Current Medicinal Chemistry - Volume 14, Issue 17, 2007

The endogenous polyamines (spermine, spermidine, and putrescine) are present at relatively high concentrations in the mammalian brain and play crucial roles in a variety of aspects of cell functioning. Stroke is the third most common cause of death and the leading cause of disability among adults in the western world. Brain polyamine levels change dramatically following cerebral ischaemia. Polyamines may be involved in the pathophysiological processes underlying brain ischaemia through several possible mechanisms. These include direct effects on ion channels and receptors modulating potassium, and most importantly calcium trafficking, or through the production of toxic metabolites. Considerable evidence shows that the noncompetitive polyamine antagonists, ifenprodil and eliprodil, are neuroprotective. Interestingly, novel polyamine analogues, such as N1-dansylspermine, BU36b, and BU43b, have also recently been shown to have neuroprotective potential. The exact mechanisms of the neuroprotection afforded by the polyamine antagonists and their clinical applicability is worthy of further study.

One of the outstanding fundamental questions in cancer cell biology concerns how cells coordinate cellular growth (or macromolecular synthesis) with cell cycle progression and mitosis. Intuitively, rapidly dividing cells must have some control over these processes; otherwise cells would continue to shrink in volume with every passing cycle, similar to the cytoreductive divisions seen in the very early stages of embryogenesis. The problem is easily solved in unicellular organisms, such as yeast, as their growth rates are entirely dependent on nutrient availability. Multicellular organisms such as mammals, however, must have acquired additional levels of control, as nutrient availability is seldom an issue and the organism has a prodigious capacity to store necessary metabolites in the form of glycogen, lipids, and protein. Furthermore, the specific needs and specialized architecture of tissues must constrain growth for growth's sake; if not, the necessary function of the organ could be lost. While certainly a myriad of mechanisms for preventing this exist via initiating cell death (e.g. apoptosis, autophagy, necrosis), these all depend on some external cue, such as death signals, hypoxia, lack of nutrients or survival signals. However there must also be some cell autonomous method for surveying against inappropriate growth signals (such as oncogenic stress) that occur in a stochastic fashion, possibly as a result of random mutations. The ARF tumor suppressor seems to fulfill that role, as its expression is near undetectable in normal tissues, yet is potently induced by oncogenic stress (such as overexpression of oncogenic Ras or myc). As a result of induced expression of ARF, the tumor suppressor protein p53 is stabilized and promotes cell cycle arrest. Mutations or epigenetic alterations of the INK4α/Arf locus are second only to p53 mutations in cancer cells, and in some cancers, alterations in both Arf and p53 observed, suggesting that these two tumor suppressors act coordinately to prevent unwarranted cell growth and proliferation. The aim of this review is to characterize the current knowledge in the field about both p53-dependent and independent functions of ARF as well as to summarize the present models for how ARF might control rates of cell proliferation and/or macromolecular synthesis. We will discuss potential therapeutic targets in the ARF pathway, and some preliminary attempts at enhancing or restoring the activity of this important tumor suppressor.

Molecular hybridization is a new concept in drug design and development based on the combination of pharmacophoric moieties of different bioactive substances to produce a new hybrid compound with improved affinity and efficacy, when compared to the parent drugs. Additionally, this strategy can result in compounds presenting modified selectivity profile, different and/or dual modes of action and reduced undesired side effects. So, in this paper, we described several examples of different strategies for drug design, discovery and pharmacomodulation focused on new innovative hybrid compounds presenting analgesic, anti-inflammatory, platelet anti-aggregating, anti-infectious, anticancer, cardio- and neuroactive properties.

The hypoxia-inducible transcription factors (HIFs) are central components in the cellular responses to a lack of O2, i.e. hypoxia. Homologs of the HIF system (HIF-1, -2 and -3) are detectable in all nucleated cells of multicellular organisms. Active HIFs are heterodimers (HIF-α/β). In hypoxia the O2-labile α-subunit is translocated to the nucleus where it binds HIF-β. Over 100 HIF target genes have already been identified. The translational products of these genes increase O2 delivery to hypoxic tissues, such as erythropoietin which stimulates the production of red blood cells, and they adapt cellular metabolism to hypoxia, such as glycolytic enzymes. HIFs are inactive in normoxia because of O2-dependent enzymatic hydroxylation and subsequent degradation of their α-subunit. Three HIF-α prolyl hydroxylases (PHD1, 2 and 3) initiate proteasomal degradation while an asparaginyl hydroxylase (factor inhibiting HIF-1, FIH-1) inhibits the function of the C-terminal transactivation domain of HIF-α. In addition to O2 and 2-oxoglutarate, the HIF-α hydroxylases require Fe2+ and ascorbate as co-factors. Products of glycolysis can act as endogenous inhibitors of HIF hydroxylases which may lead to sustained activation of HIFs in cancer cells. The cofactor requirements define the routes to inhibition of the enzymes when HIF activation is desirable. In particular, 2- oxoglutarate analogues have emerged as promising tools for stimulation of erythropoiesis and angiogenesis (“HIF-stabilizers”). However, as the HIF system promotes the transcription of many genes, and other 2-oxoglutarate dependent dioxygenases are likely to be inhibited by the same analogues, careful evaluation of the inhibitors seems mandatory prior to their clinical use.

Receptor based QSAR methods represent a computational marriage of structure activity relationship analysis and receptor structure based design that is providing valuable pharmacological insight to a wide range of therapeutic targets. One implementation, called Comparative Binding Energy (COMBINE) analysis, is particularly powerful by virtue of its explicit consideration of interatomic interactions between the ligand and receptor as the QSAR variable space. This review outlines the methodological basis for the COMBINE model, contrasts it relative to other 3D QSAR techniques, and discusses sample applications that illustrate recent key innovations. One major development discussed is the rigorous integration of multiple receptors into unified COMBINE models for probing bioactivity trends as a function of amino acid variation across a series of homologous protein receptors, and as a function of conformational variation within one single protein. Other important examples include a recent extension of the method to account for covalent effects arising from ligand binding, as well as successful application of a COMBINE model to high throughput virtual screening. This review concludes with discussions about possible future methodological refinements and their applications, including potential extensions to four-dimensional QSAR, and a potential role of quantum chemistry in addressing covalent bonding effects and parametric adaptivity

Uric acid is the end-product of purine catabolism. Hyperuricaemia is implicated in disorders such as gout and urolithiasis and recent epidemiological evidence suggests an association between increasing uric acid levels and increased cardiovascular morbidity and mortality. A direct causal role remains to be established but recent studies of losartan, atorvastatin and fenofibrate suggest that uric acid reduction contributes to attenuation of cardiovascular risk. Furthermore, several small studies of xanthine oxidase inhibition (the most common method of uric acid reduction) have shown improvements in measures of cardiovascular and endothelial function of a similar magnitude to those of other proven preventative strategies. This review introduces the epidemiological data, discusses strategies to lower uric acid and outlines the available clinical trial data supporting uric acid reduction as a potential and novel method of reducing the burden of cardiovascular disease.

Cigarette smoking plays a major role in the development of atherosclerosis and is associated with increased morbidity and mortality for coronary heart disease, stroke and peripheral vascular disease. In spite of the abundance of epidemiological evidence that links cigarette smoking to vascular disease, the pathologic mechanisms for such interaction are not clear. The endothelium is a major target organ that undergoes activation when exposed to common vascular triggers, including hypertension, hypercholesterolemia, hyperglycaemia and smoking. Changes in endothelial function may lead to a dysfunctional vascular phenotype characterized by anomalous responses of the vascular tone, abnormal endothelial proliferation and prothrombotic activation. Several studies have demonstrated that smoking may alter endothelial function by a direct toxic effect and consequently trigger haemostatic activation and thrombosis. In this article we will review the evidence that loss of normal endothelial function may result in a loss of the balance of the haemostatic system and in changes of the platelet physiology that may be relevant for the pathogenic effect of smoking on the development of atherothrombosis.

1α,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] can exert its biological actions through binding with the nuclear vitamin D receptor (VDR), a ligand-activated transcription factor. Next to control of bone and mineral homeostasis, these actions include an immunomodulatory effect and a potent growth-inhibitory, antiproliferative or prodifferentiating action on a wide variety of cell types. The molecular mechanisms underlying this antiproliferative action form an intriguing research topic and they remain, although thoroughly studied, not completely understood. Important cell cycle regulators are involved such as cyclins, cyclin dependent kinases and their corresponding inhibitors as well as E2F transcription factors and accompanying pocket proteins. Whether 1,25-(OH)2D3 influences the expression of all these proteins directly through the nuclear VDR or rather in an indirect manner is not always clear. The antiproliferative action makes 1,25-(OH)2D3 a possible therapeutic tool to treat hyperproliferative disorders, among which different types of cancer. Clinical application, however, is severely hampered by calcemic effects such as hypercalcemia, hypercalciuria and increased bone resorption. Rational design of chemically modified 1,25-(OH)2D3-analogs tries to overcome this problem. As such, several thousands of analogs have been synthesized and evaluated, some of which display the desired dissociation between beneficial antiproliferative and unwanted calcemic effects. A number of those analogs are ‘superagonistic’ and have a several-fold stronger antiproliferative action than the parent compound. This review focuses on recent findings about the complex mechanisms behind the antiproliferative and prodifferentiating effect of 1,25- (OH)2D3. Furthermore, the mode of action and possible clinical application of chemically modified 1,25-(OH)2D3-analogs will be discussed.