Current Medicinal Chemistry - Volume 10, Issue 6, 2003

Hydroxyurea is used to treat a variety of cancers and sickle cell disease. Despite this widespread use, a complete mechanistic understanding of the beneficial actions of this compound remains to be understood. Hydroxyurea inhibits ribonucleotide reductase and increases the levels of fetal hemoglobin, which explains a portion of the effects of this drug. Administration of hydroxyurea to patients results in a significant increase in levels of iron nitrosyl hemoglobin, nitrite and nitrate suggesting the in vivo metabolism of hydroxyurea to nitric oxide. Formation of nitric oxide from hydroxyurea may explain a portion of the observed effects of hydroxyurea treatment. At the present, the mechanism or mechanisms of nitric oxide release, the identity of the in vivo oxidant and the site of metabolism remain to be identified. Chemical oxidation of hydroxyurea produces nitric oxide and nitroxyl, the one-electron reduced form of nitric oxide. These oxidative pathways generally proceed through the nitroxide radical (2) or C-nitrosoformamide (3). Biological oxidants, including both iron and copper containing enzymes and proteins, also convert hydroxyurea to nitric oxide or its decomposition products in vitro and these reactions also occur through these intermediates. A number of other reactions of hydroxyurea including the reaction with ribonucleotide reductase and irradiation demonstrate the potential to release nitric oxide and should be further investigated. Gaining an understanding of the metabolism of hydroxyurea to nitric oxide will provide valuable information towards the treatment of these disorders and may lead to the development of better therapeutic agents.

The 17β-hydroxysteroid dehydrogenases (17β-HSDs) play an important role in the regulation of steroid hormones, such as estrogens and androgens, by catalysing the reduction of 17-ketosteroids or the oxidation of 17β-hydroxysteroids using NAD(P)H or NAD(P)+ as cofactor. The enzyme activities associated with the different 17β-HSD isoforms are widespread in human tissues, not only in classic steroidogenic tissues, such as the testis, ovary, and placenta, but also in a large series of peripheral intracrine tissues. In the nineties, several new types of 17β-HSD were reported, indicating that a fine regulation is carried out. More importantly, each type of 17β-HSD has a selective substrate affinity, directional (reductive or oxidative) activity in intact cells, and a particular tissue distribution. These findings are important for understanding the mode of action of the 17β-HSD family. From a therapeutic point of view, this means that selectivity of drug action could be achieved by targeting a particular 17β-HSD isozyme. Consequently, each study that leads to better knowledge of the inhibition of 17β-HSDs deserves attention from scientists working in this and related fields. Being involved in the last step of the biosynthesis of sex steroids from cholesterol, the 17β-HSD family constitutes an interesting target for controlling the concentration of estrogens and androgens. Thus, inhibitors of 17β-HSDs are useful tools to elucidate the role of these enzymes in particular biological systems or for a therapeutic purpose, especially to block the formation of active hydroxysteroids that stimulate estrogeno-sensitive pathologies (breast, ovarian, and endometrium cancers) and androgeno-sensitive pathologies (prostate cancer, benign prostatic hyperplasia, acne, hirsutism, etc). Few review articles have however focussed on 17β-HSD inhibitors although this family of steroidogenic enzymes includes interesting therapeutic targets for the control of several diseases. Furthermore, inhibitors of 17β-HSDs constitute a growing field in biomedical research and there is a need for an exhaustive review on this topic. In addition to giving an up-to-date description of inhibitors of all 17β-HSD isoforms (types 1-8), the present review will also address, when possible, the isoform selectivity and residual estrogenic or androgenic activity often associated with steroidal inhibitors.

In cells, protein degradation is a key pathway for the destruction of abnormal or damaged proteins as well as for the elimination of proteins whose presence is no longer required. Among the various cell proteases, the proteasome, a multicatalytic macromolecular complex, is specifically required for the degradation of ubiquitinated proteins. In normal cells, the proteasome ensures the elimination of numerous proteins that play critical roles in cell functions throughout the cell cycle. Defects in the activity of this proteolytic machinery can lead to the disorders of cell function that is believed to be the root cause of certain diseases. Indeed, many proteins involved in the control of cell cycle transitions are readily destroyed by the proteasome once their tasks have been accomplished. Moreover, because proteasome inhibitors can provoke cell death, it has been suggested that proteasomes must be continually degrading certain apoptotic factors.For these reasons, proteasome inhibition has become a new and potentially significant strategy for the drug development in cancer treatment. The proteasome possesses three major peptidase activities that can individually be targeted by drugs. Different classes of proteasome inhibitors are reviewed here. In addition, we present new pseudopeptides with the enriched nitrogen backbones bearing a side chain and a modified C-terminal position that inhibit proteasome activity.

The β-propeller fold appears as a very fascinating architecture based on four-stranded antiparallel and twisted β-sheets, radially arranged around a central tunnel. Similar to the α / β-barrel (TIM-barrel) fold, the β-propeller has a wide range of different functions, and is gaining substantial attention. Some proteins containing β-propeller domains have been implicated in the pathogenesis of a variety of diseases such as cancer, Alzheimer, Huntington, arthritis, familial hypercholesterolemia, retinitis pigmentosa, osteogenesis, hypertension, and microbial and viral infections. This article reviews some aspects of 3D structure, amino acids sequence regularities, and biological functions of the proteins containing β-propeller domains. Major emphasis has been laid on β-propellers whose functions are associated to human diseases. Recent research efforts reported in the fields of protein engineering, drug design, and protein structure-function relationship studies, concerning the β-propeller architecture, have also been discussed.