Another approach to improve the
cellular accumulation of cisplatin-like compounds is to replace the aliphatic
amine ligand with azaheterocycles or aromatic amines. Good results were
obtained by the introduction of 7-azaindole halogen derivatives. Muchova et al.
111 synthesized ligands such ligands, which were toxic to ovarian tumour
cells, with moderately better IC50values than cisplatin in the
cisplatin-sensitive cell line A2780. The potential factors which might be
involved in the mechanism underlying the cytotoxic effects of these compounds
originate mainly from their efficient cellular accumulation. Other examples of
N-heterocycle cisplatin-like complexes have been reported by ?Starha et al.
112and ?akomska et al. 113 with use of 1,2,4-triazol-1,5a-pyrimidine and
7-azaindole, respectively. The applicability of these complexes and their fate
in biological systems are characterized by their hydrolytic stability and by
the thermodynamic aspects of their interactions with cysteine, reduced
glutathione and human serum albumin.
Ferri et al. 114 synthesized a
series of imidazole-based Pt(II) complexes, they evaluated their cytotoxicity
towards a cancer cell line partially resistant to cisplatin but sensitive to
oxaliplatin. The design of these compounds, having a heterocycle and an amine
N-donor, preserved the aliphatic amino function in order to display the optimum
trans effect and introduced a chain of appropriate length at the imidazole
moiety to improve the lipophilicity.
In order to increase the selectivity
of antitumor drugs, Huang et al. 115,116 introduced a series of
cisplatin-like compounds with mono amino phosphonate ester as the carrier
ligand and chloride as the leaving group. Because alkaline phosphatase is
overexpressed in the extra-cellular space of specific tumour cells such as
ovarian and hepatic carcinoma cells, introduction of a phosphate group for
targeted delivery appeared to be a reasonable strategy to increase solubility
and to enhance transport through the cell membrane. Some phosphate groups also
exhibit high affinity for calcium ions and have been used to design targeted
drugs for testament of bone cancer.
Novakova et al. 117 synthesized
the cisplatin-like complex, in which the two ammonia ligands are replaced by
the cyclindependent kinase inhibitor bohemine. This compound exhibited a unique
anticancer profile which may be associated with some features of the damaged
DNA and/or its cellular processing, the mechanism of action was different from
that of cisplatin.
The same research group 118 studied the
anticancer potential of Pt(II) complexes involving disubstituted and
trisubstituted derivatives of the plant hormone kinetin as carrier
ligands. The complexes were able to circumvent cisplatin resistance in
A2780cisR cells while additionally being significantly more cytotoxic to A2780
cells than cisplatin; this was mainly ascribed to hydrolytic stability and
interactions with glutathione and guanosine monophosphate.
Hui, Zhang and Chen 119
synthesized a series of dichloridoplatinum(II) complexes of podophyllotoxin.
Among these, cis-4 _-O-(2__,3__-diaminopropanoyl)podophyllotoxindichlorideplatinum(II)
displayed the most potent cytotoxicity, with a submicromolar IC50value. This
compound induces cell cycle arrest in the G2/M phase and inhibits the formation
of microtubules in HeLa cells. Furthermore, it exhibits potent DNA cleavage
Neves et al. 120 studied a series
of chloride Pt(II) complexes of 2-hydroxy-3-(aminom ethyl)-1,4-naphthoquinone
Mannich bases exhibiting high cytotoxicity towards cancer cell lines. Natural
and synthetic quinone derivatives have been widely investigated
for cancer therapy because of their capability to form reactive oxygen species
(ROS) in vivo. The PtCl2 fragment substantially affects the chemical and
biophysical properties of quinone ligands, leading to an improvement of their
DNA-binding properties and the generation compounds that cleave DNA and
catalytically inhibit topoisomerase I.
et al. 121 and Garbutcheon-Singh et al. 122 synthesized numerous active
complexes with the general formula Pt(IL)AL)2+,where IL is an aromatic
intercalating ligand and AL is an ancillary ligand. The intercalating ligands
included 1,10-phenanthrolinederivatives and dipyridoquinoxaline variants,
whereas the ancillary ligands were the R,R or S,S isomers of 1,2-diaminocyclohexaneor