Mini Reviews in Medicinal Chemistry - Volume 9, Issue 9, 2009

This review describes, briefly, the characteristics and regulation of glycogen synthase kinase 3 (GSK3) together with the role of GSK3 dysfunctions in different pathologies, and GSK3 as target for therapeutic treatment in different diseases. Several GSK3 inhibitors acting at different levels are described in this work, ranging from cations like lithium to small compounds developed by different pharmaceutical companies. Also, the use of specific interference RNA (iRNA) for the specific inhibition of the expression of the different GSK3 isoforms is discussed.

The cardioprotective effects of food rich in omega-3 (ω-3) polyunsaturated fatty acids (PUFA) on cardiovascular risk has been of interest from the moment when a low rate of coronary heart disease was documented in the Eskimo population. The aim of the present review is to discuss recent studies documenting multidirectional action of ω-3 PUFA due to its pleiotropic properties. Experimental studies in cellular and animal models have extensively documented the favorable effects of ω-3 PUFA (eicosapentaenoic acid and docosahexaenoic acid) on: inflammatory processes, endothelial dysfunction, platelet aggregation and arrhythmogenesis. It was reported that antiarrhythmic effects of ω-3 PUFA resulted from stabilization of cardiomyocyte membrane and inhibition of ion channels. Moreover, PUFA possess several pleiotropic properties i.e. anti-inflammatory, anti-atherogenic and antithrombotic. Anti-atherogenic effects (plaque stabilization) of ω-3 PUFA have recently been demonstrated. It was documented (OCEAN study) that eicosapentaenoic acid from a source of highly purified ethyl esters is incorporated into plaques in a relatively short period of time and these higher concentrations of ω-3 PUFA may stabilize vulnerable atherosclerotic plaques. The anti-inflammatory effect of ω-3 PUFA is associated with reduction of levels of TNF-α and interleukin-6. Eicosapentaenoic acid and docosahexaenoic acid inhibit arachidonic acid metabolism to inflammatory eicosanoids.

This review covers existing literature (from 1990 to 2008) on landomycins (LS), a family of glycosylated angucyclines, with an emphasis on the bioactivity scope of landomycin (La)-like structures accessible via biocombinatorial manipulations. Some LS display strong antitumor activity and have inspired several chemical studies focused mainly on their unusual deoxysugar chains. A decade of genetic studies on La-producing bacteria has provided many novel molecules with altered structure and activity. A complex nonlinear correlation between the length of the carbohydrate tail of LS and their antitumor activity has also been revealed. It implies that simpler LS than the largest member of the family, LaA, are still potential drug leads. Combinatorial biosynthesis appears to be a powerful tool to search the chemical space around the La scaffold.

Paget's disease of bone is a focal skeletal disorder characterized by the formation of structurally abnormal bone, deformity and other complications leading to significant disability and bone pain. Recently, the availability of newer, more potent nitrogen-containing bisphosphonates has improved treatment outcomes, allowing a more effective and convenient management of this disorder.

The relevance of tumor markers in clinical diagnosis of cancer has given rise to the development of new approaches based on the use of nanoparticles to improve the features of the immunoassays developed for their control. This article reviews the usefulness of different nanoparticles to develop direct, sandwich and competitive assays for the individual and multiplexed determination of these compounds.

The present review after providing a short overview on PPARs and their pleiotropic action focuses on the QSAR studies reported mainly for PPAR-γ agonists. The different 3D and 2D QSAR models are discussed, their impact in better understanding of the mechanism of action is analyzed and their contribution in the design of new molecules is outlined.

To develop new and more efficient anti-cancer strategies it will be important to characterize the products of transcription factor activity essential for tumorigenesis. One such factor is hypoxia-inducible factor-1α (HIF-1α), a transcription factor induced by low oxygen conditions and found in high levels in malignant solid tumors, but not in normal tissues or slow-growing tumors. In fast-growing tumors, HIF-1α is involved in the activation of numerous cellular processes including resistance against apoptosis, over-expression of drug efflux membrane pumps, vascular remodeling and angiogenesis as well as metastasis. In cancer cells, HIF-1α induces over-expression and increased activity of several glycolytic protein isoforms that differ from those found in non-malignant cells, including transporters (GLUT1, GLUT3) and enzymes (HKI, HKII, PFK-L, ALD-A, ALD-C, PGK1, ENO-α, PYK-M2, LDH-A, PFKFB-3). The enhanced tumor glycolytic flux triggered by HIF-1α also involves changes in the kinetic patterns of expressed isoforms of key glycolytic enzymes. The HIF-1α induced isoforms provide cancer cells with reduced sensitivity to physiological inhibitors, lower affinity for products and higher catalytic capacity (Vmaxf) in forward reactions because of marked over-expression compared to those isoforms expressed in normal tissues. Some of the HIF1α-induced glycolytic isoforms also participate in survival pathways, including transcriptional activation of H2B histone (by LDH-A), inhibition of apoptosis (by HKII) and promotion of cell migration (by ENO-α). HIF-1α action may also modulate mitochondrial function and oxygen consumption by inactivating the pyruvate dehydrogenase complex in some tumor types, or by modulating cytochrome c oxidase subunit 4 expression to increase oxidative phosphorylation in other cancer cell lines. In this review, the roles of HIF-1α and HIF1α- induced glycolytic enzymes are examined and it is concluded that targeting the HIF1α-induced glucose transporter and hexokinase, important to glycolytic flux control, might provide better therapeutic targets for inhibiting tumor growth and progression than targeting HIF1α itself.

ATP binding cassette transporters are implicated in multidrug resistant phenotypes of tumor cells and may be cancer stem cell markers. Inhibitors of drug efflux pumps represent an emerging group of potentially useful agents for the improvement of antitumor therapy. Here we provide an overview of drug transporter functions and modulation.

Hyperandrogenic disorders are frequent in women. The most common cause is polycystic ovary syndrome, a condition found up to 7% in women of reproductive age. The effects of testosterone and dihydrotestosterone are elicited via androgen receptors. Androgen receptor acts as a ligand-dependent transcription factor that regulates the expression of several target genes. There are several pharmacological possibilities for the treatment of androgen excess, as inhibition of the biologic activity of androgens can be carried out at different levels. The androgen receptor, the 5α-reductase enzyme, and the hypothalamic-pituitary-gonad axis are the most frequent targets of antiandrogenic therapies. This review summarizes the structural and chemical features of currently available antiandrogenic drugs, including cyproterone acetate, spironolactone, flutamide and finasteride. Also, it presents some recent advances in the chemistry and pharmacology of novel steroidal and non-steroidal antiandrogens, and 5α-reductase inhibitors. Finally, recent knowledge on non-classical antiandrogenic drugs, such as insulin-sensitizers, ketoconazole, and GnRH-agonists are briefly discussed.

The neutralization of VEGF is the current treatment of choice for age-related macular degeneration. Current approaches include anti-VEGF-antibodies and -Fab Fragments, aptamers, soluble receptors (Traps) and siRNA. The molecular properties of VEGF and its antagonists are reviewed and the pathways of action of these substances are discussed.

Iron is essential for human life, however it can be toxic through Fe ability to generate oxygen-derived radicals. This work reviews the main features of Fe binding in the cell and its association to these processes. The chemical nature of the Fe extracted by chelation therapy in pathophysiological situations is also analyzed.