Current Medicinal Chemistry - Volume 16, Issue 9, 2009

MicroRNAs (miRNAs) are small non-protein-coding RNA that negatively control mRNA expression at a posttranscriptional level. They regulate various cellular functions and bioinformatic data suggest that they collectively control about 30% of human mRNAs. MiRNAs have been recently implicated in several carcinogenic processes, where they can act either as oncogenes or as tumor suppressors. This is the case in lung cancer, i.e. the leading cause of cancer deaths in Western countries, in which about 40-45 miRNAs have been found to be aberrantly expressed, thereby constituting a specific miRNA signature. Some of these miRNAs can play an important role in lung carcinogenesis. Indeed, some transcripts of the let-7 family that are significantly down-regulated in lung tumors have been identified as tumor suppressors through their ability to control several oncogenic pathways, including the RAS pathway. Identification of a growing number of other potential oncogenic or tumor suppressor miRNAs in lung cancers is in constant progress. Recent evidence supports the use of specific miRNA signatures to predict clinical outcome. This review aims to report the current knowledge about the role of miRNAs in lung cancer carcinogenesis, their potential for improving diagnosis and prognosis and their impact on future therapeutic strategies.

Chalcones are a group of plant-derived polyphenolic compounds belonging to the flavonoids family and possess a wide variety of cytoprotective and modulatory functions. The results showed that chalcones inhibit the proliferation of MCF-7 and MDA-MB-231 by inducing apoptosis and blocking cell cycle progression in the G2/M phase. Immunoblot assay showed that chalcones significantly decreased the expression of cyclin Bl, cyclin A and Cdc2 protein, as well as increased the expression of p21 and p27 in a p53-independent manner, contributing to cell cycle arrest. In this research we tried to review the anticancer effect of chalcones derivatives, and to evaluate new QSARs which will help in the understanding of the role of chalcones and of their analogues on cancer. Simultaneously a comparative study will be presented. Our QSAR results reveal that in almost all cases, the clog P parameter plays an important part in the QSAR relationships (linear or bilinear model). In some cases the steric factors such as the CMR or the substituents MR (linear) are important. Electronic effects are comparatively unimportant. The study shows that log P as calculated from the Clog P program is suitable for this form of QSAR study.

Pharmacologic blockade of β-adrenergic receptors is a frequent therapeutic intervention in critically ill patients. Today's strategies predominantly include the treatment of cardiovascular diseases like hypertension and cardiac arrhythmias. Furthermore, β-adrenergic antagonists are routinely used to prevent the catecholamine-induced hypermetabolism in critically ill patients suffering from severe burn injury. In addition to these well known beneficial effects of β-adrenoceptor blocking agents it has been demonstrated, that the adrenergic system is involved in the modulation of cellular immune functions. Therefore, the immunomodulatory properties of β-adrenergic antagonists have been established during the last years and the scientific focus was addressed on the proposed immunologic side effects of a β-adrenergic blockade and its potential effect on the clinical course of critical illness. This manuscript reviews the rational and the effect of the therapeutic use of β-adrenergic antagonists in critically ill patients on the base of the current literature and further emphasizes on potential immunologic side effects.

Macrophage migration inhibitory factor (MIF), the pro-inflammatory cytokine, first described in 1966, plays an essential role in both, innate and adaptive immune response. It has been implicated in tumour growth and angiogenesis and it exerts an antagonistic action against glucocorticoid immunosuppressive effect. Its perplexing enzymatic tautomerase activity has attracted considerable interest in the last decade. It has been suggested, that a multitude of autoimmune/ inflammatory/neoplastic disease states might benefit from therapeutic measures, targeting MIF. Hence, small molecule inhibitors of MIF are relentlessly sought as potential anti-inflammatory (antitumour) agents, while a true in vivo substrate for MIF still remains unidentified. One of the first studied MIF inhibitor group was the D-dopachrome family, and its carboxyderivatives have shown good inhibitory effect, as well as the fluorosubstituted phenylpyruvic acid class. The substance ISO-1 of isoxazoline skeleton was the first small molecular inhibitor of MIF, not related to its known substrates. N-acetyl-p-benzoquinone, an acetaminophen metabolite and its synthetic derivatives exerted submicromolar IC50 values. An acetylenic compound, the 2-oxo-4-phenyl-3-butynoate is a potent active-site-directed irreversible inhibitor of the phenyl pyruvate tautomerase activity of MIF. Some oxygen heterocycles, coumarines and chromenes, have also drawn attention as MIF inhibitors. The α,β-unsaturated carbonyl compounds constitute a large novel class of MIF inhibitors. Several potent inhibitors were found among the cinnamic acid derivatives, the α,β-unsaturated cyclic ketones, and the natural curcuminoids. Some other plant derived compounds were also studied. One of the latest developments in the field is the synthesis of AVP-13546, an exceptionally potent inhibitor. The structural pattern of MIF enzyme inhibitors exhibits wide variety; compounds having quite different molecular backbones belong to the MIF inhibitor family. In this paper, the separate classes of MIF inhibitors are discussed.

Chronic hepatitis C affects 130,000,000 people worldwide. Hepatitis C virus (HCV) is a single-strand RNA virus responsible for most cases of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma (HCC) in the Western world. The gold standard for the treatment of chronic hepatitis C (combination of pegylated-interferon α and ribavirin) results in a sustained virological response (namely, clearance of serum HCV RNA 6 months after therapy withdrawal) in only about half treated patients. Therefore, there is a race to develop new drugs for the treatment of HCV infection. One of the most promising approaches is to use protease inhibitors, i.e. drugs inhibiting NS3/NS4A HCV protease, which plays a crucial role in the viral life cycle. Telaprevir (VX-950) is the protease inhibitor in the most advanced phase of clinical testing. Telaprevir is orally available and when used in monotherapy it induced a median decline of 4 logs of HCV RNA after two weeks of therapy. However, mutants with a lower sensitivity to telaprevir have been demonstrated in a high proportion of patients within 14 days of monotherapy. The drug has been used in clinical trials in combination with pegylatedinterferon and ribavirin. This triple combination resulted in a higher rate of SVR but also in a higher rate of side effects (rash, gastrointestinal disorders, and anemia) than standard treatment. This review focuses on the mechanism of action, pharmacokinetics, clinical efficacy, and tolerability of telaprevir, and on possible use of this drug in combination with other drugs for the treatment of HCV infection.

Cyclodepsipeptides show an interesting spectrum of biological activity. Members of this new class of potential drugs may also serve as lead compounds for more pharmacologically potent and toxicologically safe derivatives. Some of these natural products and (semi-)synthetic derivatives have already been evaluated in clinical trials. A common feature of cyclodepsipeptides is their ionophoric properties. However, their pharmacologically relevant action does not seem to correlate with this feature; rather it is based on interactions with distinct cellular compartments and signal transduction pathways. Cyclodepsipeptides, which are currently being evaluated in clinical trials, are used in refractory cancer therapy, usually in combination with other cytotoxic drugs. A series of cyclooctadepsipeptides, however, shows a completely different spectrum of biological activity, namely, potent anthelmintic properties. A number of cyclodepsipeptides have been well characterized in vitro and in vivo, and interesting modes of action, such as antiplasmodial, antiviral, insecticidal, cytotoxic, and antiproliferative properties have been observed. Whether these natural products will be of benefit for patients must be evaluated in clinical trials. Recently, a number of cyclodepsipeptides from marine sponges, bacteria and fungi have been identified. Subsequent structural determination revealed unique structural features within some of these compounds. It was suggested that the cyclic depsipeptide structure is important for the biological activity because the linear homologues were inactive. The scope of activity of these newly isolated natural products spans a range from cytoprotective activity against HIV-1 infection, growth inhibitory effects toward cancer cells, and antimycobacterial, and antimalarial activity.

Substantial body of data generated from cultured bone cells and rat models of osteoporosis supports a significant bone-conserving effect of phytochemicals. Flavonoids including isoflavones, stilbenes and lignans with variable efficacy have shown promising therapeutic application in osteoporosis. Majority of the phytochemicals assessed for their effects on bone cells revealed multiple beneficial actions such as promoting osteoblast functions, and inhibiting osteoclast and adipocyte functions. A variety of molecular targets mediate multiple effects of phytochemicals in bone cells. In vivo, quite a few phytochemicals have been found to afford bone-sparing effect and in some cases even bone restoring effect. However, important pharmacokinetic and bioavailaibility studies associated with these phytochemicals are mostly lacking. As a result, translating these findings to the clinic has been challenging, and so far only a few clinical studies have attempted to evaluate the effect of phytochemicals in menopausal osteoporosis. Clinical studies so far performed are with dietary supplements rather than pure phytochemicals. Clinical trials with pure molecules necessitate preclinical regulatory and safety studies that are not available with the phytochemicals except ipriflavone with bone-conserving properties. Ipriflavone is the only marketed anti-osteoporosis agent that was obtained following a lead from natural substance. As phytochemicals have multiple beneficial influences on bone cells, making analogues of the most potent molecule for developing synthetic series with rational drug design approach could pay rich dividends in menopausal osteoporosis therapy.

Canonical transient receptor potential (TRPC) channels are Ca2+-permeable non-selective cation channels, which on stimulation allow influx of Na+ and Ca2+ ions into cells. It is proposed that stimulation of TRPC conductances by neurotransmitters and hormones such as noradrenaline, angiotensin II and endothelin-1 have important functions in vascular smooth muscle cells including vasoconstriction, cell growth and proliferation. Moreover constitutive TRPC activity contributes to setting the resting membrane potential of vascular myocytes. Activation of TRPC channels is thought to provide a direct Ca2+ influx pathway and evoke indirect Ca2+ entry by inducing depolarisation and opening of voltagegated Ca2+ channels and by stimulating the reverse mode of the Na+/Ca2+ exchanger. Therefore identification of native TRPC channel proteins, which underlie these mechanisms, will provide important information on physiological functioning of vascular tissue and these conductances are pharmacological targets for the prevention of cardiovascular diseases such as hypertension. This review focuses on different experimental approaches that have been used to elucidate the molecular identity of TRPCs in native vascular myocytes. It will discuss the advantages and problems associated with using siRNA and antisense technologies in primary cell cultures, cell lines and transgenic mice models. In addition we describe recent work, which combines studies on the effect of anti-TRPC antibodies and pharmacological agents on biophysically characterised single cation channel currents to identify TRPC channel proteins in freshly dispersed vascular myocytes. These data provide strong evidence that native vascular myocytes contain diverse TRPC-mediated channels which are usually composed of complex heterotetrameric structures possessing marked pharmacological differences.

The goal of cancer chemotherapy with classical drugs - the destruction of the tumor cells - is often complicated by significant toxicity. As an alternative, induced differentiation modulates the cell programme by transforming malignant cells into mature cells with no proliferative potential. Our data demonstrate that (+/-)-1-{[3-(2-hydroxyethoxy)-1- isopropoxy]propyl}-5-fluorouracil inhibits proliferation, induces myogenic differentiation, increases the expression of proteins specifically present in normally differentiated skeletal muscle cells, and modifies the adhesion capacity of these cells against the rhabdomyosarcoma cell line RD. From a designing point of view, a benzene ring was fused to the side chain in order to increase the lipophilicity and anticancer activity of our molecules. Herein we report the preparation and biological activity of three compounds having the general formula (+/-)-1-[2-(5-substituted-2-hydroxybenzyloxy)-1- methoxyethyl]-5-fluorouracils. A catechol-derived compound such as (+/-)-1-[3-(2-hydroxyphenoxy)-1-methoxypropyl]- 5-fluorouracil and two salicyl-derived compounds such as (+/-)-(Z)-1-[4-(2-hydroxyphenyl)-1-methoxy-but-3-enyl]-5- fluorouracil [(Z)-43] and its dihydrogenated derivative (+/-)-1-[4-(2-hydroxyphenyl)-1-methoxybutyl]-5-fluorouracil were prepared to complete the set of six O,N-acetals. The most active compound against the MCF-7 breast cancer cell line was (+/-)-(Z)-43 with an IC50 = 9.40 ± 0.64 μM. Differentiated breast cancer cells generate fat deposits within the cytoplasm. The MCF-7 cells treated with (+/-)-(Z)-43 caused an increase in the lipid content over control cells after 3 days of treatment. Our results suggest that there may be significant potential advantages in the use of this new differentiating agent for the treatment of breast cancer.