Current Topics in Medicinal Chemistry - Volume 4, Issue 15, 2004

Metals are both targets and tools for chemotherapeutic intervention. Metals in Medicine is a dynamic interdisciplinary research field whose major goals are to contribute to an understanding of the role of endogenous and exogenous metals in disease, and to exploit this knowledge for managing or curing fatal illnesses. In 2000, the National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health held a meeting entitled “Metals in Medicine: Targets, Diagnostics, and Therapeutics” (http: / / www.nigms.nih.gov / news / meetings / metals.html) to explore obstacles and opportunities in metalbased and metal-targeted drug development and to foster collaborations between academia and pharmaceutical industry. More recently, the first Gordon Research Conference on “Metals in Medicine“ was organized by N. Farrell, M. J. Clarke, and C. F. Shaw (New London, NH, 2002), another important milestone in promoting this exciting research area. This issue of Current Topics in Medicinal Chemistry was inspired by these events and attempts to be a representative collection of recent advancements in the field. The eight contributions deal with the development of metal-containing pharmaceuticals for the therapy of life-threatening diseases, such as cancer and HIV / AIDS, and new strategies for targeting metalloproteins and metal pools. I thank the authors for their excellent contributions and their patience throughout this project and hope that this special issue will stimulate new developments within a growing community of researchers interested in the various aspects of metals in biology and disease.

NAMI-A, i. e. (imH)[trans-RuCl4(dmso-S)(im)] (im = imidazole, dmso = dimethylsulfoxide), is a Ru(III) complex that, after extensive preclinical investigations that evidenced its remarkable and specific activity against metastases, has recently and successfully completed a Phase I trial (first ruthenium complex ever to reach clinical testing). This review article, after a brief summary of the main chemical and pharmacological aspects of NAMI-A, focuses on the development of new classes of ruthenium complexes originated from the NAMI-A frame. In particular, the chemical and biological features of the following classes of compounds will be treated: i) NAMI-A-type complexes, derived from NAMI-A by changing the nature of the N-ligand, ii) dinuclear NAMI-A-type compounds containing heterocyclic bridging N-N ligands, iii) new Ru-dmso nitrosyls broadly derived from NAMI-A-type complexes. Several of these new compounds were found to have antimetastatic activity comparable to, or even better than, NAMI-A; however, the nature of the target(s) responsible for the antimetastatic activity remains unclear. Common to any type of NAMI-A-type compound, both monomeric and dimeric, cell cytotoxicity (which is generally very low) is not sufficient to explain their potent and peculiar antitumor activity. All active NAMI-A-type compounds share the capacity to modify important parameters of metastasis such as tumor invasion, matrix metallo proteinases activity and cell cycle progression.

Nuclear DNA is the cellular target for many cancer treatments, and DNA-directed chemotherapies continue to play an important role in drug discovery in the postgenomic era. The majority of DNA-targeted anticancer agents bind through covalent interactions, non-covalent intercalation or groove binding, or hybrid binding modes. The sequence and regiospecificity of these interactions and the resulting structural alterations within the biopolymer play an important role in the mechanism of action of these drugs. DNA-binding proteins and / or DNA-processing enzymes, which also interact with DNA in a sequence- and groove-specific manner, are mediators of the cytotoxic effect produced by these agents. Thus one major goal in the design of new clinical agents of this type is to produce new types of adducts on DNA, which may lead to unprecedented cell kill mechanisms. Platinum-intercalator conjugates are such a class of hybrid agents acting through a dual DNA binding mode. The platinum center (usually a cis-diaminedichloroPt(II) unit) dominates the DNA adduct profiles in the majority of these species-the result of the metal's tendency to form cross-links in runs of consecutive guanine bases in the major groove of DNA. This paradigm has been broken recently for the first time with the design of cytotoxic platinum-acridinylthiourea conjugates, a class of adenine-affinic minor-groove directed agents. This review summarizes major advancements in the chemistry and biology of platinum-intercalators from 1984 to 2004, with emphasis being placed on the interplay between chemical structure, mechanism of DNA binding, and biological properties.

The zinc-dependent enzymes known as matrix metalloproteinases (MMPs) are medicinal targets due to the activity of these enzymes associated with diseases such as cancer, heart disease, and arthritis. The development of most MMP inhibitors (MPIs) has followed a basic design formula: a peptidomimetic backbone is attached to a zinc-binding group (ZBG). MPI backbones have varied enormously and improved with increased knowledge of MMP structure and function while hydroxamic acids have been used as the ZBG in most inhibitors. The problems associated with hydroxamic acid and other current ZBGs have been identified; the incorporation of more potent and selective ZBGs for the active site zinc(II) ion is necessary to improve the development of second-generation inhibitors. Herein, we highlight ZBGs that have been proposed as alternatives to hydroxamic acids. In addition, techniques used to identify new ZBGs are also discussed. New insights from a bioinorganic approach using model complexes of the MMP active site are presented as tools in examining the mode of binding for various known and novel ZBGs. Novel computational methods are highlighted that allow for modeling the drug-protein interactions with non-hydroxamate inhibitors of MMPs. We suggest that significant efforts to augment ZBGs combined with the available information on inhibitor backbone design will accelerate the discovery of improved MPIs. Newly devised drug design methods will help to realize this proposal.

The trivalent gallium cation is capable of inhibiting tumor growth, mainly because of its resemblance to ferric iron. It affects cellular acquisition of iron by binding to transferrin, and it interacts with the iron-dependent enzyme ribonucleotide reductase, resulting in reduced dNTP pools and inhibition of DNA synthesis. The abundance of transferrin receptors and the up-regulation of ribonucleotide reductase render tumor cells susceptible to the cytotoxicity of gallium. Remarkable clinical activity in lymphomas and bladder cancer has been documented in clinical studies employing intravenous gallium nitrate, which is currently being re-evaluated in non-Hodgkin's lymphoma. An improved therapeutic index is expected to result from prolonged exposure to low steady-state plasma gallium levels. Attempts to accomplish this by oral administration of gallium chloride failed because of insufficient intestinal absorption. Complexation of gallium with ligands, which stabilize gallium against hydrolysis and facilitate membrane permeation, has been recognized as a promising strategy for overcoming these limitations. Two such gallium complexes, namely tris(3-hydroxy-2-methyl- 4H-pyran-4-onato)gallium(III) (gallium maltolate) and tris(8-quinolinolato)gallium(III) (KP46), which both exhibit high bioavailability when administered via the oral route, are currently being evaluated in the clinical setting.

Whilst nitric oxide (NO) has emerged as one of the most versatile and ubiquitous molecules in the human body with a diverse range of physiological functions, dysfunction in NO biosynthesis or metabolism has led to the pathogenesis of a number of disease states. A variety of therapeutic strategies have therefore emerged that either reduce or increase endogenous NO levels depending on the disease pathology. The predominant strategy to date to reduce levels of NO is to utilise specific isoform selective inhibitors of nitric oxide synthases, the enzymes responsible for NO biosynthesis. An alternative line of attack, not r elate d to specificity for a particular enzyme, but rather on compartmental localisation and pharmacokinetics, is to re move or sc ave nge the exce ss NO re sponsible for the dise ase pathology. In this regard, a number of NO scavenger molecules have demonstrated pharmacological activity across a broad spectrum of disease states. This review will highlight the rationale behind the development, and the current state of play, of one such class of NO scavengers, complexes of the d-block transition metal ruthenium. Prior to this, a brief overview of the remarkable diversity of NO, both from a chemical and biological viewpoint, will be provided for perspective.

Despite advances made in its therapeutic management, human immunodeficiency virus (HIV) infection has remained an intractable problem, and complete eradication of the virus an unrealized goal. Experience in the clinical application of combination therapy using a variety of reverse transcriptase and protease inhibitors have revealed a number of challenges, in spite of the observed albeit temporary success in reduction of patient viral loads. Problems with current protocols include poor patient compliance, and the presence of latent reservoirs of virus that ultimately result in the appearance of phenotypic resistance. These considerations necessitate continued research and development into alternative strategies to circumvent the aforementioned problems. One approach to minimizing and / or eliminating the appearance of escape mutants and latent viral reservoirs is the targeting of essential and mutationally intolerant enzymes such as the nucleocapsid protein, which contains two highly conserved zinc knuckles. Concerns have been raised regarding the targeting of this protein, since the ubiquitous occurrence of important mammalian zinc finger proteins implies that drug specificity towards the nucleocapsid protein may be difficult to attain. In this review, strong evidence supporting the hypothesis that this protein can be targeted to the exclusion of other cellular zinc finger proteins is presented. The effects of small molecule induced abrogation of nucleocapsid protein mediated activities, as well as efforts to develop nucleocapsid protein inhibitors as antiretrovirals are also discussed.

Iron chelators may be of value as therapeutic agents in the treatment of cancer. They may act by depleting iron, a necessary nutrient, and limiting tumor growth. Alternatively or additionally, they may form redox-active metal complexes that cause oxidative stress via production of reactive oxygen species, damaging critical intracellular targets and thereby eliciting a cytotoxic response. Studies in vitro have evaluated the structure-activity relationships and mechanism of action of many classes of iron chelators, including desferrioxamine (DFO), pyridoxal isonicotinoyl hydrazone (PIH) analogs, desferrithiocin (DFT) analogs, tachpyridine, the heterocyclic carboxaldehyde thiosemicarbazones, and OTrensox. Animal studies have confirmed the antitumor activity of several chelators. Dexrazoxane has been approved for use in combination with doxorubicin, and its effectiveness in allowing higher doses of doxorubicin to be administered is, in part, based on the interactions of both drugs with iron. Clinical trials of the antitumor activity of chelators have been largely limited to DFO, which has been extensively studied as a consequence of its approved use for treatment of secondary iron overload. While the modest antitumor effects of DFO are encouraging, it is likely that more effective iron chelators may be identified.

The remarkable discovery of the enediyne antitumor antibiotics almost two decades ago has led to significant developments in the systematic design and study of simple synthetic enediyne constructs and their Bergman cyclization reactivities. Advances in understanding both the geometric and electronic factors that are important in influencing the activation barrier to formation of the potent 1,4-phenyl diradical intermediate in simple organic enediynes have been made as a first step to the development of synthetic agents for biomedical uses. Progress in these areas has also served as a benchmark and guideline for a new wave of inorganic metalloenediyne constructs that display variable and wide-ranging reactivity or stability depending upon the geometric or electronic structure of the resulting complex. In general, metal sites offer additional structural flexibilities over their carbocyclic or acyclic organic analogues, which contributes greatly to their intriguing Bergman cyclization reactivities. This is true not only for thermal cyclization of metal-bound enediyne ligands in which the metal acts as a scaffold or Lewis acid, but also for photoelectronic or photothermal Bergman cyclization which can be achieved via metal-ligand charge transfer excited states. These reactivity developments parallel new protein targeting strategies for simple enediynes constructs, suggesting that a combined approach of controlled initiation and site specific targeting may allow enediynes to truly reach their full potential in biomedical applications.