Chemical synthesis and biological evaluation of novel lysophospholipid analoguesg

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Publication Type thesis
School or College College of Pharmacy
Department Medicinal Chemistry
Author Jiang, Guowei
Title Chemical synthesis and biological evaluation of novel lysophospholipid analoguesg
Date 2006-12
Description Phospholipids, including lysobisphosphatidic acid (LBPA) and lysophosphatidic acid (LPA), have been shown to mediate a variety of biological effect and are involved in various pathophysiological process, such as Niemann-Pick type C (NPC) disease, cancer, cardiovascular disease, and wound healing. Development of new metabolically-stabilized LBPA and LPA analogues will help determine the relationships between these lysophospholipids and their role in normal physiology and disease state. In Chapter 2, a versatile, efficient and practical method for the preparation of enantiomerically-pure lysobisphosphatidic acid (LBPA), bisether analogues and phosphorothioate analogues of LBPA is described. The ether analogue of (S,S)-lysobisphosphatidic acid (LBPA) and its enantiomer were synthesized from a single enantiomer (S)-solketal by simply changing the sequence of deprotection steps. In Chapters 3 and 4, a series of novel a-substituted methylene phosphonate analogues and phosphonothioate analogues of LPA were synthesized. Each a-substituted methylene phosphonate analogue contains a hydrolysis-resistant phosphonate mimic of the labile monophosphate of natural LPA. The pharmacological properties of these phosphono-LPA analogues were characterized in terms of LPA receptor subtype-specific agonist and antagonist activity. Most importantly, the a-bromomethylene and a-chloromethylene phosphonates showed pan-LPA receptor subtype antagonist activity. The a-bromomethylene phosphonates are the first reported antagonists for the LPA4 GPCR. Each of the a-substituted methylene phosphonates inhibited lysoPLD, with the Linsubstituted methylene phosphonate showing the most potent inhibition.
Type Text
Publisher University of Utah
Subject Synthesis; Lysophosphatidic Acid receptors
Subject MESH Lysophospholipids; Phospholipids
Dissertation Institution University of Utah
Dissertation Name MS
Language eng
Relation is Version of Digital reproduction of "Chemical synthesis and biological evaluation of novel lysophospholipid analoguesg". Spencer S. Eccles Health Sciences Library. Print version of "Chemical synthesis and biological evaluation of novel lysophospholipid analoguesg.". available at J. Willard Marriott Library Special Collection. QP6.5 2006 .L53.
Rights Management © Guowei Jian
Format Medium application/pdf
Format Extent 2,011,928 bytes
Identifier undthes,4581
Source Original: University of Utah Spencer S. Eccles Health Sciences Library (no longer available).
Master File Extent 2,011,961 bytes
ARK ark:/87278/s68w3g4p
Setname ir_etd
ID 191340
Reference URL https://collections.lib.utah.edu/ark:/87278/s68w3g4p