Current Topics in Medicinal Chemistry - Volume 11, Issue 21, 2011

The general concept of chemotherapy was introduced by Ehrlich about a century ago in which a systematic variation of structures and studies on the biological activity of antimicrobials resulted in the development of salvarsan. The concept has been followed by researchers all over the world and numerous compounds have been screened for other medicinal applications since Ehrlich's pioneering work, including many for their tumor-inhibiting properties. The approach of relating structural changes with biological activity was also successful in the quest for anticancer chemotherapeutics and several classes of anticancer compounds are available now, among which platinum compounds are some of the most widely used drugs. For the latter compound group, Ehrlich's approach was applied after the development of cisplatin as a lead structure, and has been followed since by many individual contributors rather than a single research group. In recent years, the metal-based anticancer research community has designed compounds that exhibit new modes of action, and in particular, breaking the paradigm of maintaining “platinum-type” structural motifs and mechanisms. In this issue of Current Topics in Medicinal Chemistry on “Metal-based Compounds in Anticancer Research” we have aimed to collate reviews to give the reader an idea of some of the current strategies applied. Furthermore, the number of used bioanalytical/biophysical and molecular biology methods is steadily increasing, providing better insight into the modes of action of chemotherapeutics, as highlighted in some of the contributions to this special issue. At the same time, we acknowledge that it was not possible to cover all topics in this issue of Current Topics in Medicinal Chemistry due to space restrictions. In this context, reviews on topics covering a wide range of approaches in drug discovery for cancer chemotherapy have been included in this issue. This comprises newer developments in platinum drugs, such as Pt(IV) prodrugs which are reviewed by Wee Han Ang, Ramasamy Jothibasu and Mengtao Ma with special consideration of prodrug strategies, photodynamic therapy and drug targeting. Adoracion G. Quiroga describes the properties of non-classical Pt complexes to overcome current limitations of Pt-based anticancer agents, also mediated by the ligands coordinated to the metal center, and catalytic processes induced by metal complexes in biological fluids. The form of administration of drug compounds to living systems is of crucial importance in controlling the pharmacokinetic properties of drug substances. Nicholas P. Farrell introduces the reader to different formulations of established platinum anticancer chemotherapeutics for drug delivery. As important as formulation of a drug candidate, is the identification of its molecular target. In this context, Michael Groessl and Paul J. Dyson review bioanalytical/ biophysical techniques and critically discuss their strengths and limitations, and illuminate the information accessible from these techniques. The application of several of these techniques to identify the molecular mechanisms and targets of anticancer gold compounds is the topic of the contribution by Angela Casini and Luigi Messori. Likewise, Iztok Turel and Jakob Kljun describe the role of anticancer metallodrug binding to DNA, being known as the crucial factor in the anticancer activity of the clinically-used platinum drugs, and different DNA binding modes of metal ions, and in this respect they also discuss the treatment of other diseases and imaging applications. Andrew D. Phillips, with us, summarizes some of the recent contributions to the field of polynuclear and some non-platinum species with tumor-inhibiting properties, with a special focus on the comparison of anticancer properties of the polynuclear compounds and their mononuclear analogues. However, as important as the treatment of cancer might be, is the prevention of cancer. One factor which contributes to carcinogenesis is oxidative stress and Elena R. Milaeva summarizes recent research on potential therapeutic candidates as antioxidants with ROS scavenging properties. As can be seen from the topics covered, there is another lesson that can be learned from Ehrlich's research, namely that a team effort is most efficient to develop a new drug. This fact is even more relevant in modern times with the requirements established by federal drug agencies for the introduction of drugs to the market. Only joint efforts of synthetic and analytical chemists, biologists, pharmacists, medical doctors and industrial partners will result in the marketing of new drugs. The researchers in the field of metal-based drugs have a filled pipeline with promising compounds available for the treatment of different diseases, just waiting for further development. Finally, we would like to thank all the contributing authors of this issue and the referees for their valuable contributions. We hope that the readers will appreciate the selection of reviews and that this special issue will stimulate discussion within the research field and attract groups with complementary areas to join forces to fight cancer.

Over the past four decades, the search for improved platinum drugs based on the classical platinum(II)- diam(m)ine pharmacophore has yielded only a handful of successful candidates. New methodologies centred on platinum( IV) complexes, with better stability and expanded coordination spheres, offer the possibility of overcoming limitations inherent to platinum(II) drugs. In this review, novel strategies of targeting and killing cancer cells using platinum( IV) constructs are discussed. These approaches exploit the unique electrochemical characteristics and structural attributes of platinum(IV) complexes as a means of developing anticancer prodrugs that can target and selectively destroy cancer cells. Anticancer platinum(IV) prodrugs represent promising new strategies as targeted chemotherapeutic agents in the ongoing battle against cancer.

The potential and limitations of the non classical metallodrugs with platinum as metal are discussed in this section, focusing not only in their design but in their mechanism of action and interaction with other biomolecules to introduce and encourage the readers on the potential of this field.

This review summarizes clinical and pre-clinical results on platinum anti-cancer drug formulations. A concise summary of the use of oxidation state to modulate cancer pharmacology is given for Pt(IV) complexes, distinct from the clinically used Pt(II) drugs. The chemistry of platinum drug formulation combines aspects of kinetics of active moiety release from nominally weak-binding ligands (bond cleavage from platinum-carboxylate and platinum-phosphate) in polymers and nanoparticles with pharmacological considerations of plasma distribution and cellular accumulation. The action of any molecular entity as a drug is influenced by its ADME profile - absorption, distribution, metabolism and excretion. The purpose of drug formulation is to alter any or all of these parameters with the ultimate goal of improving the efficacy and reducing side effects with the possibility to target drugs directly to the tumor site. The diverse array of approaches includes liposomes, polymers (not limited to peptides, dendrimers, biodegradable polymers, polysaccharides, and metallic nanoparticles). Functionalization of the surfaces of nanoparticles with antibodies or cellular surface recognition motifs may further target specific cancers.

Platinum-based drugs present one of the pillars of anticancer chemotherapy, and pharmaceuticals incorporating metals such as ruthenium, gallium, titanium and gold, some of which have already entered clinical trials, show promising features including activity against platinum-resistant tumors and/or reduced side-effects. The mode of action of these novel metallodrugs has only been partly elucidated, and even for established treatments, some questions concerning the interactions with targets such as DNA and proteins on a molecular level remain unanswered. In order to tackle the challenging problem of characterizing the behavior of metallodrugs in complex biological media and tissues in vitro and in vivo, bioanalytical and biophysical methodologies are employed. The current state of these techniques, their strengths and limitations, and the information they can provide for achieving this demanding goal, are described in this review.

Nowadays, gold compounds constitute a family of very promising experimental agents for cancer treatment. Indeed, several gold(I) and gold(III) compounds were shown to manifest outstanding antiproliferative properties in vitro against selected human tumor cell lines and some of them performed remarkably well even in tumor models in vivo. Notably, the peculiar chemical properties of the gold centre impart innovative pharmacological profiles to gold-based metallodrugs most likely in relation to novel molecular mechanisms. The precise mechanisms through which cytotoxic gold compounds produce their biological effects are still largely unknown. Within this frame, the major aim of this review is to define the possible modes of action and the most probable biomolecular targets for a few representative gold compounds on which extensive biochemical and cellular data have been gathered. In particular, we will focus on auranofin and analogues, on gold(III) porphyrins and gold(III) dithiocarbamates. For these three families markedly distinct molecular mechanisms were recently invoked: a direct mitochondrial mechanism involving thioredoxin reductase inhibition in the case of the gold(I) complexes, the influence on some apoptotic proteins - i.e. MAPKs and Bcl-2 - for gold(III) porphyrins, and the proteasome inhibition for gold(III) dithiocarbamates. In a few cases the distinct mechanisms may overlap. The general perspectives for the development of new gold compounds as effective anticancer agents with innovative modes of action are critically discussed.

In this review several types of interactions between metal ions and DNA are given, starting from basic binding to the use of metal complexes in cancer treatment and diagnostics. Metal cations help to neutralize the negative charge of DNA and thus enable the normal functions of DNA but many other interactions are also possible and are discussed in this paper. Various consequences of such interactions can be reversible (e. g. conformational changes) or irreversible (e. g. cleavage). It is known that some metal ions can also damage DNA which can provoke mutations and in some cases leads to cancer. It is clear that we know a lot about metal-DNA interactions but much more information is needed to understand the role of metal ions completely and to use this knowledge successfully.

Polynuclear compounds are a relatively new and successful approach in metal-based cancer chemotherapy as typified by the trinuclear Pt compound BBR3464 which was evaluated in clinical trials. In this review, we discuss newer developments of polynuclear ruthenium, osmium and gold complexes, focusing on their anticancer activity. The compounds presented are often supposed to exert their anticancer activity by different modes of action as compared to established drugs, including newly proposed mechanisms such as enzyme inhibition, crosslinking of biomacromolecules or through photo-activation, though many of the examples are also capable of binding to DNA nucleobases. Important metabolization and chemical characteristics of such compounds are discussed, and if the appropriate data is available, molecular modes of action are highlighted.

The oxidative stress that is associated with the abnormal level of reactive oxygen species (ROS) is considered to be involved in the carcinogenesis process. The antioxidative defense system in the living organism regulates the toxic impact of ROS and there is strong evidence that the antioxidants prevent carcinogenesis. This review will focus on a novel approach to design synthetic metal-based antioxidants and to study their in vitro, ex vivo and in vivo activities in the cellular oxidation processes that might be involved in promotion of carcinogenesis. The antioxidants are divided into several groups depending on the nature of the ligands used: 2,6-dialkylphenols, flavonoids, polyphenols, peptides, purines, pyridines and their derivatives. Some currently achieved results in testing metal complexes as antioxidants show that they could potentially facilitate the scavenging of excess ROS, and thus restore redox balance in the damaged cells and organs. Therefore there is a strong need of the design of novel potential therapeutic candidates for prevention the oxidative stress-related carcinogenesis based on metal complexes.