Development of Probes for Bile Acid Transporters and Synthetic Approaches to the Core of Massadine
thesisposted on 01.02.2019, 00:00 authored by Hyunjin Lee
My graduate work comprises two components: 1) The development of novel probes to study the activities of bile acid (BA) by exploiting a self-cleavable disulfide linker. 2) The synthetic studies toward the racemic and enantioselective versions of a carbocycle core of massadine wherein the application of a formal [3+2] cycloaddition of α,β-unsaturated esters and lithium(trimethylsilyl)diazomethane (LTMSD) is used as a key strategy. The first part involves the design and development of a bile acid (BA) transporter probe for investigating BA transporter activity in real time. BA probes (BA-SS-Luc) containing a luciferin moiety connected via a disulfide cleavable linker were found to be useful tool to measure bile acid uptake in real time in vitro. For the future study, this quantitative approach will be applied to identify compounds that modulate BA transporter activity in vivo. The second part deals with synthetic studies of a carbocycle core of massadine, which is a member of structurally complex dimeric pyrrole- imidazole alkaloids. Due to its unique structural diversity, complexity and significant biological activities, massadine, has been a highly sought- after target for total synthesis among many research groups. Our synthetic approach toward the synthesis of the core skeleton relies on the formal [3+2] cycloaddition between LTMSD and α,β-unsaturated esters followed by protonylitic N–N bond cleavage to construct α-amino-β-cyano groups with excellent stereochemical control. These functional groups would act as a synthetic handle to construct the remaining structural features of massadine.