Elsevier

Coordination Chemistry Reviews

Volume 310, 1 March 2016, Pages 41-79
Coordination Chemistry Reviews

Review
New trends in platinum and palladium complexes as antineoplastic agents

https://doi.org/10.1016/j.ccr.2015.11.004Get rights and content

Highlights

Abstract

The discovery of cisplatin (cis-Pt(NH3)2Cl2) as an antineoplastic agent has focussed attention on the rational design of metal complexes that can be potentially used in cancer chemotherapy. Today, the pharmaceutical industry invests more than $1 billion each year in the development of new metal-based drugs to improve biological activities, in terms of cellular selectivity, therapeutic efficiency and minimization of side effects. Chemotherapies based on transition metals play a key role in cancer treatment, and among them platinum and palladium are the most fruitful. This article reviews the main recent advances in the design and synthesis of platinum- and palladium-based drugs, their structural features and biological studies of them. The rationale for the choice of the ligand, related to leaving groups, the geometry of the complex and the oxidation state of the metal ion, is discussed. An overview of the main biological techniques and approaches for testing the interaction of these molecules with the biological environment, mainly DNA, to validate the effect is also provided.

Introduction

Cancer is one of the main causes of morbidity and death worldwide, with approximately 14 million new cases and 8.2 million cancer-related deaths reported in 2012, thus affecting life expectancy and producing a negative impact on society [1].

The discovery of cisplatin (cis-Pt(NH3)2Cl2) as an antineoplastic agent has focussed attention on the rational design of metal complexes that can be potentially used in cancer chemotherapy [2], [3], [4], [5], [6]. Today, the pharmaceutical industry invests more than $1 billion each year in the development of new metal-based drugs with improved biological activities, in terms of cellular selectivity and therapeutic efficiency, but also to minimize side effects [7], [8], [9]. Serious side effects such as emesis, renal toxicity, bone marrow suppression, neurotoxicity, hearing loss and drug resistance are connected with the use of cisplatin in clinical application [10].

The economic interest in metal-based compounds for pharmaceutical uses is also attested by the appearance of more than 60 patents in the period from 2013 to 2015 concerning only platinum complexes for tumour treatments.

Despite the interest in new metal ions, platinum complexes are, at present, the only metal-based drugs currently used in clinical settings (Fig. 1), and about 10 other platinum complexes are currently in clinical trials [11].

However, research on other metal complexes is constantly increasing, and many metal ions, mainly belonging to the class of noble metals, have been studied [12]. Among them, interest in palladium is increasing because it forms complexes similar to platinum but with different kinetics and stability of both the main ligand and the leaving groups and, in addition, at a lower cost.

Cisplatin is still considered the main architecture for the main development of platinum-based and other metal-based systems. This is because the platinum drugs used in the clinic up to now are similar to cisplatin, exerting the same mechanism of action in which the cross-linking of DNA by covalent bonds is predominant. At the same time, because these complexes are structurally derived from cisplatin, the drawbacks of cisplatin are inherited. This has resulted in many scientists being engaged in the design of novel metal complexes deriving not only from the cisplatin architecture but also from different architectures, such as monofunctional complexes [13], [14] and positively charged multinuclear complexes [15]. Therefore, further molecular architectures and oxidation states are continuously being prepared with the aim to improve the efficacy and specificity in tumour treatments.

In Fig. 2 the main approaches in the design of novel platinum-based drugs are reported, together with some examples of complexes that have been studied or are being studied.

In this review, we consider platinum and palladium complexes developed for antineoplastic aims in the period from 2013 to 2015. The complexes are grouped and discussed essentially following the guidelines in Fig. 2. The approaches and results are discussed, focussing on the type of complexes developed, their topology and the corresponding structural aspects. We also discuss the main biological approaches used to validate the efficacy of the complexes.

Section snippets

Platinum(II) complexes

Since the quite serendipitous discovery of cisplatin antitumour activity [16] (Fig. 1), a plethora of strictly related platinum complexes have been invented, synthesized and tested. Carboplatin, oxaliplatin (both marketed worldwide), nedaplatin (approved in Japan), lobaplatin (approved in China), heptaplatin (approved in Korea) [17] (Fig. 1) and picoplatin are the result of the search for new and better performing (less toxic, broader activity spectrum, overcome drug resistance, etc.)

Platinum(IV) complexes

Some problems linked to anticancer Pt(II)-based compounds, such as unselective binding to off-target biomolecules, side effects and the need for intravenous administration, can be overcome by the use of Pt(IV) octahedral complexes which feature two additional binding sites. The relative kinetic inertness which characterizes the latter in comparison with the Pt(II) square planar congeners makes them suitable for oral administration, decreasing both the possibility of side reactions in the

Platinum(II) and palladium(II) as a structural moiety for non-covalent interaction with DNA

DNA is an anionic polyelectrolyte that plays a fundamental role in the storage and expression of genetic information in a cell. The study of interaction of DNA with cationic metal complexes and the cytotoxic effects of such interactions has been a very active area during recent decades. These metal complexes bind to DNA through a series of binding modes, among them the main one is the covalent binding discussed in Section 2. However, metal systems can interact with DNA also by non-covalent

Photoactivated complexes

In the quest for even more selective anticancer therapies, several approaches to localize the cytotoxic effects of the drug to the tumour site have been investigated as already outlined. One of these approaches exploits the use of light and its interaction with matter, the beneficial effects of which have been known since antiquity. Transition metal complexes, and in particular those containing platinum and palladium, having a wide variety of electronic transition state available are suitable

Other complexes

Many active complexes are difficult to rationalize in terms of molecular structure, both from the ligand and from the complex point of view. Currently, many of them, although active, are difficult to classify. Some of them have been tested in biological studies. In the last 3 years, several compounds have fallen in this category [184], [185], [186], [187], [188], [189], [190], [191]; here we report those for which important results have been obtained in terms of antineoplastic as well as

Biological studies

The choice of the correct experimental procedure through which the biological activity of the drug is monitored and to possibly dissect its molecular mechanism of action is a crucial point. The exact mechanism of antitumour action of platinum-containing drugs (cisplatin as the reference compound) is not completely understood; however, DNA is often believed to be the main target of these drugs or at least the first target to be tested for novel metal complexes.

In the last decade some

Conclusions

Although metal-based drugs in cancer chemotherapy have a history of about 40 years, there is still growing interest in the design of new metal-based anticancer agents to overcome the problems of clinically used drugs but with maintenance of their efficacy. Starting from the progenitor drug cisplatin, first approved by the FDA in 1978 for the treatment of ovarian carcinoma, the second generation of square planar Pt(II) complexes was introduced to improve safety (carboplatin), to imprive the

Acknowledgements

We acknowledge financial support from the Department of Base Sciences and Foundations and the Department of Biomolecular Sciences of the University of Urbino.

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