Current Medicinal Chemistry - Volume 17, Issue 3, 2010

Curcumin, commonly called diferuloyl methane, is a hydrophobic polyphenol derived from rhizome (turmeric) of the herb Curcuma longa. Extensive research over the last half century has revealed important functions of curcumin. In vitro and in vivo research has shown various activities, such as anti-inflammatory, cytokines release, antioxidant, immunomodulatory, enhancing of the apoptotic process, and anti-angiogenic properties. Curcumin has also been shown to be a mediator of chemo-resistance and radio-resistance. The anti-cancer effect has been seen in a few clinical trials, mainly as a native chemoprevention agent in colon and pancreatic cancer, cervical neoplasia and Barrets metaplasia. Some clinical studies with healthy volunteers revealed a low bioavailability of curcumin, casting doubt on the use of curcumin only as food additive. Our clinical experience with curcumin, along with the anti-metabolite gemcitabine in the treatment of patients with advanced pancreatic carcinoma, produced an objective response in less than 10% of patients, with a minor effect on survival. However, the safety of this combination was proved. Curcumin's potent anti-proliferative activity interacting with several intracellular signal transduction pathways may potentiate the anti-tumor effect of gemcitabine. The preclinical data lead to various, but still scarce, clinical studies (some on-going) that demonstrated the possible efficacy of this treatment as a chemopreventive or chemotherapeutic agent. This review will focus on the clinical evidence, including our experience with curcumin as a chemopreventive and therapeutic agent and the in vitro background results.

Amyloid beta (Aβ) is the main component of one of the major pathological hallmarks of Alzheimer's disease and is generally considered as one of the earliest factors that induce the pathogenic cascade. Aβ is produced from a larger precursor protein through proteolytic cleavage by secretase activities, which results in fragments that differ in size depending on the cleavage site used to create the C-terminus. In addition, heterogeneity at the N-terminus is created by proteases/ peptidases. Moreover, various amino acid modifications further enhance the heterogeneity of Aβ that accumulates in Alzheimer brain. All these species with their different N-and with or without modifications have different aggregation properties. Aβ requires an aggregated state to be pathogenic and the exact aggregation state is a major determinant of the cellular effects of Aβ: smaller oligomeric aggregates are more neurotoxic, whereas large fibrillar aggregates are generally more associated with a glial response. It is therefore increasingly clear that Aβ is not a single entity, but a peptide with multiple molecular appearances. In this review we will discuss the mechanisms leading to the generation of the different Aβ species and their involvement in Alzheimer pathogenesis. This will be discussed in the framework of therapeutic approaches that target one of the steps in the biogenesis of toxic Aβ species: inhibition of the formation of Aβ, inhibition of aggregation and stimulation of its degradation or clearance.

Background: Homocysteine (Hcy) exerts multiple neurotoxic mechanisms that have been linked to the pathogenesis of neurodegenerative disorders. Several studies observed elevated plasma Hcy levels in Parkinson's Disease (PD) patients treated with L-dopa, compared to healthy controls and to patients with other neurodegenetative disorders. Objective: We performed an overview of published evidences assessing the possible correlations between Hcy levels and the incidence or pathogenesis of PD. Methods: A Medline literature search was performed to identify all available studies on Hcy and the incidence or pathophysiology of PD up to 30/09/2009. Results: 30 studies were included in this overview (20 studies on humans, 10 experimental studies). The relationship between metilentetrahydrofolate-reductase genotype (the most common genetic cause of hyperhomocysteinemia) and the development of PD was contradictory. Dietary patterns and B-vitamins levels (important determinants of Hcy levels) were associated with a not-significant increased risk of PD in three prospective studies. Investigations on plasma and cerebrospinalfluid Hcy concentrations in L-dopa naive PD patients gave conflicting results; some studies observed increased Hcy levels in L-dopa naive PD patients compared to controls, while others found no difference. In vitro, Hcy caused dosedependent depletion of dopaminergic mesencephalic neurons, by numerous pathogenetic mechanisms. In vivo brain administration of Hcy induced motor and behavioural changes, similar to those observed in animal models of PD. Conclusions: Based on the available data, the possibility that the hyperhomocysteinemia may contribute to the pathogenesis of PD remains uncertain. L-dopa treatment represents the major determinant of the hyperhomocysteinemia observed in PD.

The transmission of genetic information relies on a coordinated network of cell cycle controls. Abnormalities in this network can result in genomic instability and lead to the transformation of normal cells into cancer cells. Chromosomal DNA replication is not only central to cellular division but also plays a crucial role in the maintenance of genomic integrity. DNA replication errors increase genetic instability, and may be a causative factor in diseases such as cancer and neuronal disorders. Replication in eukaryotes initiates from discrete genomic regions, termed origins, according to a strict, often tissue-specific, temporal program. The genetic program that controls activation of replication origins in mammalian cells has still not been elucidated. There is evidence that specification of replication sites and timing of replication are dynamic processes that are regulated by tissue-specific and developmental cues and that are responsive to epigenetic modifications. Here, we focus on the spatiotemporal regulation of DNA replication in the human genome. There is growing evidence that chromosome band patterns and epigenetic transformation of chromatin influence the timing of replication. On the basis of this evidence, we propose that the chromatin regions showing switches in replication timing from early to late in S phase are correlated with chromosome band boundaries. These chromatin regions generally display transitions in GC contents and include more non-B-form DNA structures than other genomic regions. We also examine here the effect of changes in replication timing on genomic stability and the possible role of replication timing in the etiology of diseases such as cancer. Replication timing assays are one of many promising techniques under investigation that may in future allow much earlier cancer detection than is possible today.

Staurosporine, pyridone 6 and hydroxyfasudil are cyclic amide (pyridone/lactam) moiety containing heterocycles that are discovered/developed as potent protein kinase inhibitors targeting on the ATP (Adenosine-5'-triphosphate) binding pocket. Despite different molecular shapes (pentacycle, tetracycle and bicycle, respectively), they all bind to the residues of the hinge region at ATP binding pocket of protein kinases in a very similar manner: the cyclic amide moiety occupies the adenine region of ATP binding pocket and forms at least two hydrogen bonding interaction with the hinge region via its hydrogen bond acceptor/donor pair. Using a few examples of cyclic amide (pyridone/lactam) moiety containing heterocyclic protein kinase inhibitors, this review discusses their therapeutic application, structural basis of kinase inhibition, as well as their associated syntheses. It is anticipated that the design, synthesis and profiling of the kinasebiased library based upon the cyclic amide (pyridone/lactam) moiety containing core scaffolds may significantly enhance the efficiency of high-throughput screenings (HTS), accelerate hit-to-lead process and improve the success rate in the development of protein kinase inhibitors for the treatment of various diseases especially cancer.

Angiogenesis plays an important role in the pathogenesis of inflammatory diseases, including rheumatoid arthritis (RA). The site and extent of inflammation and subsequent joint destruction in the rheumatoid synovium is dependent on the development of new vasculature. Inhibition of angiogenesis, extensively studied in cancer, might therefore be of interest as treatment option for RA. Hypoxia-inducible factor-1 (HIF-1) has been reported to play a critical role in the regulation of hypoxia driven angiogenesis. HIF-1 is a transcription factor that is constitutively expressed in many cells. It gains transcriptional activity in hypoxic cells leading to the expression of genes involved in angiogenesis. The synovium is hypoxic, but also in an inflammatory environment such as seen in RA, inflammatory cytokines may be important inducers of HIF-1 expression and/or activation. Many drugs currently used in the treatment of RA have anti-angiogenic effects, which are exerted at different levels. Blocking of TNF-α, for instance, reduces TNF-α induced VEGF production. Studies aiming at direct inhibition of proangiogenic factors, such as inhibiting VEGF- or FGF-receptor signalling or blocking VEGF by monoclonal anti-VEGF antibody therapeutics, are in progress. Inhibition of HIF-1 expression or activation, either by blocking signal transduction pathways leading to HIF-1 induction or by inhibiting accumulation of HIF -1 protein, represents a new strategy, which is of interest for the treatment of RA. This review will concisely summarize the general knowledge on the molecular control of gene expression by HIF-1, its involvement in RA, and potential for therapeutic intervention at the level of HIF-1 activity.

In recent years, phosphonic acids and their derivatives have received increasing attention as analogues of a series of naturally occurring phosphates and as “bio-isosteric phosphorus analogues” of aminoacids. Unlike a phosphate group, the phosphonate moiety is not readily hydrolyzed, in a biological environment, by the enzymes involved in the phosphate cleavage. This feature makes these compounds extremely useful in several applications, in metabolic regulation, in enhancement or inhibition studies, in the development of potential drugs against several metabolic disorders. The great potential of these compounds in biological applications resulted in an intense effort directed to the development of efficient synthetic methods for their preparation, with particular attention to stereoselective synthesis. The purpose of this review is to give an up-to-date account of the chemistry, the synthesis and the biological activity of aminophosphonic acids and their derivatives.