Current Medicinal Chemistry - Volume 19, Issue 18, 2012

The first review regarding the potential of aurones as promising drug candidates was reported in 2003. Since, considerable efforts have been made to explore the pharmacological and therapeutical activities of aurones. In this regard, many biological areas were concerned, including major pathological, such as cancer and neurodegenerative disorders. The aim of the present report is to highlight the progress made during the last ten years on the medicinal chemistry of aurones. A special focus will be made on the structure-activity relationship aspects among aurones and especially in case where aurones were found highly active than the corresponding flavones and chalcones.

Extensive research within the last two decades revealed that most chronic illnesses, including cancer, neurological, autoimmune and cardiovascular diseases are mediated through chronic inflammation. Thus, suppressing chronic inflammation has the potential to delay, prevent, and treat those diseases. However, side effects and high costs of current anti-inflammatory drugs force the development of new drugs. Natural products represent an important source of new bioactive compounds. Among them, phenolic compounds, which are widely distributed in plants, have been described as having many therapeutic effects. Several reviews have addressed the anti-inflammatory activity of phenols, attributing their properties not only to the antioxidant capacity, but also to inflammatory mediators’ modulation, namely cytokines and pro-inflammatory proteins, such as inducible nitric oxide synthase and cyclooxygenase-2. Signal transduction pathways precede changes in inflammatory mediators’ expression. However, only a restricted number of studies have addressed the effect of phenols on a specific signal transduction pathway. The present review attempts to summarize and highlight a broad range of inflammation-associated signaling pathways modulated by phenols namely: nuclear factor (NF)-κB, activator protein (AP)-1, peroxisome proliferator-activated receptor (PPAR) and nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factors; mitogen-activated protein kinases (MAPKs); protein tyrosine kinases (PTKs); tyrosine phosphatidylinositol 3-kinase (PI3K)/Akt and ubiquitin-proteasome system. As a consequence of phenols effect on signaling pathways, described above, their action on inflammatory mediators’ production is mentioned. Finally, it is established that the structure-activity relationships of phenolic compounds are a valuable information source on the development of new anti-inflammatory drugs from natural products.

Epidemiological evidence has shown that a high dietary intake of vegetables and fruit rich in polyphenols is associated with a reduction of cancer incidence and mortality from coronary heart disease. The healthy effects associated with polyphenol consumption have made the study of the mechanisms of action a matter of great importance. In particular, the hydroxybenzoic acid protocatechuic acid (PCA) has been eliciting a growing interest for several reasons. Firstly, PCA is one of the main metabolites of complex polyphenols such as anthocyanins and procyanidins that are normally found at high concentrations in vegetables and fruit, and are absorbed by animals and humans. Since the daily intake of anthocyanins has been estimated to be much higher than that of other polyphenols, the nutritional value of PCA is increasingly recognized. Secondly, a growing body of evidence supports the concept that PCA can exert a variety of biological effects by acting on different molecular targets. It has been shown that PCA possesses antioxidant, anti-inflammatory as well as antihyperglycemic and neuroprotective activities. Furthermore, PCA seems to have chemopreventive potential because it inhibits the in vitro chemical carcinogenesis and exerts pro-apoptotic and anti-proliferative effects in different tissues. This review is aimed at providing an up-dated and comprehensive report on PCA giving a special emphasis on its biological activities and the molecular mechanisms of action most likely responsible for a beneficial role in human disease prevention.

Metformin is an antidiabetic drug used widely in clinical practice. Its main clinical effect is to reduce blood glucose levels by improving insulin resistance. Nonalcoholic fatty liver disease is characterized by chronic liver damage and can develop into liver cirrhosis. Nonalcoholic fatty liver disease is associated with obesity and contributes to insulin resistance, and metformin is used to treat individuals with these conditions. The mechanisms underlying the clinical effects of metformin in treating nonalcoholic fatty liver disease are unclear. This article summarizes the literature on the mechanisms associated with liver glucose metabolism and the beneficial effects of metformin on this common liver disease.

Rheumatoid arthritis (RA) is a chronic, inflammatory disease that afflicts 1-2% of the world population, characterized by an immune mediated inflammatory synovitis that leads to joint destruction, functional impairment, and reduced quality of life. The treatment goals of RA should be longterm substantial relief of pain, arrested joint inflammation and damage, and improved function. Current treatment can be divided into four classes, namely general analgesics and non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, disease modifying anti-rheumatic drugs (DMARDs) and biological agents (tumor-necrosis factor modifiers). However, gastrointestinal (GI) side effects of NSAIDs cannot be neglected, direct joint injections of glucocorticoids cannot be injected more than once every 3 months, synthetic DMARDs is far from optimal and only minority of patients achieved longterm remission, the biologics are very expensive to manufacture, need to be injected, and can cause allergic reactions. An alternative and good approach to the treatment of this disease is to lower the levels of tumour necrosis factor-α (TNF-α) in RA, which can be achieved by selectively inhibiting the tumour necrosis factor-α converting enzyme (TACE) that generate these cytokines using cheaper small molecules. This review focuses on the current status of selective small molecule inhibitors of TACE, with respect to lead compound search, inhibitors design approach, structure-activity relationship (SAR) and pharmacological studies in animals and humans. Through these methods, new hope is emerging for the treatment of RA through selective inhibition of TACE.

Now cisplatin and its analogs are some of the most effective chemotherapeutic agents in clinical use as the first line of treatment in testicular and ovarian cancers. Unfortunately, they have several major drawbacks, such as cumulative toxicities of nephrotoxicity and ototoxicity, inherent or treatment-induced resistance. This has provided the motivation for developing novel metal complexes as anticancer agents with different mechanism of action. In recent years, significant attention has been devoted to the role of G-quadruplexes in cancer. It was found that the stabilization of G-quadruplexes by small molecules has been shown to inhibit the transcriptional activity of some oncogenes. Thus, the G-quadruplex motif has emerged as a promising target for the design of selective anticancer drugs. Apart from the purely organic heteroaromatic compounds reported as G-quadruplex binders, it has recently been shown that metal complexes can also interact strongly and selectively with quadruplex DNA and have potential anticancer activity. This review will highlight recent progress of the metal complexes as anticancer drugs targeting G-quadruplex DNA, and discuss their future potential in the medical fields. Considering the significant roles of the metal ions, the metal complexes will be discussed as follows: (1) Ruthenium(II) complexes; (2) Nickel(II) complexes; (3) Zinc(II) complexes; (4) Manganese(III) complexes; (5) Copper(II) complexes; (6) Palladium(II)/Platinum(II); (7) Other metal complexes.

Targeted drug delivery has attracted much attention in improving the curative effect of existing chemotherapy drugs, and many published studies have suggested the disulfide linkage for key unit in constructing a targeting conjugate. An appropriate disulfide bond, through which cytotoxic agents and drug carriers were linked together, would guarantee the conjugate stable during circulation in vivo and, readily cleavable to release the drug. The aim of this article is to review various design strategies based on disulfide linkage which have been used to assemble a tumor-targeting conjugate, with the goal of presenting a promising avenue in the field of targeted drug delivery.

Nitrogen atom containing heterocyclic compounds, pyridazines, pyridazinones and phthalazines are important structural feature of many biologically active compounds and show diverse pharmacological properties. Pyridazines and phthalazines hold considerable interest relative to the preparation of organic intermediates and physiologically active compounds. On the basis of literature, pyridazines, pyridazinone and phthalazines further focus our attention because of their easy fictionalization at various ring positions, which makes them attractive synthetic compounds for designing and development of the novel pyridazines and phthalazines drugs in future.

Objective: Endophytes, microorganisms that reside in the tissues of living plants, are a promising source of novel compounds with biological activity, or an alternative source of compounds originally isolated from higher plants. The intent of this review is to provide insights into their occurrence in nature, the products that they make, and how some of these organisms are beginning to show some potential for human use. Methods: Information for analysis of endophytic microorganisms was obtained from libraries and Internet scientific databases such as Scirus, Google Scholar, CAB-Abstracts, MedlinePlus, PubMed, SciFinder, Scopus and Web of Science. Results: Many of the compounds reported here were isolated exclusively from endophytes in culture, while other compounds had been previously reported as chemical constituents of higher plants. A survey of the literature shows endophytic microorganisms are mainly known for their alkaloids with cytotoxic, chemopreventive, anti-metastatic and antitumor properties used in the treatment of several types of cancer. The studies of these alkaloids highlight the existence of various potential leads for the development of novel anti-cancer agents. Modern pharmacology studies demonstrated that their crude extracts and active compounds possess wide pharmacological actions, especially for anti-microbial drug discovery, with neuroprotective, antioxidant, nematicidal, antiplasmodium, anti-inflammatory activities. Aim of the Review: This review summarizes the up-to-date and comprehensive information on compounds from endophytes fungi from 1995 to 2011 that relates to 313 compounds isolated from endophytic microorganisms, together with the botany, phytochemistry, pharmacology and toxicology, and discusses possible trends and the scope for future research of endophytes.

Methylimidoselenocarbamates have previously proven to display potent antitumor activities. In the present study we show that these compounds act as multikinase inhibitors. We found that the most effective compound, quinoline imidoselenocarbamate EI201, inhibits the PI3K/AKT/mTOR pathway, which is persistently activated and contributes to malignant progression in various cancers. EI201 blocked the phosphorylation of AKT, mTOR and several of its downstream regulators (p70S6K and 4E-BP1) and ERK1/2 in PC-3, HT-29 and MCF-7 cells in vitro, inducing both autophagy and apoptosis. EI201 also contributes to the loss of maintenance of the selfrenewal and tumorigenic capacity of cancer stem cells (CSCs). 0.1 μmol/L EI201 triggered a reduction in size and number of tumorspheres in PC-3, HT-29 and MCF-7 cells and 4 μmol/L induced the elimination of almost all the tumorspheres in the three studied cell lines. In addition, EI201 suppressed almost 80% prostate tumor growth in vivo (p < 0.01) compared to controls at a relatively low dose (10 mg/kg) in a mouse xenograft model. There was a significant decrease in the subcutaneous primary tumor [18F]-FDG uptake (76.5% reduction, p < 0.05) and in the total tumor burden (76.8% reduction, p < 0.05) after EI201 treatment compared to vehicle control, without causing toxicity in mice. Taken together, our results support further development of EI201 as a novel multi-kinase inhibitor that may be useful against cancers with aberrant upregulation of PI3K/AKT and MAPK signaling pathways.

Tryptamine (T) and several T derivatives (Ts) inhibit in a voltage-dependent manner the NMDA receptor (NR). This effect is influenced by substituents at various positions, but has not yet been subjected to a detailed SAR study. Here, 64 Ts have been tested as inhibitors of [3H]MK-801 binding to NRs on rat brain membranes. For comparison, they were also tested as inhibitors of [3H]8-OHDPAT binding to 5-HT1A and of [3H]ketanserin binding to 5-HT2A receptors. Since most of these Ts have not been tested before at any of these receptors, we start with a review of the effects of Ts on 5-HT1A and 5-HT2A binding sites. NRs were inhibited with IC50s from 2 to 7 μM by Ts with alkyl or halogen at positions 2, 5, and/or 7. Inhibition by some Ts was attenuated more than 10-fold by 30 μM spermine. The most potent inhibitors at 5-HT1A receptors were 5-carboxamido-T (IC50 0.00015 μM) and serotonin (0.0016 μM), at 5-HT2A receptors 2-Me-4,7-Cl2-T (1.2 μM) and 2,7-Me2-4-Cl-T (2.0 μM). Fujita-Ban modified Free-Wilson analyses pointed to the individual significance of particular substituents. Also QSARs based on molecular operating environment descriptors resulted in sound correlations at all 4 targets. No similarities between the NR and 5-HT receptors could be found. At the NR, only L-Trp-NH2 bound 10 times better than at both 5-HT receptors studied. L-Trp-NH2 may be a structural lead to endogenous non-competitive NR antagonists.

In recent years, a great deal of research has been devoted to identify new natural sources of phytosterols and to improve methods for their recovery and purification. In this regard, unexplored natural sources of bioactive ingredients are gaining much attention since they can lead to the isolation of new compounds or bioactivities. The field of available natural sources has been further increased by including algae and, even more interestingly, microalgae. In the present study, a multidisciplinary approach has been used considering, in an integrated view, extraction, chemical composition and bioactivity of phytosterols from the microalga Dunaliella tertiolecta. A novel methodology to extract, separate and characterize microalgal-derived phytosterols has been developed. In addition, recoverable and reusable eluents have been selected in order to reduce the quantities of employed organic solvents. Finally, we addressed the question whether orally administered phytosterols reach the brain and if those interfere with the major neurotransmitter systems, such as the dopaminergic, serotoninergic and noradrenergic ones, in several brain areas of rats. Flash Liquid Chromatography has been used to separate the Total Sterol (TS) fraction, composed of twelve sterols, with a purity of 97.87% and a recovery percentage of 98%, while the “flash version” of Silver Ion Liquid Chromatography has been used to purify the most abundant phytosterols in TS, (22E,24R)- methylcholesta-5,7,22-trien-3β-ol (ergosterol) and (22E,24R)-ethylcholesta-5,7,22-trien-3β-ol (7-dehydroporiferasterol), with a purity of 97.4%. These two combined methods did not need sophisticated technologies but only cheap laboratory supplies. Moreover, the possibility of recovering and recycling the solvents used as eluents made it a cleaner process. Finally, for the first time, a neuromodulatory action of Dunaliella tertiolecta-derived phytosterols has been found in selective brain areas of rats.