Synthesis of analogs of sphingophospholipids, glycolipids, and plasmalogen
Item
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Title
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Synthesis of analogs of sphingophospholipids, glycolipids, and plasmalogen
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Identifier
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d_2009_2013:6f23fbfc9c3c:10321
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identifier
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10201
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Creator
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Lankalapalli, Ravi Shankar,
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Contributor
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Robert Bittman
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Date
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2009
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Language
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English
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Publisher
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City University of New York.
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Subject
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Organic chemistry
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Abstract
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This dissertation presents the asymmetric syntheses of naturally occurring sphingoid bases and novel sphingolipid analogs, including (a) an unnatural sphingomyelin with a Delta4-cis double bond in the long-chain base (cis-SM), (b) L-threo-beta-glucosyl and galactosyl-ceramides, (c) a photoactivatable analog of beta-galactosyl sphingosine (psychosine), and (d) caged sphingosine 1-phosphate and ceramide 1-phosphate analogs. Also included in this dissertation is a novel synthesis of an unnatural analog of the glycerophospholipid plasmalogen with a trans- O-vinyl ether linkage at the sn-1 position of the glycerol backbone.;Chapter 1 presents the first synthesis of (2S,3 R,4Z)-N-palmitoylsphingomyelin (cis-SM). The Cu2+-mediated oxidation of 1-palmitoyl-2-linoleoylphosphatidylcholine in liposomes was inhibited more effectively by cis-SM than by the natural trans-SM.;Chapter 2 presents a short synthesis of the (E)- O-vinyl analog of plasmalogen (1-O-(1'-( E)-octadecenyl)-2-O-oleoyl-sn-glycero-3-phosphocholine). To elucidate the role of the double bond in natural plasmalogen in protecting lipids from oxidative damage we synthesized this unnatural analog, which possesses a trans-vinyl ether linkage. The key step of this synthesis is the iridium-catalyzed isomerization of an allylic ether to a trans-vinyl ether.;Chapter 3 presents the synthesis of L-threo-beta-glucosyl- and galactosyl-ceramides with various N-acyl chains and also a sulfatide analog of beta-galactosylceramide. These analogs may be promising as new anti-inflammatory glycolipids to treat liver diseases and also may serve as agents for blocking raft formation in living cells. A Koenigs-Knorr reaction and the Schmidt trichloroacetimidate method were used for the glycosylation reactions.;Chapter 4 presents the synthesis of the first photoactivatable analog of psychosine. This probe, which contains a benzophenone linked to the long-chain base, may be a useful tool in the identification of receptors of psychosine. A cross-metathesis and a microwave-assisted SN2 reaction are the key steps of this synthesis.;Chapter 5 presents the first synthesis of coumarin- and a novel 3-bromo-4-hydroxynitrophenyl benzyl-caged sphingosine and ceramide phosphoesters. These caged compounds may have the facility to enter the cytosol of cultured cells and, upon irradiation with long wavelength ultraviolet light, could evoke an intracellular response which will be helpful in finding the intracellular receptors for sphingosine 1-phosphate and ceramide 1-phosphate. Phosphoramidite chemistry was applied for coupling the cages to a protected sphingosine analog. A one-pot removal of the protective groups afforded the final product in this synthesis.
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Type
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dissertation
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Source
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2009_2013.csv
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degree
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Ph.D.
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Program
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Chemistry
