Multi-inhibitor prodrug constructs for simultaneous delivery of anti-inflammatory agents to mustard-induced skin injury.

Published on Aug 1, 2016in Annals of the New York Academy of Sciences4.728
· DOI :10.1111/NYAS.13177
Carl Jeffrey Lacey4
Estimated H-index: 4
(Lehigh University),
Irene M. Wohlman3
Estimated H-index: 3
(RU: Rutgers University)
+ 8 AuthorsNed D. Heindel20
Estimated H-index: 20
(Lehigh University)
Sources
Abstract
The molecular pathology of sulfur mustard injury is complex, with at least nine inflammation-related enzymes and receptors upregulated in the zone of the insult. A new approach wherein inhibitors of these targets have been linked by hydrolyzable bonds, either one to one or via separate preattachment to a carrier molecule, has been shown to significantly enhance the therapeutic response compared with the individual agents. This article reviews the published work of the authors in this drug development domain over the last 8 years.
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The design of multitarget-directed ligands is a promising strategy for discovering innovative drugs. Here, we report a mechanistic study that clarifies key aspects of the dual inhibition of the fatty acid amide hydrolase (FAAH) and the cyclooxygenase (COX) enzymes by a new multitarget-directed ligand named ARN2508 (2-[3-fluoro-4-[3-(hexylcarbamoyloxy)phenyl]phenyl]propanoic acid). This potent dual inhibitor combines, in a single scaffold, the pharmacophoric elements often needed to block FAAH an...
23 CitationsSource
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14 CitationsSource
#1Marco Migliore (IIT: Istituto Italiano di Tecnologia)H-Index: 8
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20 CitationsSource
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Abstract Novel ethynylphenyl carbonates and carbamates containing carbon- and silicon-based choline mimics were synthesized from their respective phenol and aniline precursors and screened for anticholinesterase and anti-inflammatory activities. All molecules were micromolar inhibitors of acetylcholinesterase (AChE), with IC50s of 28–86 μM; the carbamates were two-fold more potent than the carbonates. Two of the most potent AChE inhibitors suppressed 12-O-tetradecanoylphorbol-13-acetate (TPA)-in...
4 CitationsSource
#1Sandra Gouveia-Figueira (Umeå University)H-Index: 13
#2Jessica Karlsson (Umeå University)H-Index: 5
Last. Christopher J. Fowler (Umeå University)H-Index: 69
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Background Increased endocannabinoid tonus by dual-action fatty acid amide hydrolase (FAAH) and substrate selective cyclooxygenase (COX-2) inhibitors is a promising approach for pain-relief. One su ...
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#1Natalia Malek (Sapienza University of Rome)H-Index: 11
#2Monika MrugalaH-Index: 1
Last. Katarzyna StarowiczH-Index: 30
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The pharmacological inhibition of anandamide (AEA) hydrolysis by fatty acid amide hydrolase (FAAH) attenuates pain in animal models of osteoarthritis (OA) but has failed in clinical trials. This may have occurred because AEA also activates transient receptor potential vanilloid type 1 (TRPV1), which contributes to pain development. Therefore, we investigated the effectiveness of the dual FAAH–TRPV1 blocker OMDM-198 in an MIA-model of osteoarthritic pain. We first investigated the MIA-induced mod...
44 CitationsSource
#1Anju Lulla (St. John's University)H-Index: 2
#2Sandra E. Reznik (St. John's University)H-Index: 17
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Previous studies in this and other laboratories have demonstrated that ebselen (EB-1), an organoselenium compound, spares cells from mechlorethamine (HN2) toxicity in vitro. In the present study, the hypothesis that EB-1 will reduce dermal toxicity of HN2 in vivo is put forward and found to have merit. Using the mouse ear vesicant model (MEVM), HN2, applied topically, showed a dose-dependent effect upon ear swelling and thickness 24 h after treatment; whereas tissue injury consistent with vesica...
4 CitationsSource
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Sulfur mustard (bis(2-chloroethyl) sulfide, SM) is a highly reactive bifunctional alkylating agent inducing edema, inflammation, and the formation of fluid-filled blisters in the skin. Medical countermeasures against SM-induced cutaneous injury have yet to be established. In the present studies, we tested a novel, bifunctional anti-inflammatory prodrug (NDH 4338) designed to target cyclooxygenase 2 (COX2), an enzyme that generates inflammatory eicosanoids, and acetylcholinesterase, an enzyme med...
18 CitationsSource
#1John S. Graham (DA: United States Department of the Army)H-Index: 18
#2Bruce A. Schoneboom (DA: United States Department of the Army)H-Index: 3
Abstract Sulfur mustard (2,2′-dichlorodiethyl sulfide; SM) is a potent vesicating chemical warfare agent that poses a continuing threat to both military and civilian populations. Significant SM injuries can take several months to heal, necessitate lengthy hospitalizations, and result in long-term complications affecting the skin, eyes, and lungs. This report summarizes initial and ongoing (chronic) clinical findings from SM casualties from the Iran–Iraq War (1980–1988), with an emphasis on cutan...
60 CitationsSource
The serine hydrolase, fatty acid amide hydrolase (FAAH), is responsible for the intracellular degradation of anandamide and other bioactive fatty acid ethanolamides involved in the regulation of pain, inflammation, and other pathophysiological processes. The catalytic site of FAAH is composed of multiple cavities with mixed hydrophobic and hydrophilic properties, the role of which remains incompletely understood. Anandamide is thought to enter the active site through a “membrane-access” (MA) cha...
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#2Ying He (Third Military Medical University)
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Nitrogen mustard (NM) causes severe skin injury with an obvious inflammatory response, which is lack of effective and targeted therapies. Vitamin D3 (VD3) has excellent anti-inflammatory properties and is considered as a potential candidate for the treatment of NM-induced dermal toxicity; however, the underlying mechanisms are currently unclear. Cyclooxygenase-2 (COX2; a widely used marker of skin inflammation) plays a key role in NM-induced cutaneous inflammation. Herein, we initially confirmed...
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#1Christophe Guillon (Lehigh University)H-Index: 8
#2Anna M. Vetrano (RU: Rutgers University)H-Index: 15
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Abstract A set of 4-(R2-imino)-3-mercapto-5-(R1)-4H-1,2,4-triazoles derivatives were synthesized, characterized and evaluated for their ability to inhibit nitric oxide (NO) production in PAM212 mouse keratinocytes, which led to the discovery and the subsequent evaluation of their growth inhibitory cytotoxic potency toward that same mouse cell line together with a number of human cells lines (PC3, HT-29 and HeLa). Some limited SAR could be established for both NO production inhibition potency and...
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#2Gabriella M. Composto (RU: Rutgers University)H-Index: 5
Last. Diane E. Heck (NYMC: New York Medical College)H-Index: 4
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Abstract Sulfur mustard (SM, bis(2-chloroethyl sulfide) is a potent vesicating agent known to cause skin inflammation, necrosis and blistering. Evidence suggests that inflammatory cells and mediators that they generate are important in the pathogenic responses to SM. In the present studies we investigated the role of mast cells in SM-induced skin injury using a murine vapor cup exposure model. Mast cells, identified by toluidine blue staining, were localized in the dermis, adjacent to dermal app...
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