Current Medicinal Chemistry - Volume 9, Issue 2, 2002

Multidrug resistance is one of the main obstacles in the chemotherapy of cancer. Its inhibition by combination of chemosensitizers with antitumor compounds is a very active field of research, since safe and potent reversal agents would be beneficial for clinical use. Most modulators act by binding to membrane transport proteins (specially P-gp and MRP) and inhibiting their drug-effluxing activity, or by indirect mechanisms related to phosphorylation of the transport proteins or expression of the mdr1 and mrp1 genes. The main body of the review focuses on the study of the known MDR modulators, which are classified according to their chemical structures. General structure-activity studies of this therapeutic group are hampered by the very heterogeneous chemical structure of the compounds, although some conclusions have been drawn from the study of homogeneous series of molecules.

Xanthine oxidase (XO) is a highly versatile flavoprotein enzyme, ubiquitous among species (from bacteria to human) and within the various tissues of mammals. The enzyme catalyses the oxidative hydroxylation of purine substrates at the molybdenum centre (the reductive half-reaction) and subsequent reduction of O2 at the flavin centre with generation of reactive oxygen species (ROS), either superoxide anion radical or hydrogen peroxide (the oxidative half-reaction). Many diseases, or at least symptoms of diseases, arise from a deficiency or excess of a specific metabolite in the body. For an example of an excess of a particular metabolite that produces a disease state is the excess of uric acid which can led to gout. Inhibition of XO decreases the uric acid levels, and results in an antihyperuricemic effect. Allopurinol, first synthesised as a potential anticancer agent, is nowadays a clinically useful xanthine oxidase inhibitor used in the treatment of gout. There is overwhelming acceptance that xanthine oxidase serum levels are significantly increased in various pathological states like hepatitis, inflammation, ischemia-reperfusion, carcinogenesis and aging and that ROS generated in the enzymatic process are involved in oxidative damage. Thus, it may be possible that the inhibition of this enzymatic pathway would be beneficial. In this review the State of the Art will be presented, which includes a summary of the progress made over the past years in the knowledge of the structure and mechanism of the enzyme, associated pathological states, and in the efforts made towards the development of new xanthine oxidase inhibitors.

Cytokines and chemokines play a very important role in a number of inflammatory diseases. In activated T cells, transcription factors such as the activator protein-1 (AP-1) regulate IL-2 production and production of matrix metalloproteinases, the nuclear factor kappa B (NF-κB) is essential for the transcriptional regulation of the proinflammatory cytokines IL-1, IL-6, IL-8 and TNFα, and nuclear factor of activated T-cells (NFAT) is required for the transcriptional regulation of IL-2, IL-3, IL-4, IL-5, IL-8, IL-13, TNFα, and GM-CSF. During the last few years, several groups have developed inhibitors of AP-1, NF-κB or both, and NFAT. This review article presents the recent progress in the development of inhibitors for AP-1, NF-κB, and NFAT mediated transcriptional activation.

One of the most interesting groups of substances of marine origin, from structural and pharmacological points of view are polyether toxins, which generally pre-sent a great diversity in size and potent biological activities. The subject of this review is limited to okadaic acid (OA). It was the first example of a group of polyether toxins produced by marine microalgae, which is responsible for the natural phenomena known as Diarrhetic Shellfish Poisoning, DSP red tides. These toxins are accumulated in the digestive glands of the shellfish with a disastrous effect upon the shellfish industry in many parts of the world. Thus, it has been demonstrated that OA is a highly selective inhibitor of protein phosphatases type 1 (PP1) and 2A (PP2A), subsequently that it causes dramatic increases in phosphorylation of numerous proteins as well as being a potent tumour promoter. For that reason, OA is an extremely useful tool for studying the cellular processes that are regulated by reversible phosphorylation of proteins as signal transduction, cell division and memory.

A high proportion (∼40%) of breast cancers are hormone dependent. The female hormones estradiol and androstenediol are believed to play a key role in the initiation and promotion of this disease. In the fight against hormone dependent breast cancers, extensive research has been undertaken to produce compounds which are potent inhibitors against the cytochrome P-450 enzyme aromatase (AR), which converts the C19 androgens to the C18 estrogens. However, the administration of AR inhibitors alone has failed to produce the expected decrease in plasma levels of estrone. The major impetus to the development of steroid sulfatase inhibitors has therefore been the realisation that in order to improve therapeutic response for women with hormone-dependent breast cancer, not only must the AR enzyme be inhibited, but also the synthesis of estrogens via alternative routes. The steroid sulfatase enzyme regulates the formation of estrone (which can subsequently be converted to the potent estrogen estradiol) from estrone sulfate, a steroid conjugate present in high concentrations in tissue and blood in women with breast cancer. The sulfatase enzyme system also controls the formation of dehydroepiandrosterone (DHEA) from the DHEA-sulfate. This is important since DHEA can be converted to 5-androstene-3β,17β-diol, which possesses estrogenic properties capable of stimulating the growth of breast cancer cells in vitro and in vivo. Considerable progress has been made in recent years in the development of a number of potent steroid / estrone sulfatase inhibitors, as such both steroidal and non-steroidal compounds have been considered and a number of highly potent inhibitors have been produced and evaluated against what is now considered a crucial enzyme in the fight against hormone dependent breast cancer. The review therefore considers the work that has been undertaken todate, as well as possible future development with respect to ‘dual inhibitors’ of both estrone sulfatase and AR.

A large number of techniques have been applied to monitor the function of free metal ions in biological systems. Fluorescent ion probes have evolved into an extremely useful tool for contemporary experimentalists. Polycarboxylate indicators are widely used in the determination of metal ion concentrations, especially due to their cell membrane permeability. The design of these probes required detailed knowledge in related fields of medicine, biology, and chemistry, and their preparation demanded the expertise of organic synthesis. In this review, the basic rationale for the selection of particular chemical structures are analyzed, synthetic pathways leading to the desired structures are presented, often via a retrosynthetic approach, and properties and relative advantages of the use of these probes are described. References to specific applications are limited, given the large number of reviews on related subjects. Topics such as those related to dextran conjugates that are broad enough to be the subject of a different review are not included, and leakage resistance and near-membrane probes are mentioned briefly in separate sections, although these are chemically similar to typical polycarboxylate dyes. While reference to topics mentioned in related reviews is unavoidable, presentation of material in this review is from the point of view of a medicinal chemist rather than that of the many experts using these pioneering techniques.