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Pharmaceuticals, Volume 7, Issue 2 (February 2014), Pages 113-219

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Research

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Open AccessArticle The Dipeptide Monoester Prodrugs of Floxuridine and Gemcitabine—Feasibility of Orally Administrable Nucleoside Analogs
Pharmaceuticals 2014, 7(2), 169-191; doi:10.3390/ph7020169
Received: 26 November 2013 / Revised: 15 January 2014 / Accepted: 22 January 2014 / Published: 27 January 2014
Cited by 5 | PDF Full-text (514 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Dipeptide monoester prodrugs of floxuridine and gemcitabine were synthesized. Their chemical stability in buffers, enzymatic stability in cell homogenates, permeability in mouse intestinal membrane along with drug concentration in mouse plasma, and anti-proliferative activity in cancer cells were determined and compared to their
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Dipeptide monoester prodrugs of floxuridine and gemcitabine were synthesized. Their chemical stability in buffers, enzymatic stability in cell homogenates, permeability in mouse intestinal membrane along with drug concentration in mouse plasma, and anti-proliferative activity in cancer cells were determined and compared to their parent drugs. Floxuridine prodrug was more enzymatically stable than floxuridine and the degradation from prodrug to parent drug works as the rate-limiting step. On the other hand, gemcitabine prodrug was less enzymatically stable than gemcitabine. Those dipeptide monoester prodrugs exhibited 2.4- to 48.7-fold higher uptake than their parent drugs in Caco-2, Panc-1, and AsPC-1 cells. Floxuridine and gemcitabine prodrugs showed superior permeability in mouse jejunum to their parent drugs and exhibited the higher drug concentration in plasma after in situ mouse perfusion. Cell proliferation assays in ductal pancreatic cancer cells, AsPC-1 and Panc-1, indicated that dipeptide prodrugs of floxuridine and gemcitabine were more potent than their parent drugs. The enhanced potency of nucleoside analogs was attributed to their improved membrane permeability. The prodrug forms of 5¢-L-phenylalanyl-l-tyrosyl-floxuridine and 5¢-L-phenylalanyl-L-tyrosyl-gemcitabine appeared in mouse plasma after the permeation of intestinal membrane and the first-pass effect, suggesting their potential for the development of oral dosage form for anti-cancer agents. Full article
(This article belongs to the collection Prodrugs: from Design to Clinic)
Open AccessArticle Mitochondrial FAD-linked Glycerol-3-phosphate Dehydrogenase: A Target for Cancer Therapeutics
Pharmaceuticals 2014, 7(2), 192-206; doi:10.3390/ph7020192
Received: 10 January 2014 / Revised: 29 January 2014 / Accepted: 6 February 2014 / Published: 11 February 2014
Cited by 3 | PDF Full-text (421 KB) | HTML Full-text | XML Full-text
Abstract
Imbalances in cellular redox state are frequently observed in cancer cells, and contribute significantly to cancer progression and apoptotic resistance. Hydrogen peroxide (H2O2) is one reactive oxygen species (ROS) that is produced in excess within cancer cells. In this
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Imbalances in cellular redox state are frequently observed in cancer cells, and contribute significantly to cancer progression and apoptotic resistance. Hydrogen peroxide (H2O2) is one reactive oxygen species (ROS) that is produced in excess within cancer cells. In this study, we investigated the mitochondrial glycerol-3-phosphate-dependent (GPD2) ROS production in PC-3 cells and demonstrated the importance of excessive H2O2 production on their survival. By exploiting the abnormal H2O2 production of PC-3 cells, we initiated a high-throughput screening of the Canadian Compound Collection, composed of 29,586 small molecules, targeting the glycerophosphate-dependent H2O2 formation in PC-3 cells. Eighteen compounds were identified to have significant inhibitory activity. These compounds have not been previously characterized as inhibitors of the enzyme. Six of these compounds were further analyzed in PC-3 cells and dose response studies displayed an inhibitory and anti-oxidative potency that ranged from 1 µM to 30 µM. The results presented here demonstrate that inhibitors of mitochondrial GPD2 activity elicit anti-proliferative effects on cancer cells. Full article
(This article belongs to the Special Issue Mitochondrial Target-Based Drug Discovery)
Open AccessArticle Design of Prodrugs to Enhance Colonic Absorption by Increasing Lipophilicity and Blocking Ionization
Pharmaceuticals 2014, 7(2), 207-219; doi:10.3390/ph7020207
Received: 20 January 2014 / Revised: 8 February 2014 / Accepted: 12 February 2014 / Published: 24 February 2014
Cited by 5 | PDF Full-text (128 KB) | HTML Full-text | XML Full-text
Abstract
Prodrugs are chemistry-enabled drug delivery modifications of active molecules designed to enhance their pharmacokinetic, pharmacodynamic and/or biopharmaceutical properties. Ideally, prodrugs are efficiently converted in vivo, through chemical or enzymatic transformations, to the active parent molecule. The goal of this work is to
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Prodrugs are chemistry-enabled drug delivery modifications of active molecules designed to enhance their pharmacokinetic, pharmacodynamic and/or biopharmaceutical properties. Ideally, prodrugs are efficiently converted in vivo, through chemical or enzymatic transformations, to the active parent molecule. The goal of this work is to enhance the colonic absorption of a drug molecule with a short half-life via a prodrug approach to deliver sustained plasma exposure and enable once daily (QD) dosing. The compound has poor absorption in the colon and by the addition of a promoiety to block the ionization of the molecule as well as increase lipophilicity, the relative colonic absorption increased from 9% to 40% in the retrograde dog colonic model. A combination of acceptable solubility and stability in the gastrointestinal tract (GI) as well as permeability was used to select suitable prodrugs to optimize colonic absorption. Full article
(This article belongs to the collection Prodrugs: from Design to Clinic)

Review

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Open AccessReview From Single Target to Multitarget/Network Therapeutics in Alzheimer’s Therapy
Pharmaceuticals 2014, 7(2), 113-135; doi:10.3390/ph7020113
Received: 16 December 2013 / Revised: 13 January 2014 / Accepted: 17 January 2014 / Published: 23 January 2014
Cited by 29 | PDF Full-text (389 KB) | HTML Full-text | XML Full-text
Abstract
Brain network dysfunction in Alzheimer’s disease (AD) involves many proteins (enzymes), processes and pathways, which overlap and influence one another in AD pathogenesis. This complexity challenges the dominant paradigm in drug discovery or a single-target drug for a single mechanism. Although this paradigm
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Brain network dysfunction in Alzheimer’s disease (AD) involves many proteins (enzymes), processes and pathways, which overlap and influence one another in AD pathogenesis. This complexity challenges the dominant paradigm in drug discovery or a single-target drug for a single mechanism. Although this paradigm has achieved considerable success in some particular diseases, it has failed to provide effective approaches to AD therapy. Network medicines may offer alternative hope for effective treatment of AD and other complex diseases. In contrast to the single-target drug approach, network medicines employ a holistic approach to restore network dysfunction by simultaneously targeting key components in disease networks. In this paper, we explore several drugs either in the clinic or under development for AD therapy in term of their design strategies, diverse mechanisms of action and disease-modifying potential. These drugs act as multi-target ligands and may serve as leads for further development as network medicines. Full article
(This article belongs to the Special Issue CNS-Drugs and Therapy)
Open AccessReview Mercury-Supported Biomimetic Membranes for the Investigation of Antimicrobial Peptides
Pharmaceuticals 2014, 7(2), 136-168; doi:10.3390/ph7020136
Received: 16 December 2013 / Accepted: 17 January 2014 / Published: 23 January 2014
Cited by 7 | PDF Full-text (1206 KB) | HTML Full-text | XML Full-text
Abstract
Tethered bilayer lipid membranes (tBLMs) consist of a lipid bilayer interposed between an aqueous solution and a hydrophilic “spacer” anchored to a gold or mercury electrode. There is great potential for application of these biomimetic membranes for the elucidation of structure-function relationships of
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Tethered bilayer lipid membranes (tBLMs) consist of a lipid bilayer interposed between an aqueous solution and a hydrophilic “spacer” anchored to a gold or mercury electrode. There is great potential for application of these biomimetic membranes for the elucidation of structure-function relationships of membrane peptides and proteins. A drawback in the use of mercury-supported tBLMs with respect to gold-supported ones is represented by the difficulty in applying surface sensitive, spectroscopic and scanning probe microscopic techniques to gather information on the architecture of these biomimetic membranes. Nonetheless, mercury-supported tBLMs are definitely superior to gold-supported biomimetic membranes for the investigation of the function of membrane peptides and proteins, thanks to a fluidity and lipid lateral mobility comparable with those of bilayer lipid membranes interposed between two aqueous phases (BLMs), but with a much higher robustness and resistance to electric fields. The different features of mercury-supported tBLMs reconstituted with functionally active membrane proteins and peptides of bacteriological or pharmacological interest may be disclosed by a judicious choice of the most appropriate electrochemical techniques. We will describe the way in which electrochemical impedance spectroscopy, potential-step chronocoulometry, cyclic voltammetry and phase-sensitive AC voltammetry are conveniently employed to investigate the structure of mercury-supported tBLMs and the mode of interaction of antimicrobial peptides reconstituted into them. Full article

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