Please use this identifier to cite or link to this item: http://scholarbank.nus.edu.sg/handle/10635/22107
Title: Design, synthesis and biological studies of coumarin-based probes and tetrahydrolipstatin analogs
Authors: NGAI MUN HONG
Keywords: coumarin fluorophore, tetrahydrolipstatin, beta-lactone, tandem Mukaiyama aldol-lactonization, click chemistry, fatty acid synthases
Issue Date: 19-Jul-2010
Source: NGAI MUN HONG (2010-07-19). Design, synthesis and biological studies of coumarin-based probes and tetrahydrolipstatin analogs. ScholarBank@NUS Repository.
Abstract: A coumarin-based fluorescent probe containing a thiol-reacting maleimide group was synthesized. A cysteine containing tetrapeptide Arg-Gly-Asp-Cys was successfully labelled with the coumarin probe. In addition, an antibody was labelled with the coumarin probe via the selenol-promoted reduction of the native disulfide bond. Besides that, one-pot synthesis of maleimido-carboxylic N-hydroxysuccinimide (NHS) esters were accomplished by cyclized maleamic acids with NHS and DCC. Tetrahydrolipstatin (THL) is an FDA-approved anti-obesity drug that selectively inhibits gastrointestinal lipases and fatty acid synthases (FAS). My study focuses on the synthesis of alkyne-modified THL analogs for identification of new cellular targets. Terminal alkyne group was introduced at the left or right side chains, and also at the amino ester group of THL. The beta-lactone moiety of THL analogs was synthesized by ZnCl2-mediated tandem Mukaiyama aldol-lactonization (TMAL). The gamma-hydroxy group was introduced via Keck allylation or resolution of the homoallylic alcohol as its (R)-O-acetylmendelic ester. Three THL probes, THL-L, THL-R and THL-T were tested for potential biological activities. All three compounds showed antiproliferation activity against HepG2 cells. Besides the known FAS, eight new proteins (GAPDH, ?-tubulin, Hsp90AB1, ANXA2, RPL7a, RPL14, RPS9 and an unnamed protein) were identified through activity-based proteome profiling approach. Another approach for the synthesis of THL analogs was developed by introducing diversity by click chemistry. The key beta-lactone was reacted with eighteen aliphatic and aromatic azides with different electronic properties under click reaction conditions to give THL dialkyne analogs after desilylation. Four analogs were identified to possess similar anti-proliferative activity against HepG2 cells as compared to THL.
URI: http://scholarbank.nus.edu.sg/handle/10635/22107
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