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Pharmaceuticals, Volume 5, Issue 12 (December 2012), Pages 1265-1408

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Research

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Open AccessArticle Cell Penetrating Peptoids (CPPos): Synthesis of a Small Combinatorial Library by Using IRORI MiniKans
Pharmaceuticals 2012, 5(12), 1265-1281; doi:10.3390/ph5121265
Received: 10 October 2012 / Revised: 13 November 2012 / Accepted: 14 November 2012 / Published: 23 November 2012
Cited by 6 | PDF Full-text (1121 KB) | HTML Full-text | XML Full-text
Abstract
Cell penetrating peptoids (CPPos) are potent mimics of the corresponding cell penetrating peptides (CPPs). The synthesis of diverse oligomeric libraries that display a variety of backbone scaffolds and side-chain appendages are a very promising source of novel CPPos, which can be used to
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Cell penetrating peptoids (CPPos) are potent mimics of the corresponding cell penetrating peptides (CPPs). The synthesis of diverse oligomeric libraries that display a variety of backbone scaffolds and side-chain appendages are a very promising source of novel CPPos, which can be used to either target different cellular organelles or even different tissues and organs. In this study we established the submonomer-based solid phase synthesis of a “proof of principle” peptoid library in IRORI MiniKans to expand the amount for phenotypic high throughput screens of CPPos. The library consisting of tetrameric peptoids [oligo(N-alkylglycines)] was established on Rink amide resin in a split and mix approach with hydrophilic and hydrophobic peptoid side chains. All CPPos of the presented library were labeled with rhodamine B to allow for the monitoring of cellular uptake by fluorescent confocal microscopy. Eventually, all the purified peptoids were subjected to live cell imaging to screen for CPPos with organelle specificity. While highly charged CPPos enter the cells by endocytosis with subsequent endosomal release, critical levels of lipophilicity allow other CPPos to specifically localize to mitochondria once a certain lipophilicity threshold is reached. Full article
(This article belongs to the Special Issue Cell-penetrating Peptides 2012)
Open AccessArticle Synthesis and COX-2 Inhibitory Activity of 4-[(E)-2-(4-Oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethenyl]benzene-1-sulfonamide and Its Analogs
Pharmaceuticals 2012, 5(12), 1282-1290; doi:10.3390/ph5121282
Received: 11 October 2012 / Revised: 14 November 2012 / Accepted: 23 November 2012 / Published: 27 November 2012
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Abstract
Some novel 3-phenyl-2-[(E)-2-phenylethenyl]-3,4-dihydroquinazolin-4-one derivatives possessing para-sulfonamides groups on the phenyl ring of the 2-phenylethenyl moiety have been synthesized and their COX-2 inhibitory activity evaluated. The stuctures of the synthesized compounds were confirmed  on the basis of  FT-IR, 1H-NMR, 13
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Some novel 3-phenyl-2-[(E)-2-phenylethenyl]-3,4-dihydroquinazolin-4-one derivatives possessing para-sulfonamides groups on the phenyl ring of the 2-phenylethenyl moiety have been synthesized and their COX-2 inhibitory activity evaluated. The stuctures of the synthesized compounds were confirmed  on the basis of  FT-IR, 1H-NMR, 13C-NMR and mass spectral data. The COX-2 inhibition screening assay revealed that 4-[(E)-2-{3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl}ethenyl]benzene-1-sulfonamide had a  maximum COX-2 inhibition (47.1%), at a concentration of 20 μM. Full article
Open AccessArticle Integration of Ligand-Based Drug Screening with Structure-Based Drug Screening by Combining Maximum Volume Overlapping Score with Ligand Docking
Pharmaceuticals 2012, 5(12), 1332-1345; doi:10.3390/ph5121332
Received: 7 October 2012 / Revised: 24 November 2012 / Accepted: 30 November 2012 / Published: 4 December 2012
Cited by 5 | PDF Full-text (292 KB) | HTML Full-text | XML Full-text
Abstract
Ligand-based and structure-based drug screening methods were integrated for in silico drug development by combining the maximum-volume overlap (MVO) method with a protein-compound docking program. The MVO method is used to select reliable docking poses by calculating volume overlaps between the docking pose
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Ligand-based and structure-based drug screening methods were integrated for in silico drug development by combining the maximum-volume overlap (MVO) method with a protein-compound docking program. The MVO method is used to select reliable docking poses by calculating volume overlaps between the docking pose in question and the known ligand docking pose, if at least a single protein-ligand complex structure is known. In the present study, the compounds in a database were docked onto a target protein that had a known protein-ligand complex structure. The new score is the summation of the docking score and the MVO score, which is the measure of the volume overlap between the docking poses of the compound in question and the known ligand. The compounds were sorted according to the new score. The in silico screening results were improved by comparing the MVO score to the original docking score only. The present method was also applied to some target proteins with known ligands, and the results demonstrated that it worked well. Full article
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Open AccessArticle Biosimilars: Company Strategies to Capture Value from the Biologics Market
Pharmaceuticals 2012, 5(12), 1393-1408; doi:10.3390/ph5121393
Received: 8 November 2012 / Revised: 5 December 2012 / Accepted: 6 December 2012 / Published: 12 December 2012
Cited by 24 | PDF Full-text (640 KB) | HTML Full-text | XML Full-text
Abstract
Patents for several biologic blockbusters will expire in the next few years. The arrival of biosimilars, the biologic equivalent of chemical generics, will have an impact on the current biopharmaceuticals market. Five core capabilities have been identified as paramount for those companies aiming
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Patents for several biologic blockbusters will expire in the next few years. The arrival of biosimilars, the biologic equivalent of chemical generics, will have an impact on the current biopharmaceuticals market. Five core capabilities have been identified as paramount for those companies aiming to enter the biosimilars market: research and development, manufacturing, supporting activities, marketing, and lobbying. Understanding the importance of each of these capabilities will be key to maximising the value generated from the biologics patent cliff. Full article
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Review

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Open AccessReview Multiple Facets of cAMP Signalling and Physiological Impact: cAMP Compartmentalization in the Lung
Pharmaceuticals 2012, 5(12), 1291-1331; doi:10.3390/ph5121291
Received: 18 September 2012 / Revised: 15 November 2012 / Accepted: 20 November 2012 / Published: 30 November 2012
Cited by 8 | PDF Full-text (884 KB) | HTML Full-text | XML Full-text
Abstract
Therapies involving elevation of the endogenous suppressor cyclic AMP (cAMP) are currently used in the treatment of several chronic inflammatory disorders, including chronic obstructive pulmonary disease (COPD). Characteristics of COPD are airway obstruction, airway inflammation and airway remodelling, processes encompassed by increased airway
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Therapies involving elevation of the endogenous suppressor cyclic AMP (cAMP) are currently used in the treatment of several chronic inflammatory disorders, including chronic obstructive pulmonary disease (COPD). Characteristics of COPD are airway obstruction, airway inflammation and airway remodelling, processes encompassed by increased airway smooth muscle mass, epithelial changes, goblet cell and submucosal gland hyperplasia. In addition to inflammatory cells, airway smooth muscle cells and (myo)fibroblasts, epithelial cells underpin a variety of key responses in the airways such as inflammatory cytokine release, airway remodelling, mucus hypersecretion and airway barrier function. Cigarette smoke, being next to environmental pollution the main cause of COPD, is believed to cause epithelial hyperpermeability by disrupting the barrier function. Here we will focus on the most recent progress on compartmentalized signalling by cAMP. In addition to G protein-coupled receptors, adenylyl cyclases, cAMP-specific phospho-diesterases (PDEs) maintain compartmentalized cAMP signalling. Intriguingly, spatially discrete cAMP-sensing signalling complexes seem also to involve distinct members of the A-kinase anchoring (AKAP) superfamily and IQ motif containing GTPase activating protein (IQGAPs). In this review, we will highlight the interaction between cAMP and the epithelial barrier to retain proper lung function and to alleviate COPD symptoms and focus on the possible molecular mechanisms involved in this process. Future studies should include the development of cAMP-sensing multiprotein complex specific disruptors and/or stabilizers to orchestrate cellular functions. Compartmentalized cAMP signalling regulates important cellular processes in the lung and may serve as a therapeutic target. Full article
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Open AccessReview Mechanistic and Pharmacological Issues of Aspirin as an Anticancer Agent
Pharmaceuticals 2012, 5(12), 1346-1371; doi:10.3390/ph5121346
Received: 6 November 2012 / Revised: 16 November 2012 / Accepted: 30 November 2012 / Published: 5 December 2012
Cited by 20 | PDF Full-text (446 KB) | HTML Full-text | XML Full-text
Abstract
Recent findings have shown that aspirin, taken for several years, reduces the long-term risk of some cancers, particularly colorectal cancer. The result that aspirin benefit is detectable at daily low-doses (at least 75mg), the same used for the prevention of cardiovascular disease, positions
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Recent findings have shown that aspirin, taken for several years, reduces the long-term risk of some cancers, particularly colorectal cancer. The result that aspirin benefit is detectable at daily low-doses (at least 75mg), the same used for the prevention of cardiovascular disease, positions the antiplatelet action of aspirin at the center of its antitumor efficacy. At low-doses given every 24 h, aspirin is acting by a complete and persistent inhibition of cyclooxygenase (COX)-1 in platelets (in the pre-systemic circulation) while causing a limited and rapidly reversible inhibitory effect on COX-2 and/or COX-1 expressed in nucleated cells. Aspirin has a short half-life in human circulation (approximately 20 min); nucleated cells have the ability to resynthesize the acetylated COX-isozymes within a few hours, while platelets do not. COX-independent mechanisms of aspirin, such as the inhibition of Wnt/ b-catenin and NF-kB signaling and the acetylation of extra-COX proteins, have been suggested to play a role in its chemo-preventive effects, but their relevance remains to be demonstrated in vivo at clinical doses. In conclusion, the results of clinical pharmacology and the analysis of randomized and epidemiological studies suggest that colorectal cancer and atherothrombosis share a common mechanism of disease, i.e. enhanced platelet activation in response to injury at distinct sites. Full article
(This article belongs to the Special Issue Cyclooxygenase(COX) Inhibitors)
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Open AccessReview The Liver as a Target Organ for Gene Therapy: State of the Art, Challenges, and Future Perspectives
Pharmaceuticals 2012, 5(12), 1372-1392; doi:10.3390/ph5121372
Received: 16 November 2012 / Revised: 5 December 2012 / Accepted: 6 December 2012 / Published: 10 December 2012
Cited by 9 | PDF Full-text (419 KB) | HTML Full-text | XML Full-text
Abstract
The liver is a target for gene therapy of inborn errors of metabolism, of hemophilia, and of acquired diseases such as liver cancer and hepatitis. The ideal gene transfer strategy should deliver the transgene DNA to parenchymal liver cells with accuracy and precision
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The liver is a target for gene therapy of inborn errors of metabolism, of hemophilia, and of acquired diseases such as liver cancer and hepatitis. The ideal gene transfer strategy should deliver the transgene DNA to parenchymal liver cells with accuracy and precision in the absence of side effects. Liver sinusoids are highly specialized capillaries with a particular endothelial lining: the endothelium contains open fenestrae, whereas a basal lamina is lacking. Fenestrae provide a direct access of gene transfer vectors to the space of Disse, in which numerous microvilli from parenchymal liver cells protrude. The small diameter of fenestrae in humans constitutes an anatomical barrier for most gene transfer vectors with the exception of adeno-associated viral (AAV) vectors. Recent studies have demonstrated the superiority of novel AAV serotypes for hepatocyte-directed gene transfer applications based on enhanced transduction, reduced prevalence of neutralizing antibodies, and diminished capsid immune responses. In a landmark clinical trial, hemophilia B was successfully treated with an AAV8 human factor IX expressing vector. Notwithstanding significant progress, clinical experience with these technologies remains very limited and many unanswered questions warrant further study. Therefore, the field should continue to progress as it has over the past decade, cautiously and diligently. Full article
(This article belongs to the Special Issue Gene Therapy)

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