Date of Award

Spring 1-1-2014

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry & Biochemistry

First Advisor

Xiang Wang

Second Advisor

Tarek Sammakia

Third Advisor

Maciej A. Walczak

Fourth Advisor

Zhongping Tan

Fifth Advisor

Erin A. Tripp

Abstract

My research contains two divisions:

The first one is to develop novel synthetic methods for polycyclic indole alkaloids, such as strictamine. As one of the constituents of Rhazya alkaloids, strictamine was first isolated from the flower of Alstonis scholaris, which has been used as folk medicine in India, by H. K. Schnoes, etc in 1966, while the absolute structure was resolved with the aid of X-ray crystallography in 1977. The densely fused pentacyclic skeleton of the indole alkaloid has attracted considerable interest and posed great challenge to organic chemists. Since its isolation, several groups have reported their synthetic studies, but no total synthesis is completed. In 2013 we succeeded in constructing the bridged skeleton under the catalysis of gold complex and further studies of strictamine is in progress.

The second one is focused on the development of chemical probes for jumonji C domain-containing histone demethylases (JHDMs). As one of the most important epigenetic modifications, histone methylation is closely associated with heritable changes without altering DNA sequence. Based on the enzymatic mechanisms, histone demethylases can be categorized into two classes: flavin adenine dinucleotide (FAD)-dependent monoamine oxidases (LSD1 and 2) and JHDMs. Compared to LSDs, JHDMs have a much broader substrate scope and can modify lysine residues at all methylation states. In 2011, our group reported the discovery of methylstat as the first cell-active selective small-molecule inhibitor of JHDMs. Based on the structure of methylstat, we designed and synthesized a series of fluorescent probes for quantitative analysis of JHDMs in fluorescence polarization (FP) assays. Also, a library of over 100 compounds was prepared. Their binding affinities to JHDM1A were evaluated in FP assays and structure-activity relationship (SAR) was further studies.

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Chemistry Commons

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