Synthesis of fluorescent styryl dye library and its applications in bioimaging.

摘要

This thesis describes the synthesis of fluorescent styryl dye libraries and their applications in bioimaging. Chapter 1 focuses on developing a new family of RNA-selective, live cell imaging probes for studying nuclear structure and functions. A combinatorial library of fluorescent styryl molecules was synthesized and screened for in vitro RNA response and live cell nuclear imaging. Three RNA-selective dyes (E36, E144 and F22) were identified with better imaging properties relative to commercially available dye as well as being cell-permeant, photostable, well-tolerated and good counterstain compatibility with DNA marker (Hoechst and DAPI) by the living cells.; Chapter 2 describes two generations of styryl based compounds being developed as potential in vivo imaging agents for beta-amyloid plaques of Alzheimer's disease (AD). Surpassed the disadvantages of solution phase chemistry, a fluorescent styryl dye library was developed using solid phase synthetic method. 13 compounds were found showing good binding affinity to beta-amyloid fibrils in solution and two of them, 2C40 and 2E10, have demonstrated unique staining both in their color and localization to beta-amyloid plaques of an AD model mouse brain section in vitro. To further study this line of compounds, a second generation of styryl-based neutral compounds were prepared. Among 56 candidates, 14 compounds were found showing good beta-amyloid plaques staining on AD human brain sections in vitro. Their binding affinity to beta-amyloid fibril was then determined by a fluorescence intensity change measurement. Interestingly, a class of quinaldine/biphenyl styryl scaffold compounds has shown a distinguished binding to beta-amyloid fibrils. A representative compound STB-8 was then applied to ex vivo and in vivo imaging experiments in AD transgenic mouse model, demonstrating a successful penetration through brain blood barrier (BBB) and specific staining of the beta-amyloid plaque.; Ceramide has been found related to a number of important functions that regulate cellular homeostasis. Chapter 3 briefly describes a ceramide library preparation using facile synthetic pathway: the active ester chemistry on solid phase.