| 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. |
