Cisplatin is an essential antineoplastic agent whose introduction in clinical use revolutionized the treatment of several solid malignancies, especially those of germinative origin. The unfavorable toxicological profile of this drug, however as well as the resistance of some common malignancies solicited the search of platinum complexes, characterized by lower toxicity and/or broader antitumor spectrum. Thus during the last three decades a plethora of several thousand platinum coordination compounds have been synthesized and evaluated as potential antineoplastic agents. Despite of the numerous compounds investigated however only few of the proved to be of clinical significance and actually none of them could be considered as an ideal substitute for cisplatin regarding both lower toxicity and broader spectrum of anticancer activity. To a great extent the platinum-based drug discovery was confined at structural modification of the parent compound in line with the classic structure-activity relationship concept. Conversely, since the majority of platinum complexes developed so far are closely related structural analogues of cisplatin, it is not surprising that they produce similar cellular effects and any altered pattern of antitumor activity and/or toxicity is likely to be due to pharmacokinetic, rather than truly mechanistic, factors. Studies over the last few years have shown that the structural resemblance to cisplatin is not an absolute requirement for cytotoxicity, which broadens the search for cisplatin analogues towards non-classical compounds with prominent structural/pharmacodynamic dissimilarity to the prototype. This review covers the major approaches to elaboration of non-classical platinum complexes with emphasis on complexes interacting with DNA in a cisplatin-dissimilar fashion and complexes with tumor-targeted cytotoxicity.
Zirconium complexes of mendiaxon, warfarin, coumachlor, and niffcoumar have been synthesized by reaction of the ligands with zirconium chloride in stoichiometric ratio 1:2. The formation of the complexes has been proved on the basis of elemental analysis, IR‐spectroscopy, 1H‐NMR spectroscopy, and thermal studies. Differential thermal analyses and thermogravimetric analyses have been applied to study the compositions of the new complexes. It is concluded that the lactone‐ and the keto‐carbonyl groups of warfarin, coumachlor, and niffcoumar are bonded to the metal ion as bidentate ligands, but mendiaxon is bonded as monodentate ligand. Cytotoxic screening by MTT‐assay was carried out. Among these compounds the zirconium complex of mendiaxon showed highest cytotoxic activity against human promyelocytic leukemic HL‐60 cells. The inorganic salt was found to be active against this cell line.
Complexes of lanthanum(III) with bis-coumarins:
3,3′-benzylidene-bis(4-hydroxy-2H-1-benzopyran-2-one)
(L1) and
bis(4-hydroxy-2-oxo-2H-chromen-3-yl)-(1H-pyrazol-3-yl)-methane
(L2) were synthesized by reaction of lanthanum(III)
salt and the ligands, in amounts equal to metal : ligand molar
ratio of 1 : 2. The complexes were prepared by adding an aqueous
solution of lanthanum(III) salt to an aqueous solution of the
ligand subsequently raising the pH of the mixture gradually to circa 5.0 by adding dilute solution of sodium hydroxide.
The lanthanum(III) complexes with bis-coumarins were characterized
by different physicochemical methods—elemental analysis, IR-,
-, and -NMR-spectroscopies, and mass
spectral data. The spectral data of lanthanum(III) complexes were
interpreted on the basis of comparison with the spectra of the
free ligands. This analysis showed that in the
complexes, the ligands coordinated to the metal ion through both
deprotonated hydroxyl groups. On the basis of the
ν(C=O) red shift observed, participation of the
carbonyl groups in the coordination with the metal ion was also
suggested. In the present study, we performed a cytotoxic-effects
screening of the lanthanum complexes with L1 and
L2 in a panel of human tumor cell lines, using the
standard MTT-dye reduction assay for cell viability. The panel
consisted of the acute myeloid leukemia-derived HL-60 and the
chronic myeloid leukemia-derived BV-173. Following a 24- hour
treatment of BV-173 cells with lanthanum complex of L1
at 100 or 200 μM led to a DNA-laddering. The findings
suggest that the observed cytotoxicity of the lanthanum complex of
L1 on BV-173 is at least partly mediated through
induction of programmed cell death.
Three novel stable Pt(III) complexes with distorted octahedral structure and (dz2)1 ground state have been obtained in the course of Pt(II)-hematoporphyrin IX ((7,12-bis(1-hydroxyethyl)-3,8,13,17-tetramethyl-21H-23H-porphyn-2,18-dipropionic acid), Hp) interaction in alkaline aqueous medium and aerobic conditions.
A redox interaction also takes place together with the complexation process leading to the formation of Pt(III) species and organic radicals. The processes in the reaction system and the structure of the complexes formed cis-[Pt(III)false(NH3false)2(Hp−3H)false(H2Ofalse)2]⋅H2O
1, [Pt(III)(Hp−3H)false(H2Ofalse)2]⋅H2O
2, and [Pt((O,O)Hp−2H)Clfalse(H2Ofalse)3] 3, were studied by UV-Vis, IR, EPR and XPS spectra, thermal (TGS, DSC), potentiometric and magnetic methods. The newly synthesized complexes show promising cytotoxic activity comparable with that of
cis-platin in in vitro tests against a panel of human leukemia cell lines. The observed cytotoxicity of the complex 2 against SKW-3 cells (KE-37 derivative) is due to induction of cell death through apoptosis.
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