Mini Reviews in Medicinal Chemistry - Volume 4, Issue 1, 2004

Supplementation of essential trace elements has become an increasingly important field of research in modern pharmacology. The present review presents general aspects related to the essentiality of inorganic systems in living organisms, followed by a detailed discussion of the supplementation of iron, copper, zinc, chromium, selenium, magnesium and some other minor trace elements. Some recent advances in this field as well as future challenges and perspectives are also discussed.

Effective chelation treatment of metal intoxications requires that the pharmacokinetics of the administered chelator in fact leads to chelation of the toxic metal, preferably forming a less toxic species which is effectively excreted. This depends on physical and chemical characteristics of metals and chelators as e.g. ionic diameter, ring size and deformability, hardness / softness of electron donors and acceptors, administration route, bioavailability, metabolism, organ and intra / extra cellular compartmentalization, and excretion. In vivo chelation is unlikely to reach equilibrium determined by the standard stability constant, as rate effects and ligand exchange reactions as well as the pharmacokinetics of the chelator considerably influence complex formation. Hydrophilic chelators enhance renal metal excretion, but mainly their extracellular distribution limit their effect to mainly extracellular metal pools. Lipophilic chelators can decrease intracellular stores, but may redistribute toxic metals to e.g. the brain. In chronic metal induced disease, necessitating life-long chelation, toxicity and side effects of the chelator may limit the treatment. The metal selectivity of chelators is important, due to the risk of essential metals depletion. Dimercaptosuccinic acid and dimercaptopropionic sulfonate are presently gaining increased acceptance among clinicians, undoubtedly improving the management of human metal intoxications including lead, arsenic and mercury compounds. Still, development of new safer chelators suited for long-term oral administration for chelation of metal deposits, mainly iron, is an important challenge to the future research.

Parasitic diseases represent a major world health problem with very limited therapeutic options, most of the available treatments being decades old and suffering from limited efficacy and / or undesirable collateral effects. The use of metal complexes as chemotherapeutic agents against these ailments appears as a very attractive alternative. Although the design of metal complexes with good therapeutic index is still rather empirical, a number of potential metal-based antiparasitic drugs have become available. In this review, advances in the use of metal complexes for the treatment of trypanosomiasis, malaria, and leishmaniasis as important representatives of the general area of tropical diseases is described.

The more significant bioactivities of a variety of semicarbazones (anti-protozoa, anticonvulsant) and thiosemicarbazones (antibacterial, antifungal, antitumoral, antiviral) and their metal complexes are reviewed together with proposed mechanisms of action and structure-activity relationships. Clinical or potential pharmacological applications of these versatile compounds are discussed.

To treat patients suffering from diabetes mellitus, we developed several types of orally active vanadyl complexes to replace painful insulin injections, and prepared them in the form of enteric-coated capsules containing vanadium compounds. Pharmacokinetic analysis demonstrated that these capsules enhance the bioavailability of pharmacologically active vanadyl species.

Most anticancer titanium compounds act against tumors in the gastrointestinal tract. Activity towards breast, lung and skin (melanoma) cancers is shown by some as well. Among their appealing properties is that they do not show common side effects of widely used cytostatic agents such as emesis, alopecia or bone marrow impairment. These features make titanium compounds interesting for combined therapy and further study. This review focuses on two drugs that reached clinical trials, namely, titanocene dichloride and budotitane. We try to integrate the biological fate of the related Ti-cyclopentadienyl and Ti-β-diketonato families of drugs, delineating the structure-activity relationship. We also discuss novel related species with increased solubility for improved drug delivery and some potentially useful polynuclear compounds.

The favourable nuclear properties of copper-67 and rhenium-188 for therapeutic application are described, together with methods for the chemical synthesis of a number of derivatives. Survival from invasive bladder cancer has changed little over the past 20 years. The intravesicular administration of Cu-67 or Re-188 radiopharmaceuticals in the treatment of bladder cancer offers some promise for improvement in this situation.

β-lactam ring-containing compounds such as penicillins, ampicillin, amoxicillin, cephalosporins and carbapenem are among the most famous antibiotics. This article reviews the recent developments in the study of such compounds. The introductory paragraph, which highlights the significance of the subject and cites most of the leading references of the previous century, is followed by an overview of β-lactams and some novel methodologies for the synthesis of bi-, tri- and polycyclic derivatives. The rest of the sections deal with design, synthesis and biological activity of monobactams and carbapenems. Many of them have potential antibacterial activity, even against some resistant strains, and enzyme inhibitory activity.

β-lactam ring-containing compounds such as penicillins, ampicillin, amoxicillin, cephalosporins and carbapenems are among the most famous antibiotics. This article reviews the recent developments in study of cephems, oxacephems, penams and sulbactam. Many of the compounds reviewed have potential antibacterial activity, even against resistant strains such as MRSA, and enzyme inhibitory activity.