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Pharmaceuticals, Volume 7, Issue 2 (February 2014) – 5 articles , Pages 113-219

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128 KiB

Open AccessArticle

Design of Prodrugs to Enhance Colonic Absorption by Increasing Lipophilicity and Blocking Ionization

by Rebecca Nofsinger, Sophie-Dorothee Clas, Rosa I. Sanchez, Abbas Walji, Kimberly Manser, Becky Nissley, Jaume Balsells, Amrithraj Nair, Qun Dang, David Jonathan Bennett, Michael Hafey, Junying Wang, John Higgins, Allen Templeton, Paul Coleman, Jay Grobler, Ronald Smith and Yunhui Wu

Pharmaceuticals 2014, 7(2), 207-219; https://doi.org/10.3390/ph7020207 - 24 Feb 2014

Cited by 15 | Viewed by 10606

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 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 Special Issue Prodrugs: from Design to Clinic)

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421 KiB

Open AccessArticle

Mitochondrial FAD-linked Glycerol-3-phosphate Dehydrogenase: A Target for Cancer Therapeutics

by Gurmit Singh

Pharmaceuticals 2014, 7(2), 192-206; https://doi.org/10.3390/ph7020192 - 11 Feb 2014

Cited by 28 | Viewed by 8062

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 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)

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514 KiB

Open AccessArticle

The Dipeptide Monoester Prodrugs of Floxuridine and Gemcitabine—Feasibility of Orally Administrable Nucleoside Analogs

by Yasuhiro Tsume, Blanca Borras Bermejo and Gordon L. Amidon

Pharmaceuticals 2014, 7(2), 169-191; https://doi.org/10.3390/ph7020169 - 27 Jan 2014

Cited by 11 | Viewed by 8601

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 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 Special Issue Prodrugs: from Design to Clinic)

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1206 KiB

Open AccessReview

Mercury-Supported Biomimetic Membranes for the Investigation of Antimicrobial Peptides

by Lucia Becucci and Rolando Guidelli

Pharmaceuticals 2014, 7(2), 136-168; https://doi.org/10.3390/ph7020136 - 23 Jan 2014

Cited by 22 | Viewed by 6656

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 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

(This article belongs to the Special Issue Identification and Characterization of Antimicrobial Peptides with Therapeutic Potential)

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389 KiB

Open AccessReview

From Single Target to Multitarget/Network Therapeutics in Alzheimer’s Therapy

by Hailin Zheng, Mati Fridkin and Moussa Youdim

Pharmaceuticals 2014, 7(2), 113-135; https://doi.org/10.3390/ph7020113 - 23 Jan 2014

Cited by 102 | Viewed by 13657

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 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)

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