The Use of the Coenzyme Q10 as a Food Supplement in the Management of Fibromyalgia: A Critical Review.

The coenzyme Q10 is a naturally occurring benzoquinone derivative widely prescribed as a food supplement for different physical conditions and pathologies. This review aims to sum up the key structural and functional characteristics of Q10, taking stock of its use in people affected by fibromyalgia. A thorough survey has been conducted, using Pubmed, Scifinder, and ClinicalTrials.gov as the reference research applications and registry database, respectively. Original articles, reviews, and editorials published within the last 15 years, as well as open clinical investigations in the field, if any, were analyzed to point out the lights and shadows of this kind of supplementation as they emerge from the literature.

Aurones: A Golden Resource for Active Compounds.

Deemed as poorly represented in nature, aurones have been often overlooked by researchers compared to other members of the flavonoid superfamily. However, over the past two decades, they have been reassessed by the scientific community, who are increasingly appreciating their ability to modulate several biological pathways. This review summarizes the recent literature on this class of compounds, which has been analyzed from both a chemical and a functional point of view. Original articles, reviews and editorials featured in Pubmed and Scifinder over the last twenty years have been taken into account to provide the readers with a view of the chemical strategies to obtain them, their functional properties, and their potential of technological use. The resulting comprehensive picture aims at raising the awareness of these natural derivatives as effective drug candidates, fostering the development of novel synthetic analogues.

Aldose reductase inhibitors: 2013-present.

INTRODUCTION: Aldose reductase (ALR2) is both the key enzyme of the polyol pathway, whose activation under hyperglycemic conditions leads to the development of chronic diabetic complications, and the crucial promoter of inflammatory and cytotoxic conditions, even under a normoglycemic status. Accordingly, it represents an excellent drug target and a huge effort is being done to disclose novel compounds able to inhibit it. AREAS COVERED: This literature survey summarizes patents and patent applications published over the last 5 years and filed for natural, semi-synthetic and synthetic ALR2 inhibitors. Compounds described have been discussed and analyzed from both chemical and functional angles. EXPERT OPINION: Several ALR2 inhibitors with a promising pre-clinical ability to address diabetic complications and inflammatory diseases are being developed during the observed timeframe. Natural compounds and plant extracts are the prevalent ones, thus confirming the use of phytopharmaceuticals as an increasingly pursued therapeutic trend also in the ALR2 inhibitors field. Intriguing hints may be taken from synthetic derivatives, the most significant ones being represented by the differential inhibitors ARDIs. Differently from classical ARIs, these compounds should fire up the therapeutic efficacy of the class while minimizing its side effects, thus overcoming the existing limits of this kind of inhibitors.

Synthetic analogues of flavonoids with improved activity against platelet activation and aggregation as novel prototypes of food supplements.

We investigated the ability of quercetin and apigenin to modulate platelet activation and aggregation, and compared the observed efficacy with that displayed by their synthetic analogues 2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-ones, 1-4, and 2,3-diphenyl-4H-pyrido[1,2-a]pyrimidin-4-ones, 5-7. Platelet aggregation was explored through a spectrophotometric assay on platelet-rich plasma (PRP) treated with the thromboxane A2 mimetic U46619, collagen and thrombin in presence/absence of various bioisosteres of flavonoids (12.5-25-50-100 µM). The platelet density, (mean platelet component, MPC), was measured by the Advia 120 Hematology System as a marker surrogate of platelet activation. The induced P-selectin expression, which reflects platelet degranulation/activation, was quantified by flow cytometry on PRP. Our synthetic compounds modulated significantly both platelet activation and aggregation, thus turning out to be more effective than the analogues quercetin and apigenin when tested at a concentration fully consistent with their use in vivo. Accordingly, they might be used as food supplements to increase the efficacy of natural flavonoids.

Progresses in the pursuit of aldose reductase inhibitors: the structure-based lead optimization step.

Aldose reductase (ALR2) is a crucial enzyme in the development of the major complications of diabetes mellitus. Very recently it has been demonstrated that the ARL2 inhibitor, fidarestat, significantly prevents inflammatory signals (TNF-α, LPS) that cause cancer (colon, breast, prostate and lung), metastasis, asthma, and other inflammatory diseases. Currently, fidarestat is in phase III clinical trial for diabetic neuropathy and was found to be safe. Thus the finding of novel, potent ARL2 inhibitors is today more than in the past in great demand as they can pave the way for a novel therapeutic approach for a number of diseases besides the diabetes. Herein, starting from the virtual screening-derived ALR2 inhibitor S12728 (1), a rational receptor-based lead optimization has been undertaken. The design and synthetic efforts here reported led to the discovery of several new compounds endowed with low micromolar/submicromolar activities.

Identification of novel molecular scaffolds for the design of MMP-13 inhibitors: a first round of lead optimization.

Osteoarthritis (OA) is the leading cause of joint pain and disability in middle-aged and elderly patients, and is characterized by progressive loss of articular cartilage. Among the various matrix metalloproteinases (MMPs), MMP-13 is specifically expressed in the cartilage of human OA patients and is not present in normal adult cartilage. Thus, MMP-13-selective inhibitors are promising candidates in osteoarthritis therapy. Recently, we designed an N-isopropoxy-arylsulfonamide-based hydroxamate inhibitor, which showed low nanomolar activity and high selectivity for MMP-13. In parallel to further studies aiming to assess the in vivo activity of our compound, we screened the Life Chemicals database through computational docking to seek for novel scaffolds as zinc-chelating non-hydroxamate inhibitors. Experimental evaluation of 20 selected candidate compounds verified five novel leads with IC(50) in the low µM range. These newly discovered inhibitors are structurally unrelated to the ones known so far and provide useful scaffolds to develop compounds with more desirable properties. Finally, a first round of structure-based optimization on lead 1 was accomplished and led to an increase in potency of more than 5 fold.

Pursuing aldose reductase inhibitors through in situ cross-docking and similarity-based virtual screening.

Aldose reductase (ALR2) is a critical enzyme in the development of the major complications of diabetes mellitus. Herein, new molecular entities active against ALR2 were discovered through an integrated receptor- and ligand-based virtual screening campaign. Twelve candidates were found to inhibit this enzyme in the micromolar range including two ligands having an IC(50) below 3 muM. Six new compounds, structurally unrelated to the known ARIs, have been identified, opening up opportunity for lead optimization.

Computational studies of epidermal growth factor receptor: docking reliability, three-dimensional quantitative structure-activity relationship analysis, and virtual screening studies.

An aberrant activity of the epidermal growth factor receptor (EGFR) has been shown to be related to many human cancers, such as breast and liver cancers, thus making EGFR an attractive target for antitumor drug discovery. In this study we evaluated the reliability of various kinds of docking software and procedures to predict the binding disposition of EGFR inhibitors. By application of the best procedure and use of more than 200 compounds, a receptor-based 3D-QSAR model for EGFR inhibition was developed. On the basis of the results obtained, the possibility of developing virtual screening studies was also evaluated. The VS procedure that proved to be the most reliable from a computational point of view was then used to filter the Maybridge database in order to identify new EGFR inhibitors. Enzymatic assays revealed that among the eight top-scoring compounds, seven proved to inhibit EGFR activity at a concentration of 100 microM, two of them exhibiting IC(50) values in the low micromolar range and one in the nanomolar range. These results demonstrate the validity of the methodologies followed. Furthermore, the two low micromolar compounds may be considered as very interesting leads for the development of new EGFR inhibitors.