DESIGN AND SYNTHESIS OF BIO-SIGNALING LIPIDS AND THEIR BIOACTIVE PROBES

Abstract

Lipids molecules often share highly similar structural frameworks among species, however minor variation in their chemical composition influence their interactions with proteins interactors. Many of these interactions are stereospecific and regioselective, meaning that only certain specific arrangements of atom allow proper biological recognition. As such the design of accurate and functional lipid probes demands precision to ensure that they mimic natural lipids, can provide meaningful insights into their interactions and functions in biological system. One of the main obstacles in this field is the lack of established synthetic methods for many of these complex lipid structures, because of significant synthetic challenges, control of stereo and regio selectivity and with lipid stability. A growing body of literature underscores the critical role of these lipid classes play in modulating key biological processes, particularly in context of metabolic, inflammation and neurological disorders. The expanding interest in these lipid classes within the literature highlights a need for reliable synthetic access, which our work addressees. The work demonstrates synthetic framework on biorthogonal bifunctional probes for monoacylglycerol (MAG) and Lysophosphatidylserine (LPS) lipids coupled with metabolic and cellular systems for in depth functional studies, by introduction of photoreactive group and biorthogonal handle without compromising the integrity of lipid molecular structure. This approach opens the doors for exploration of specific receptors where these lipids are interacting, hence lays the foundation for systematic investigation into lipid mediated signaling. Another part of this work introduces a synthetic pathway for a representative class of bioactive lipid Lysophosphatidylglycerol (LPG). A major challenge in studying is limited access of LPG, specially their stereoselective versions, as no synthetic route has yet been reported and hence relying on biological isolation. The combination of amphiphilicity along with stereo and regio specific structures make synthesis and purification complex. We report a facile and practical approach for LPG synthesis, built upon careful consideration of masking and demasking strategy to attain regio and stereo selectivity as well as suited for unsaturated fatty acid derivatives. The synthetic strategy also lays the groundwork for future efforts in synthesizing advanced LPG probes for precisely studying their role in complex biological systems.