Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 10, Issue 5, 2010

While cancer remains a major killer in the developed world, a broad spectrum of novel and exciting approaches are being developed and tested. The importance of metal compounds in medicine is undisputed, as can be judged by the use of many metal-based compounds in the treatment of various diseases. In terms of anti-tumour activity, a wide range of compounds of both transition metal and main group elements have been investigated for efficacy. The existence of a relationship between cancer and metals is widely acknowledged by researchers. Therefore, the aim of the theme issue “Metal-Containing Drugs and Novel Coordination Complexes in Therapeutic Anticancer Applications” of Anti-Cancer Agents in Medicinal Chemistry is to present an up-to date overview of this subject and to cover very recent developments in the field of metal-based anticancer agents. Recent advances in medicinal inorganic chemistry demonstrate significant prospects for the utilization of metals and their coordination complexes as drugs, presenting a flourishing arena for inorganic chemistry. Significant progress in metal-based agents has been achieved. Nevertheless, there is an urgent need for new drugs to treat cancer, drugs with novel mechanisms of action. Metal complexes appear to provide a rich platform for the design of novel anticancer drugs. The metal, its oxidation state, the number and types of coordinated ligands, and the coordination geometry of the complexes can provide variety of properties. On the other side, the ligands can not only control the reactivity of the metal, but also play critical roles in determining the nature of interactions involved in the recognition of biological target sites, such as DNA, enzymes and protein receptors. These variables provide enormous potential diversity for the design of metallodrugs. They also introduce many challenges. Changes in composition are likely to be accompanied by changes in the respective biological activity. Hence it is important to identify the nature of the metal complex which exists in the biological medium and is undergoing the biological test, and ideally the species which reaches the target site. There is now no doubt that medicinal inorganic chemistry, and metal coordination chemistry in particular, is worthy of exploration for drug design. Developing metal complexes as drugs, however, is not an easy task. Accumulation of metal ions in the body can lead to deleterious effects. Thus biodistribution and clearance of the metal complexes as well as its pharmacological specificity are to be considered. Favourable physiological responses of candidate drugs need to be demonstrated by in vitro study with targeted biomolecules and tissues as well as in vivo investigation before they enter clinical trials. A mechanistic understanding of how metal complexes achieve their activities is crucial to their clinical success, as well as to the rational design of new compounds with improved potency. In the first part of the Special Issue “Metal-Containing Drugs and Novel Coordination Complexes in Therapeutic Anticancer Applications” timely in-depth reviews are given. The first and this second part of the issue focused on recent advances in developing different metal-based anticancer agents, on recent efforts to prepare novel platinum, ruthenium, gold, titanium, selenium etc. complexes and reviewed some mechanistic insights into the pharmacological effects of these complexes. It is well known that for the perspective of metal-based drugs, some results are encouraging, but some others challenging. Firstly, the clinical success of a drug candidate depends not only on its bioactivity, but also on the absorption, distribution, elimination, metabolism and toxicity properties. These qualities are determined by the structure of the compound and also by external factors. The second difficulty is related to the activity/toxicity modulation. The next problem worth to be studied is the cell response to the metals. Differing from organic drugs, metals act on several key points in the life process. Thus they intervene with a pathological process from a number of targeting points. To this end, the scientists have to study the input and output relation and establish quantitative models to describe the effects of cell responses to different metals. It needs no discussion that the above-presented highlights and outlook about metal-based therapeutics provide fascinating new possibilities for research in the coming decades. It is generally appreciated that enormous progress has been made in the understanding of the mode of action of the most of metal-based agents. Application of this knowledge in drug design is close, and it is generally expected that in the next decades improved drugs will be developed based on this knowledge. The future development of medicinal inorganic chemistry of metals requires an understanding of the physiological processing of metal complexes, to provide a rational basis for the design of new metal-based drugs. Application of new methodologies such as combinatorial chemistry, extensively used in drug discovery, will be beneficial for the study of various metals and the development of their coordination complexes as therapeutics....

Historically, DNA has been the target for many metal-based anti-cancer drugs, but drawbacks of prevailing therapies have stimulated the search for new molecular targets which may present unique opportunities for therapeutic exploitation. Enzyme inhibition has recently been identified as an alternative and significant target. The pursuit of novel metallodrug candidates that selectively target enzymes is now the subject of intense investigation in medicinal bioinorganic chemistry and chemical biology. In the field of drug design, it is recognised by many that exploiting the structural and chemical diversity of metal ions for the identification of potential hit and lead candidates can dramatically increase the number of possible drug candidates that may be added to the already abundant armoury of chemotherapeutic agents. This review will focus on recent key advancements in enzyme inhibition as a key target for the development of novel metal-based anti-cancer therapeutics. The enormous clinical success of classical platinum drugs, amongst others, coupled with the wealth of knowledge accumulated in recent years on enzyme structure and function, has undoubtedly been the impetus behind the development of new metallodrug candidates with enzyme inhibitory properties. Recent trends in this field will be reviewed with a particular emphasis on metal complexes that inhibit protein and lipid kinases, matrix metalloproteases, telomerases, topoisomerases, glutathione-Stransferases, and histone deacetylases.

The research and development of metal supramolecular complexes as anticancer supramolecular drugs, which are aggregates mainly formed by one or more inorganic metal compounds with one or more either inorganic or organic molecules in general via coordination bonds, has been a quite rapidly developing, increasingly active and newly rising highlight interdisciplinary field. Numerous efforts have been directed toward metal supramolecular complexes as potential anticancer agents and the unprecedented progress has been made. This has opened up a wholly new and infinite space to create novel metal-based bioactive supermolecules. More importantly, metal-based complex supermolecules as potential anticancer agents with wide potential applications have become highlight topics in recent years, and are becoming increasingly useful and important in preventing and treating cancer diseases. In view of the rapid progress in metal complex anticancer supermolecules with rich variation of structural types, this work systematically reviewed the recent research and development of the whole range of metal-based supramolecular complexes as anticancer agents mainly in 2009. The perspectives of the foreseeable future and potential application of metal supramolecular complexes in cancer therapy were also presented. It is hoped that this review will serve as a stimulant for new thoughts in the quest for rational designs of more active and less toxic metal supramolecular complex anticancer drugs.

Platinum-based anticancer chemotherapy constitutes a cornerstone for the treatment of various solid tumors. However, existing platinum drugs like cisplatin encounter many obstacles such as drug resistance and systemic toxicity in clinical applications. Extensive attempts have been made to minimize the side effects of platinum drugs. This review concentrates on the major development of novel platinum complexes in the last five years, and highlights the complexes with DNA damage mode fundamentally different from that of cisplatin. Diverse platinum complexes are discussed in the text, including analogues of cisplatin or oxaliplatin, monofunctional platinum( II) complexes, polynuclear platinum(II) complexes, trans-platinum(II) complexes, and platinum(IV) complexes. All of these complexes display impressive antitumor activity and some of them show remarkable potentiality to circumvent the resistance to cisplatin. On the basis of these new facts, it can be concluded that structural modifications could substantially modulate the DNA binding mode and DNA damage process, and as a result largely improve the antitumor efficacy of platinum complexes.

Traditional Chinese medicines (TCM) have recently been recognized as a new source of anticancer drugs and new chemotherapy adjuvant to enhance the efficacy of chemotherapy and to diminish side effects and resistance of cancer chemotherapies. At the same time, cisplatin, one of the most widely used anticancer drugs, is effective in treating a variety of cancers, especially testicular cancer for which it has a greater than 90% cure rate, but its clinical efficacy is limited by significant side effects and acquired or intrinsic resistance. Therefore, many efforts have been devoted to designing new platinum compounds with improved pharmacological properties and a broader range of antitumour activity. New strategies have been applied in the designs of antitumour coordination compounds as drugs, such as synthesizing new ligands or metal complexes with different reaction mechanisms. Among them, new coordination compounds based on traditional Chinese medicines (TCMs) provide a novel approach to potential (pro-)drugs. This review mainly focuses on the synthesis, structure, antitumour activity and interactions with molecular targets of TCM based metal complexes. TCM alkaloids, flavonoids, cantharidin, coumarins, plumbagin, curcumin and camphoric acid metal-based antitumour agents are covered. The future development of hybrid TCM-metal complexes as antitumour drugs is discussed. The pursuit of new TCM metal-based anticancer drugs and enhancement of modern TCM holds promise for overcoming multidrug resistance (MDR).

For thousands of years medicine and natural products have been closely linked through the use of traditional medicines and natural poisons. Mushrooms have an established history of use in traditional oriental medicine, where most medicinal mushroom preparations are regarded as a tonic, that is, they have beneficial health effects without known negative side-effects and can be moderately used on a regular basis without harm. Mushrooms comprise a vast and yet largely untapped source of powerful new pharmaceutical products. In particular, and most importantly for modern medicine, they represent an unlimited source of compounds which are modulators of tumour cell growth. Furthermore, they may have potential as functional foods and sources of novel molecules. We will review the compounds with antitumor potential identified so far in mushrooms, including low-molecular-weight (LMW, e.g. quinones, cerebrosides, isoflavones, catechols, amines, triacylglycerols, sesquiterpenes, steroids, organic germanium and selenium) and high-molecular-weight compounds (HMW, e.g. homo and heteroglucans, glycans, glycoproteins, glycopeptides, proteoglycans, proteins and RNA-protein complexes).