Dr. Joseph Hajdu
(818) 677-3377

The main objective of the proposed project is to develop new synthetic methods for the preparation of phospholipid derivatives, including compounds with spectroscopically active reporter groups and their characterization as structural probes in membrane models (micelles and vesicles).  The approach will focus on developing the chemistry of the five-membered 1,3,2-dioxaphospholane ring and its substituted derivatives to elaborate phosphodiester targets and structurally related analogues.

Long term objectives:

Background and Importance:

Development of new synthetic methods for the preparation of structurally well-defined phospholipid compounds has become a timely and important problem since it was discovered that in addition to their role as a major component in all biological membranes, phospholipids are also involved in a wide range of physiological and regulatory processes.  phospholipids are essential for the functioning of a number of membrane-bound enzymes such as protein kinase C, and play an important role in signal transduction as substrates for the production of second messengers (inositol-1,4,5-trisphosphate, diacylglycerol)l and in the release arachidonic acid.  Significantly, some other most potent phospholipid compounds, which are active below the micromolar and nanomolar levels occur in low concentrations in the cell, such that preparation of synthetic derivatives represents a clear prerequisite to elucidation of their biochemical mechanism of action.

Summary of Experimental Methods:

The synthetic application will focus on preparation of
1) diacylglycerophospholipid spectroscopic probes with paramagnetic and fluorescence energy transfer donor-acceptor reported groups,
2) transition-state analogue inhibitors of phospholipase A2 enzymes, and
3) boranophospholipids with a BH3 group replacing one of the non-bridging phosphate-oxygens in the phosphodiester function.
Electron spin resonance studies using a newly developed "indicator broadener method"  will be conducted in the principal co-investigator's laboratory to determine the structural organization and dynamics of fatty acyl side chains of single- and double-labeled phospholipids.  Collaborative arrangements have been made to evaluate the synthetic compounds as phospholipase A2 substrates and inhibitors.  in addition, their thermotropic behavior and role in promoting vs inhibiting cholesterol exchange between vesicles will also be determined.

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