Synthesis, Structure, and Biological Activity of New Azine-Bridged Dinuclear Platinum(II) Complexes− a New Class of Anticancer Compounds (original) (raw)
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Cisplatin: Synthesis, antitumour activity and mechanism of action
Pharmaceutisch Weekblad Scientific Edition, 1985
A review is presented on the successful antitumour drug cis-diamminedichloroplatinum(n), better known as cisplatin. Special attention is given to the synthesis of the compound and related derivatives, and to the nature of the hydrolysis products in blood and in the cell. In the second part of the review the mechanism of action is discussed. Binding to DNA and in particular the formation of intrastrand cross-links between adjacent guanines, to which the Pt(NH3)2 > ion is chelated at the N7 atoms, seems to be a very important event. However, at the moment it is not yet known which DNA lesion is responsible for the killing of the tumour cells.
Journal of Inorganic Biochemistry, 2006
A very interesting series of water soluble platinum compounds violating some of the classical structure-activity relationships, but still showing antitumor activity, was reported by Hollis and collaborators some 25 years ago [L.S. Hollis, A.R. Amundsenm, E.W. Stern. J. Med. Chem. 32 (1989) 128-136]. The compounds, having formula [PtClA 2 L] + (A 2 = two monodentate or a bidentate amine, L = a secondary or tertiary amine or a N-donor heterocycle), were characterized by a positive charge and three non-labile N-donor ligands. We have extended the investigation to analogous compounds in which 2,9-dimethyl-1,10-phenanthroline has taken the place of the A 2 ligand(s) and L is 2-picoline (1), 6-amino-2-picoline (2), or 1-methyl-cytosine (3). The X-ray analysis of 2 has revealed a bow-like distortion of the phenanthroline plane, a sloping of the phenanthroline plane with respect to the coordination plane, and an overall shielding of the metallic core by the ortho substituents of the phenanthroline and pyridine ligands.
Molecular Aspects of Antitumor Effects of a New Platinum(IV) Drug
Molecular Pharmacology, 2006
The new platinum(IV) complex cis,trans,cis-[PtCl 2 (CH 3 COO) 2 (NH 3)(1-adamantylamine)] [adamplatin(IV)] appears promising for the perspective application in therapy of corresponding tumors. It is, therefore, of great interest to understand details of mechanisms underlying its biological efficacy. Cellular uptake of the drug, alterations in the target DNA induced by platinum drugs along with processing of platinum-induced damage to DNA and drug inactivation by sulfur-containing compounds belong to major pharmacological factors affecting antitumor effects of platinum compounds. We examined in the present work the significance of these factors in the mechanism of antitumor effects of adamplatin(IV) and compared the results with those of the parallel studies performed with "classical" cisplatin. The results show that deactivation of adamplatin(IV) by sulfur-containing compounds (such as glutathione or metallothioneins) is likely to play a less significant role in the mechanism of resistance of tumor cells to adamplatin(IV) in contrast to the role of these reactions in the effects of cisplatin. Moreover, the treatment of tumor cells with adamplatin(IV) does not result in DNA modifications that would be markedly different from those produced by cisplatin. In contrast, the effects of other factors, such as enhanced accumulation of the drug in cells, strong inhibition of DNA polymerization by these adducts, lowered DNA repair and DNA-protein cross-linking are different from the effects of these factors in the mechanism underlying activity of cisplatin. Hence, the differences between effects of adamplatin(IV) and cisplatin observed in the present work on molecular level may help understand the unique activity of adamplatin(IV).
Chemico-Biological Interactions, 1987
A two-fold difference in sensitivity to cis-diamminedichloroplatinum(I1) (cisplatin), as judged by colony forming assays, has been demonstrated in two human bladder carcinoma continuous cell lines. Approximately twice as many DNA-DNA interstrand cross-links (ISL) and a 2-fold greater inhibition of DNA synthesis occurred in the more sensitive T24 cell line than in the RT112 cell line after exposure to the same concentrations of cisplatin. Equitoxic concentrations of cisplatin resulted in similar extents of ISL and inhibition of DNA synthesis in both cell lines. Although drug uptake was identical, twice as much cisplatin was bound to the DNA of T24 cells than RT112 cells. However after equitoxic concentrations of cisplatin the DNA from both cell lines was platinated to a similar extent. In addition, levels of glutathione (GSH), glutathione reductase (GR) and total glutathione_Stransferases (GST) were higher in the less sensitive RT112 cell line.
Platinum Complexes as Anticancer Agents
Recent Patents on Anti-cancer Drug Discovery, 2006
The application of inorganic chemistry to medicine is a rapidly developing field, and novel therapeutic and diagnostic metal complexes are now having an impact on medical practice. Advances in biocoordination chemistry are crucial for improving the design of compounds to reduce toxic side effects and understand their mechanisms of action. Cisplatin, as one of the leading metal-based drugs, is widely used in the treatment of cancer. Significant side effects and drug resistance, however, have limited its clinical applications. Biological carriers conjugated to cisplatin analogs have improved specificity for tumor tissue, thereby reducing side effects and drug resistance. Platinum complexes with distinctively different DNA binding modes from that of cisplatin also exhibit promising pharmacological properties. This review focuses on recent advances in developing platinum anticancer agents with an emphasis on platinum coordination complexes.
Experimental and Theoretical Studies on the Pharmacodynamics of Cisplatin in Jurkat Cells
Chemical Research in Toxicology, 2004
For Jurkat cells in culture exposed to cisplatin (1), we measured the number of platinum adducts on DNA and showed that it is proportional to the AUC, the area under the concentration vs time curve, for cisplatin. The number of platinum-DNA adducts is measured immediately following exposure to drug. The AUC is calculated either as the product of the initial cisplatin concentration and the exposure time or as the integral under the concentration vs time curve for the unreacted dichloro species, which decreases exponentially. We also show that the number of adducts correlates with decreases in respiration, with the amount of DNA fragmentation, and with cell viability, all measured 24 h after exposure to the drug. To study the reactions of cisplatin at concentrations approaching clinical relevance (65 µM), we use two-dimensional [ 1 H 15 N]HSQC NMR and the 15 N-labeled form of the drug, cis-Pt(15 NH 3) 2 Cl 2 , 1. In the absence of cells, 1 reacts with components of the growth medium and also transforms slowly (k h) 0.205 h-1 at 37°C) into the chloro-aquo species, cis-[Pt(15 NH 3) 2 Cl(H 2 O)] + (2), which at the pH of the medium (pH 7.15), is mainly in the deprotonated chloro-hydroxy form, cis-Pt(15 NH 3) 2-Cl(OH) (4). The concentration of 2 (4), as measured by HSQC NMR, decreases due to reaction with components of the medium. In the presence of 5 million or more cells, the concentration of 1 decreases with time, but the NMR signal for 2 (4) is not seen because it is rapidly removed from solution by the cells, keeping its concentration very low. These experiments confirm that the species preferentially removed from the medium by cells is 2 (4) and not 1. Our findings are discussed in the context of a kinetic model for platination of nuclear DNA by cisplatin, which includes aquation of cisplatin outside the cell, passage of 2 (4) through the cell membrane, reaction of reactive platinum species (RPS) in the cytosol with thiols, formation of adducts between RPS and accessible sites on genomic DNA, and removal of platinum from DNA by repair. Some of the rate constants involved are measured, but others can only be estimated. Calculations with this model show that little of the platinum reacts with intracellular thiols before reaching the nuclear DNA, indicating that binding to thiols is not important in cisplatin resistance. The model also predicts the circumstances under which the amount of platination of nuclear DNA is proportional to AUC.