Current Medicinal Chemistry - Volume 20, Issue 18, 2013

Among 484 Hypericum L. (Guttiferae/Hypericaceae) species, widespread in warm temperate areas throughout the world, only H. perforatum is widely used in official medicine. Hypericum perforatum has been reported as an antidepressant, antiviral, antimicrobial, anti-inflammatory, and a healing agent. The main constituents of the Hypericum species are naphthodianthrones, primarily represented by hypericin and pseudohypericin, phloroglucinol derivatives, especially hyperforin, and flavonoids, such as quercetin, quercitrin, hyperoside and rutin. Hypericin and pseudohypericin have been found to possess antiretroviral activity. Hyperforin may also have an important contribution to the antidepressant activity of Hypericum extracts. The content of the above active constituents in some Hypericum species is higher than in H. perforatum. Also, a number of studies of the biological activities of Hypericum species have shown that the most recognized species of this genus, H. perforatum, was not the most active. Comprehensive analysis of the published research on the chemical composition and biological activity, showed that H. richeri has a similar pharmacological potential as St. Jon`s wort. The species, with high content of naphtodianthrones,which might be used against viruses and retroviruses, are: H. androseamum,H. annulatum, H. barbatum, H. boissieri, H. elegans, H. hirsutum, H. hyssopifolium, H. humifusum, H. montanum. H. montbretii, H. triquetrifolium, H. richeri, H. rochelii, H. rumeliacum, H. thasium, andH. patulum. Very few species (e.g. H. inodorum and H. moseranum) contained the similar amounts of hyperforine as H. perforatum. Since hyperforin was recognized as one of the most crucial components for the antidepressive activity, it seems that H. perforatum barely has an alternative for this purpose. Plant species containing considerable amounts of other acylphloroglucinol derivatives have the potential to demonstrate antibacterial and cytotoxic activity. Some of these species are: H. sampsonii, H. ascyron, H. foliosum, H. geminiflorum and H. scabrum. However, only a few studies concerning the activity of extracts and isolated compounds were done in vivo. Also, data on the safe usage of Hypericum constituents as phytotherapeutics are scarce. Since some of Hypericum species are scarcely distributed or endemic as well as some of the secondary metabolites are presented in very small amounts, bio-production, especially endophytes, could represent an abundant and reliable source of pharmacologically active metabolites of Hypericum species for exploitation in pharmaceutical industry.

Protein-ligand docking is currently an important tool in drug discovery efforts and an active area of research that has been the subject of important developments over the last decade. These are well portrayed in the rising number of available protein-ligand docking software programs, increasing level of sophistication of its most recent applications, and growing number of users. While starting by summarizing the key concepts in protein-ligand docking, this article presents an analysis of the evolution of this important field of research over the past decade. Particular attention is given to the massive range of alternatives, in terms of protein-ligand docking software programs currently available. The emerging trends in this field are the subject of special attention, while old established docking alternatives are critically revisited. Current challenges in the field of protein-ligand docking such as the treatment of protein flexibility, the presence of structural water molecules and its effect in docking, and the entropy of binding are dissected and discussed, trying to anticipate the next years in the field.

Arundic acid has been experimented in vitro and in vivo as a potential neuroprotective agent. It modulates astrocyte activation by inhibiting the enhanced astrocytic synthesis of S-100β protein, responsible for inducing neuronal death. The phase II clinical trials for the treatment of acute ischemic stroke, as well as clinical development in other neurodegenerative diseases including amytrophic lateral sclerosis, Alzheimer's disease and Parkinson's disease are recently completed. There is no review published in this area since its discovery as potential neuroprotective agent and the various syntheses reported for this important non-natural compound. This review summarizes the studies towards the development of arundic acid as a neuroprotective agent, the biological studies in vitro and in vivo, the phase II trials and the various efforts made for its synthesis in the last two decades.

The obesity prevalence is growing worldwide and largely responsible for the increased incidence of cardiovascular disease, the most common cause of death in the western world. Excessive food intake along with insufficient physical exercise is the basic impetus for this development. The obese state is commonly associated with an increase in leptin levels and chronic immune-mediated inflammation. Despite high leptin levels, the leptin response, normally associated with satiety and satiation, seems to be impaired and individuals continue to consume calorie-rich food. Antioxidant food additives such as sodium sulphite, sodium benzoate and curcumin were shown to suppress the leptin release in lipopolysaccharide- treated murine adipocytes. Based on this, we hypothesize that the insufficient leptin release, caused by excessive consumption of food additives, may lead to a reduced exposure of the central nervous system to leptin and ultimately propagate obesity. On the other hand, leptin has been shown to favor Th1-type activity, which ultimately decreases tryptophan levels. Tryptophan derivatives, serotonin and melatonin, induce satiety/satiation through several mechanisms. In this context, the antioxidant suppression of leptin release and Th1-type activity is beneficial to increase serotonin and melatonin levels. The molecules in the mechanism described in this review are highly integrated in the reward system, and have been implicated in the addiction behavior of obesity. Based on these facts, the involvement of antioxidant food supplements in the mechanisms of the reward-deficiency syndrome which perpetuates obesity will be discussed.

Lipids are crucial structural and bioactive components that sustain embryo, fetal and placental development and growth. Intrauterine development can be disturbed by several diseases that impair maternal lipid homeostasis and lead to abnormal lipid concentrations in the fetal circulation. Deficiency in essential fatty acids can lead to congenital malformations and visual and cognitive problems in the newborn. Either deficient mother-to-fetus lipid transfer or abnormal maternal- fetal lipid metabolism can cause fetal growth restriction. On the other hand, excessive mother-to-fetus fatty acid transfer can induce fetal overgrowth and lipid overacummulation in different fetal organs and tissues. The placenta plays a fundamental role in the transfer of lipid moieties to the fetal compartment and is affected by maternal diseases associated with impaired lipid homeostasis. Postnatal consequences may be evident in the neonatal period or later in life. Indeed, both defects and excess of different lipid species can lead to the intrauterine programming of metabolic and cardiovascular diseases in the offspring. This review summarizes the lipid impairments induced by different pathologies, including placental insufficiency, malnutrition, obesity and diabetes, and their consequent developmental defects.

Although several constitutive proteasome inhibitors have been reported these recent years, potent organic, noncovalent and readily available inhibitors are still poorly documented. Here we used a structure- and ligand-based in silico approach to identify commercially available 1,2,4-oxadiazole derivatives as non-covalent human 20S proteasome inhibitors. Their optimization led to the newly synthesized compound 4h that is a mixed proteasomal inhibitor of the chymotrypsin- like activity (Ki of 26,1 nM and K’i of 7.5 nM) which is in addition selective versus the challenging cathepsin B and calpain proteases. Molecular modelling studies corroborated the mechanism of inhibition and suggest an unusual binding of the inhibitor within the S5 binding pocket (β6 subunit). The cellular effects of our compounds validate their utility as potential pharmacological agents for anti-cancer pre-clinical studies.

In a previous work, the author has investigated the antimicrobial and cytotoxic properties of tartaric and glutamic acids silver(I) chelates. In a following work, the author has reported on the in vitro cytotoxicity and the mechanism of action of a silver(I) tartaric acid chelate synthesized by the author given the title name Aliargentumycine (AAgM) on hematopoietic malignancies. The in vitro antineoplastic activities of AAgM on solid human breast ductal carcinoma (T- 47D) and disseminated T-cell acute lymphoblastic leukemia (Jurkat) cell lines, its mechanism of action and its structural properties were investigated here. The cytotoxicity results of AAgM were compared to cisplatin, a ubiquitously used platinum-based antitumor drug. Results have indicated that AAgM demonstrated excellent cytotoxicity on both tumor cell lines studied when compared to cis-platin, especially for T-47D. Unlike cisplatin, AAgM was found to exhibit an aberrant triphasic cytotoxicity profile. Phase I exhibited cytotoxicity in the nanoconcentration range, Phase II exhibited no cytotoxicity in the intermediate range, and finally Phase III exhibited cytotoxicity in the microconcentration range. Phase II lacks of cytotoxicity might be an indication of cells reverting back to being nonmalignant in a similar way to 5-Aza-2’- deoxycytidine (decitabine). Quantitative pharmacokinetic-pharmacodynamic analyses were undertaken and were found that AAgM induced significantly better cytotoxic activities than cisplatin between 1.9-30.5 ng/mL while cisplatin did not exhibit any cytotoxicity on T-47D below 122 ng/mL. TUNEL assay was performed and AAgM was found to elicit its antineoplastic activities by apoptosis. X-ray diffraction showed that AAgM is a polymeric chain hydrate structure with no imposed symmetry and the complex around the silver is a monohydrate distorted skew trapezoidal bipyramidal sixcoordinate. AAgM is composed of lipophilic and hydrophilic moieties, making AAgM miscible in both lipids via the tartrate rings and ionic solutions via the water molecules. The results are expected to have significant implications on cancer therapy, especially solid neoplasms, which are exceptionally difficult to treat, and those derived from epithelial and mesenchymal cells, which are not prone to apoptotic responses with cdk inhibitor drugs. Also, the results should be very useful in the design of future novel silver-based antineoplastic drugs.

To compare endocrine, metabolic, and inflammatory changes induced by gastric bypass (GB) and sleeve gastrectomy (SG) in patients with type 2 diabetes mellitus (T2DM), and to investigate the mechanisms of success after metabolic surgery. Sixteen GB and 16 SG patients were followed up before and at 1 year after surgery. The 75-g oral glucose tolerance test (OGTT) was performed before and after surgery. Glucose homeostasis, serum interleukin-1β, plasma gut hormones and adipokines, and the United Kingdom Prospective Diabetes Study (UKPDS) ten-year cardiovascular risks were evaluated. The diabetes remission rate was significantly higher in GB than SG. Changes in the area under the curve (AUC) for glucose were greater in those with complete and partial remission after GB and remitters after SG than non-remitters after SG, whereas changes in AUC for C-peptide were higher in complete and partial remitters after GB than non-remitters after SG. Insulinogenic index was enhanced and serum interleukin-1β was reduced in complete remitters after GB and remitters after SG. Logistic regression analysis confirmed that insulinogenic index and interleukin-1β, not insulin resistance, were the factors determining the success of diabetes remission after metabolic surgeries. GB and SG significantly reduced the ten-year risk of coronary heart disease and fatal coronary heart disease in T2DM patients after surgery, while GB had the additional benefit of reduced stroke risk. Human diabetes remission after metabolic surgery is through insulin secretion and interleukin-1β dependent mechanisms. GB is superior to SG in cardiocerebral risk reduction in Asian non-morbidly obese, not well-controlled T2DM patients.