiproliferative effect of various classes of compounds,
Introduction
ranging from naturally occurring molecules and their deriva-
tives, to organometallic and inorganic compounds and their
Cancer is nowadays one of the leading causes of death in the application in cancer therapy. The fortuitous discovery of the
developed world. Biologically, cancer represents a vastly cytotoxic properties of cisplatin (diamminedichloroplatinum
heterogenic group of diseases sharing several common traits. (II)) in 1965, opened new avenue for the application of metal
One of these hallmarks is sustained proliferation, resulting in complexes in cancer therapy (Arnesano et al., 2011) (Fig. 1).
uncontrolled tumour growth (Hanahan and Weinberg, 2011). The antiproliferative effect of cisplatin and other compounds,
An extensive research has been done to characterize however, induces adverse effects on normal tissues,
* Corresponding author at: Department of Chemistry, Faculty of Science, Masaryk University, Kamenice 5/A14, 625 00 Brno, Czech Republic.
Tel.: +420 54949 4114; fax: +420 54949 2494.
E-mail address: (J. Havel).
1
These authors contributed equally to this paper.
2
On leave from affiliation 'b'.
1214-021X/$ – see front matter # 2015 Faculty of Health and Social Studies, University of South Bohemia in Ceske Budejovice. Published
by Elsevier Sp. z o.o. All rights reserved.
http://dx.doi.org/10.1016/j.jab.2015.03.003
Please cite this article in press as: Trudu, F., et al., Coordination compounds in cancer: Past, present and perspectives. J. Appl. Biomed.
(2015), http://dx.doi.org/10.1016/j.jab.2015.03.003
,JAB-56; No. of Pages 25
2 journal of applied biomedicine xxx (2015) xxx–xxx
Fig. 1 – Historical overview of the cytotoxic metal and metalloid complexes that have been approved or entered the clinical
practice.
decreasing therapeutic effectivity. Moreover, in many cancers, Cisplatin has been a first-line therapy in many cancers and
tumour cells may acquire resistance to the metal-based nowadays is used either alone or in combination with other
cytotoxic therapy resulting in virtually incurable relapsing compounds in many cancers, e.g. testicular, ovarian or bladder
disease (Desoize, 2004). cancers or leukaemias. Due to low chemical stability of
In the last 15 years, a great effort has been dedicated to the cisplatin, the direct intravenous administration is preferred
development of more effective and less toxic drugs. Various new over the other forms. In the blood stream, cisplatin rapidly
trans-platinum(II) and platinum(IV) complexes have been interacts with plasma proteins such as human serum albumin
synthesized, and some of them have been selected for clinical (HSA), haemoglobin (Hb) or transferrin (Tf) (Rudnev et al., 2005)
trials (Kelland et al., 1999), but with varying effectivity and and 24 h after administration, 95% of cisplatin is bound to
safety. Therefore, less toxic metals, such as ruthenium, gold or plasma proteins (Sooriyaarachchi et al., 2011). Cisplatin is
copper were introduced as promising candidates for effective widely distributed into body fluids and tissues, reaching
and safe therapy (Tiekink, 2002; Clarke, 2002; Marzano et al., the highest concentrations in kidneys (0.4–2.9 mg/g), liver
2009; Nobili et al., 2010). Various reviews have been published on (0.5–3.7 mg/g wet weight), and prostate (1.6–3.6 mg/g). Minor
the use of metal complexes as anticancer agents, with the intent concentration levels can be found in muscles, bladder, testes,
to give an overview of the proposed approaches concerning the pancreas, and spleen (Stewart et al., 1982). Penetrance of
application of these systems in clinical practice (Tiekink, 2002; cisplatin into tumour tissue differs in different cancers.
Boulikas et al., 2007; Milacic et al., 2008; Bruijnincx and Sadler, However, the concentration of cisplatin and its analogues
2008; Todd and Lippard, 2009; Vilmar and Sørensen, 2009; positively correlates with reduction of tumour mass and
Esteban-Fernández et al., 2010; Tisato et al., 2010; Wang and von clinical parameters, such as recurrence free and overall
Recum, 2011; Beija et al., 2012; Babu et al., 2013; Maldonado et al., survival, e.g. in non-small-cell lung cancer (Kim et al., 2012).
2013; Sukumar et al., 2013; Cao-Milán and Liz-Marzán, 2014; Cisplatin enters the cells either passively by a simple
Mjos and Orvig, 2014; Muhammad and Guo, 2014; Petrelli et al., diffusion or by active protein-mediated transport systems, e.g.
2014). However, the majority of the available reviews point out human organic cation transporter (hOCT2) and the copper
the most relevant examples of platinum- or non-platinum- transport protein (Ctr1) (Ishida et al., 2002; Song et al., 2004;
based compounds, eventually focusing on one particular metal Burger et al., 2010). In cytoplasm, cisplatin is hydrolysed and
ion or making a compendium on two or more metal ions. The one of the two chloride ligands is displaced by a water
aim of this review is to bridge a gap by summarizing on historical molecule to form the [PtCl(H2O)(NH3)2]+ species, allowing for
background, novel trends in synthesis of new metal complexes the binding of the platinum ion to DNA bases, especially in the
with antiproliferative effects and to describe their chemical N7 position of guanine and adenine and the N3 of cytosine,
reactivity, pharmacokinetic properties and interactions in the forming the monofunctional adduct [PtCl(DNA)(NH3)2]+. The
biological and biomedical context. second chloride ligand can be displaced by a water molecule to
Platinum-based complexes
Platinum(II) complexes
Cisplatin and transplatin
Diamminedichloroplatinum(II) is a complex with square Fig. 2 – Structures of the cis (a) and trans (b) isomers of
planar geometry and two possible cis and trans geometrical diamminedichloroplatinum(II), the cisplatin and
isomers, cisplatin and transplatin (Fig. 2). transplatin, respectively.
Please cite this article in press as: Trudu, F., et al., Coordination compounds in cancer: Past, present and perspectives. J. Appl. Biomed.
(2015), http://dx.doi.org/10.1016/j.jab.2015.03.003
, JAB-56; No. of Pages 25
journal of applied biomedicine xxx (2015) xxx–xxx 3
after 24 h, the majority of DNA adducts formed by transplatin
are still monofunctional (Bernal-Méndez et al., 1997). The
difference between cytotoxic effects of cisplatin and transpla-
tin is therefore in the formation of the 1,2-intrastrand
bifunctional adduct and in the fast conversion rate of the
monofunctional adduct into the bifunctional one.
Other cis-Pt complexes
Because of the cisplatin success in clinical therapy, various
new cis-Pt(II) complexes have been synthesized by substitu-
tion of either chlorine or ammonia ligands with different
structures. Up to now, only carboplatin and oxaliplatin, have
shown better performance than cisplatin in some types of
cancers, and their use has been approved worldwide.
The promising compound named picoplatin (cis-amine-
dichloro-(2-methylpyridine)-Pt(II)) (Fig. 4) has been introduced
for the treatment of patients with solid tumours, and its
clinical trials started in 1997 (Kelland, 2007a; Wheate et al.,
2010). Picoplatin has a marked steric bulk around the platinum
ion that reduces its inactivation by thiol-containing species. Its
cytotoxic activity is due to the interaction with DNA that leads
mainly to the formation of intrastrand adducts. Picoplatin was
found to be active against cisplatin- and oxaliplatin-resistant
cell lines (Kelland, 2007b). When used as single agent its main
dose-limiting side effect is myelosuppression. However, phase
Fig. 3 – Scheme of the reaction pathway leading to the
III trials did not confirm the previous promising results in the
formation of adducts between cisplatin (a) and DNA. One
treatment of small-cell lung cancer and new trials are not
chloride ligand is displaced by water to form the aqua-
currently planned (Lopez-Chavez and Sandler, 2012; Hamilton
complex [PtCl(H2O)(NH3)2]+ (b) which interacts with DNA
and Olszewski, 2013).
forming the monofunctional adduct [PtCl(DNA)(NH3)2]+ (c).
Recently, cis-Pt(II) complexes has been reconsidered and
This last might exchange the chloride ligand with one
used as a scaffold for biologically active ligands. One example
molecule of water forming the hydrated monofunctional
is the complex cis-[Pt(NH3)2(L)Cl] (L = 3-aza-5H-phenanthridin-
adduct [Pt(H2O)(DNA)(NH3)2]2+ (d). Both the monofunctional
6-one) which contains a poly(ADP-ribose) polymerase (PARP-1)
adduct (c) and its hydrated form (d) lead to the formation of
inhibitor as (B. Wang et al., 2014a). PARP-1 is a poly (ADP-
the bifunctional adduct [Pt(H2O)(DNA)(NH3)2]2+ (e).
ribose) polymerase involved in DNA replication, damage
repair, and transcriptional regulation. After DNA damage,
the activity of PARP-1 increases, stimulating the response of
DNA-damage repairing proteins. This platinum complex
form the adduct [Pt(H2O)(DNA)(NH3)2]2+. These species may exhibits increased activity and enhanced solubility with
re-interact with DNA by crosslinking forming a bifunctional respect to those of the free inhibitor.
adduct (Alderden et al., 2006) (Fig. 3) and trigger programmed Other cis-Pt(II) compounds conjugated with side-directing
cell death. molecules have been introduced with the aim to increase their
Several modes of cisplatin crosslinking with DNA have selectivity. Analogues of cisplatin, carboplatin and oxaliplatin
been proposed (Trzaska, 2005). The main adducts with DNA have been prepared with estrogens-like compounds in order to
form 1,2-intrastrand cross-links with two adjacent guanines increase selectivity towards hormone-dependent breast,
(1,2-d(GpG)) and 1,2-intrastrand cross-links with an adenine ovarian and uterine tumours (Descôteaux et al., 2003, 2008;
and an adjacent guanine (1,2-d(ApG)) (Jamieson and Lippard, Saha et al., 2012). The estrogens-derived cisplatin and
1999). The adducts 1,2-d(GpG) are supposed to be responsible carboplatin ligands possess a high affinity for the oestrogen
for the cytotoxic activity of the drug (Todd and Lippard, 2009).
Minor adducts are 1,3-intrastrand cross-links formed with
nonadjacent guanines and interstrand adducts.
In contrast to cisplatin, the trans isomer of the diammine-
dichloroplatinum(II), transplatin, shows only mild cytotoxic
activity. This could be explained by different way of formation
of DNA adducts. The interstrand cross-links between guanine
and cytosine are formed by both isomers, while the 1,2-
intrastrand cross-links are prevented by the geometry in the
case of transplatin (Bernal-Méndez et al., 1997). In addition, the
conversion of the monofunctional adducts into the bifunc- Fig. 4 – Structure of picoplatin (cis-amine-dichloro-(2-
tional ones occurs particularly slowly for transplatin. In fact, methylpyridine)-Pt(II)).
Please cite this article in press as: Trudu, F., et al., Coordination compounds in cancer: Past, present and perspectives. J. Appl. Biomed.
(2015), http://dx.doi.org/10.1016/j.jab.2015.03.003
journal of applied biomedicine xxx (2015) xxx–xxx
Available online at www.sciencedirect.com
ScienceDirect
journal homepage: http://www.elsevier.com/locate/jab
Review Article
Coordination compounds in cancer: Past, present
and perspectives
Federica Trudu a,b,1,2, Filippo Amato a,1, Petr Vaňhara c,
Tiziana Pivetta b, E.M. Peña-Méndez d, Josef Havel a,*
a
Department of Chemistry, Faculty of Science, Masaryk University, Brno, Czech Republic
b
Department of Chemical and Geological Sciences, University of Cagliari, Monserrato (CA), Italy
c
Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
d
Department of Chemistry, Faculty of Science, University of La Laguna, La Laguna, Tenerife, Spain
article info abstract
Article history: Metal-based coordination compounds have been used throughout the history of human
Received 24 October 2014 medicine to treat various diseases, including cancer. Since the discovery of cisplatin in 1965,
Received in revised form a great number of metal coordination complexes, such as platinum, ruthenium, gold or
4 March 2015 copper have been designed, synthesized and tested in order to develop clinically effective
Accepted 9 March 2015 and safe drugs. Currently, many reviews cover applications of cytostatic metal complexes
Available online xxx pointing out the most promising examples of platinum- and non-platinum-based com-
pounds in preclinical and clinical trials. However, recent comprehensive reviews covering
Keywords: chemical and biological aspects of metal-based coordination compounds in cancer therapy
Cancer are still rare. In this review we wish to provide an overview of the coordination chemistry of
Coordination metal complexes current and novel cytostatic compounds, including an outline of their design and rationale
Cisplatin of synthesis, and summarize bio-chemical reactivity and physicochemical properties of
Omics candidate metal complexes.
Perspectives # 2015 Faculty of Health and Social Studies, University of South Bohemia in Ceske
Budejovice. Published by Elsevier Sp. z o.o. All rights reserved.
antiproliferative effect of various classes of compounds,
Introduction
ranging from naturally occurring molecules and their deriva-
tives, to organometallic and inorganic compounds and their
Cancer is nowadays one of the leading causes of death in the application in cancer therapy. The fortuitous discovery of the
developed world. Biologically, cancer represents a vastly cytotoxic properties of cisplatin (diamminedichloroplatinum
heterogenic group of diseases sharing several common traits. (II)) in 1965, opened new avenue for the application of metal
One of these hallmarks is sustained proliferation, resulting in complexes in cancer therapy (Arnesano et al., 2011) (Fig. 1).
uncontrolled tumour growth (Hanahan and Weinberg, 2011). The antiproliferative effect of cisplatin and other compounds,
An extensive research has been done to characterize however, induces adverse effects on normal tissues,
* Corresponding author at: Department of Chemistry, Faculty of Science, Masaryk University, Kamenice 5/A14, 625 00 Brno, Czech Republic.
Tel.: +420 54949 4114; fax: +420 54949 2494.
E-mail address: (J. Havel).
1
These authors contributed equally to this paper.
2
On leave from affiliation 'b'.
1214-021X/$ – see front matter # 2015 Faculty of Health and Social Studies, University of South Bohemia in Ceske Budejovice. Published
by Elsevier Sp. z o.o. All rights reserved.
http://dx.doi.org/10.1016/j.jab.2015.03.003
Please cite this article in press as: Trudu, F., et al., Coordination compounds in cancer: Past, present and perspectives. J. Appl. Biomed.
(2015), http://dx.doi.org/10.1016/j.jab.2015.03.003
,JAB-56; No. of Pages 25
2 journal of applied biomedicine xxx (2015) xxx–xxx
Fig. 1 – Historical overview of the cytotoxic metal and metalloid complexes that have been approved or entered the clinical
practice.
decreasing therapeutic effectivity. Moreover, in many cancers, Cisplatin has been a first-line therapy in many cancers and
tumour cells may acquire resistance to the metal-based nowadays is used either alone or in combination with other
cytotoxic therapy resulting in virtually incurable relapsing compounds in many cancers, e.g. testicular, ovarian or bladder
disease (Desoize, 2004). cancers or leukaemias. Due to low chemical stability of
In the last 15 years, a great effort has been dedicated to the cisplatin, the direct intravenous administration is preferred
development of more effective and less toxic drugs. Various new over the other forms. In the blood stream, cisplatin rapidly
trans-platinum(II) and platinum(IV) complexes have been interacts with plasma proteins such as human serum albumin
synthesized, and some of them have been selected for clinical (HSA), haemoglobin (Hb) or transferrin (Tf) (Rudnev et al., 2005)
trials (Kelland et al., 1999), but with varying effectivity and and 24 h after administration, 95% of cisplatin is bound to
safety. Therefore, less toxic metals, such as ruthenium, gold or plasma proteins (Sooriyaarachchi et al., 2011). Cisplatin is
copper were introduced as promising candidates for effective widely distributed into body fluids and tissues, reaching
and safe therapy (Tiekink, 2002; Clarke, 2002; Marzano et al., the highest concentrations in kidneys (0.4–2.9 mg/g), liver
2009; Nobili et al., 2010). Various reviews have been published on (0.5–3.7 mg/g wet weight), and prostate (1.6–3.6 mg/g). Minor
the use of metal complexes as anticancer agents, with the intent concentration levels can be found in muscles, bladder, testes,
to give an overview of the proposed approaches concerning the pancreas, and spleen (Stewart et al., 1982). Penetrance of
application of these systems in clinical practice (Tiekink, 2002; cisplatin into tumour tissue differs in different cancers.
Boulikas et al., 2007; Milacic et al., 2008; Bruijnincx and Sadler, However, the concentration of cisplatin and its analogues
2008; Todd and Lippard, 2009; Vilmar and Sørensen, 2009; positively correlates with reduction of tumour mass and
Esteban-Fernández et al., 2010; Tisato et al., 2010; Wang and von clinical parameters, such as recurrence free and overall
Recum, 2011; Beija et al., 2012; Babu et al., 2013; Maldonado et al., survival, e.g. in non-small-cell lung cancer (Kim et al., 2012).
2013; Sukumar et al., 2013; Cao-Milán and Liz-Marzán, 2014; Cisplatin enters the cells either passively by a simple
Mjos and Orvig, 2014; Muhammad and Guo, 2014; Petrelli et al., diffusion or by active protein-mediated transport systems, e.g.
2014). However, the majority of the available reviews point out human organic cation transporter (hOCT2) and the copper
the most relevant examples of platinum- or non-platinum- transport protein (Ctr1) (Ishida et al., 2002; Song et al., 2004;
based compounds, eventually focusing on one particular metal Burger et al., 2010). In cytoplasm, cisplatin is hydrolysed and
ion or making a compendium on two or more metal ions. The one of the two chloride ligands is displaced by a water
aim of this review is to bridge a gap by summarizing on historical molecule to form the [PtCl(H2O)(NH3)2]+ species, allowing for
background, novel trends in synthesis of new metal complexes the binding of the platinum ion to DNA bases, especially in the
with antiproliferative effects and to describe their chemical N7 position of guanine and adenine and the N3 of cytosine,
reactivity, pharmacokinetic properties and interactions in the forming the monofunctional adduct [PtCl(DNA)(NH3)2]+. The
biological and biomedical context. second chloride ligand can be displaced by a water molecule to
Platinum-based complexes
Platinum(II) complexes
Cisplatin and transplatin
Diamminedichloroplatinum(II) is a complex with square Fig. 2 – Structures of the cis (a) and trans (b) isomers of
planar geometry and two possible cis and trans geometrical diamminedichloroplatinum(II), the cisplatin and
isomers, cisplatin and transplatin (Fig. 2). transplatin, respectively.
Please cite this article in press as: Trudu, F., et al., Coordination compounds in cancer: Past, present and perspectives. J. Appl. Biomed.
(2015), http://dx.doi.org/10.1016/j.jab.2015.03.003
, JAB-56; No. of Pages 25
journal of applied biomedicine xxx (2015) xxx–xxx 3
after 24 h, the majority of DNA adducts formed by transplatin
are still monofunctional (Bernal-Méndez et al., 1997). The
difference between cytotoxic effects of cisplatin and transpla-
tin is therefore in the formation of the 1,2-intrastrand
bifunctional adduct and in the fast conversion rate of the
monofunctional adduct into the bifunctional one.
Other cis-Pt complexes
Because of the cisplatin success in clinical therapy, various
new cis-Pt(II) complexes have been synthesized by substitu-
tion of either chlorine or ammonia ligands with different
structures. Up to now, only carboplatin and oxaliplatin, have
shown better performance than cisplatin in some types of
cancers, and their use has been approved worldwide.
The promising compound named picoplatin (cis-amine-
dichloro-(2-methylpyridine)-Pt(II)) (Fig. 4) has been introduced
for the treatment of patients with solid tumours, and its
clinical trials started in 1997 (Kelland, 2007a; Wheate et al.,
2010). Picoplatin has a marked steric bulk around the platinum
ion that reduces its inactivation by thiol-containing species. Its
cytotoxic activity is due to the interaction with DNA that leads
mainly to the formation of intrastrand adducts. Picoplatin was
found to be active against cisplatin- and oxaliplatin-resistant
cell lines (Kelland, 2007b). When used as single agent its main
dose-limiting side effect is myelosuppression. However, phase
Fig. 3 – Scheme of the reaction pathway leading to the
III trials did not confirm the previous promising results in the
formation of adducts between cisplatin (a) and DNA. One
treatment of small-cell lung cancer and new trials are not
chloride ligand is displaced by water to form the aqua-
currently planned (Lopez-Chavez and Sandler, 2012; Hamilton
complex [PtCl(H2O)(NH3)2]+ (b) which interacts with DNA
and Olszewski, 2013).
forming the monofunctional adduct [PtCl(DNA)(NH3)2]+ (c).
Recently, cis-Pt(II) complexes has been reconsidered and
This last might exchange the chloride ligand with one
used as a scaffold for biologically active ligands. One example
molecule of water forming the hydrated monofunctional
is the complex cis-[Pt(NH3)2(L)Cl] (L = 3-aza-5H-phenanthridin-
adduct [Pt(H2O)(DNA)(NH3)2]2+ (d). Both the monofunctional
6-one) which contains a poly(ADP-ribose) polymerase (PARP-1)
adduct (c) and its hydrated form (d) lead to the formation of
inhibitor as (B. Wang et al., 2014a). PARP-1 is a poly (ADP-
the bifunctional adduct [Pt(H2O)(DNA)(NH3)2]2+ (e).
ribose) polymerase involved in DNA replication, damage
repair, and transcriptional regulation. After DNA damage,
the activity of PARP-1 increases, stimulating the response of
DNA-damage repairing proteins. This platinum complex
form the adduct [Pt(H2O)(DNA)(NH3)2]2+. These species may exhibits increased activity and enhanced solubility with
re-interact with DNA by crosslinking forming a bifunctional respect to those of the free inhibitor.
adduct (Alderden et al., 2006) (Fig. 3) and trigger programmed Other cis-Pt(II) compounds conjugated with side-directing
cell death. molecules have been introduced with the aim to increase their
Several modes of cisplatin crosslinking with DNA have selectivity. Analogues of cisplatin, carboplatin and oxaliplatin
been proposed (Trzaska, 2005). The main adducts with DNA have been prepared with estrogens-like compounds in order to
form 1,2-intrastrand cross-links with two adjacent guanines increase selectivity towards hormone-dependent breast,
(1,2-d(GpG)) and 1,2-intrastrand cross-links with an adenine ovarian and uterine tumours (Descôteaux et al., 2003, 2008;
and an adjacent guanine (1,2-d(ApG)) (Jamieson and Lippard, Saha et al., 2012). The estrogens-derived cisplatin and
1999). The adducts 1,2-d(GpG) are supposed to be responsible carboplatin ligands possess a high affinity for the oestrogen
for the cytotoxic activity of the drug (Todd and Lippard, 2009).
Minor adducts are 1,3-intrastrand cross-links formed with
nonadjacent guanines and interstrand adducts.
In contrast to cisplatin, the trans isomer of the diammine-
dichloroplatinum(II), transplatin, shows only mild cytotoxic
activity. This could be explained by different way of formation
of DNA adducts. The interstrand cross-links between guanine
and cytosine are formed by both isomers, while the 1,2-
intrastrand cross-links are prevented by the geometry in the
case of transplatin (Bernal-Méndez et al., 1997). In addition, the
conversion of the monofunctional adducts into the bifunc- Fig. 4 – Structure of picoplatin (cis-amine-dichloro-(2-
tional ones occurs particularly slowly for transplatin. In fact, methylpyridine)-Pt(II)).
Please cite this article in press as: Trudu, F., et al., Coordination compounds in cancer: Past, present and perspectives. J. Appl. Biomed.
(2015), http://dx.doi.org/10.1016/j.jab.2015.03.003
