The synthesis of phosphonate analogues of phosphatidic acid and related compounds.
Item
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Title
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The synthesis of phosphonate analogues of phosphatidic acid and related compounds.
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Identifier
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AAI8914802
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identifier
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8914802
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Creator
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Waters Schwartz, Patricia Marnette.
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Contributor
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Adviser: Robert Engel
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Date
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1988
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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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Chemistry, Biochemistry | Chemistry, Organic
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Abstract
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The main focus of this thesis was the development of phosphonate analogues to be used as probes of metabolic activity and as chemotherapeutic agents. Phosphonates are compounds in which a methylene group has been substituted for the esteratic oxygen in a phosphate ester. The carbon-phosphorus bond of a phosphonate is not hydrolyzed by the enzymes normally involved in cleavage of phosphate esters.;Studies with the phosphonate analogue of glycerol-3-phosphate, 3,4-dihydroxybutylphosphonate, showed profound perturbations of phospholipid metabolism in bacterial cells. In view of these and other studies with phosphonate analogues, the synthesis of phosphonolipids isosteric to phosphatidic acid and phosphatidyl choline were attempted.;For greater solubility in aqueous systems, analogues bearing ten carbon or caproyl functional groups were synthesized. This was in addition to analogues with the naturally prevalent sixteen carbon or palmitoyl groups.;The synthesis of the following phosphonates was attempted and accomplished: 3,4-dicaproylbutyl-1-phosphonic acid, 3,4-dipalmitoylbut-1-enylphosphonate, and 3,4-dicaproylbut-1-enyl-1-phosphonate.;In studies of enzyme reactions, the loss of the electron pair of the oxygen may have a significant effect on binding of a potential substrate to the catalyst. The preparation of phosphonates containing a hydroxymethylene group or an epoxy function provide an electron rich site adjacent to the phosphorous. They also increase solubility of the analogue with respect to the natural substrate.;3,4-Dipalmitoyloxy-1-hydroxybutyl-1-phosphonate and 3,4-dicaproyloxy-1-hydroxybutyl-1-phosphonate were successfully prepared by hydroboration of the corresponding diisopropyl protected vinylphosphonate and subsequent deprotection. Several approaches for the synthesis of the 3,4-dipalmitoyloxy-1,2-epoxybutylphosphonate were undertaken without complete success.;Three phosphonate analogues of phosphatidylcholine were synthesized: 3,4-dicaproylbutyl-1-phosphonylcholine, 3,4-O-isopropylidene-3,4-dihydroxybutyl-1-phosphonylcholine and 3,4-dipalmitoyloxybut-1-enyl-1-phosphonylcholine.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
